Instructions for Paxil film-coated tablets 20 mg No. 28
Composition
active ingredient: paroxetine,
1 tablet contains paroxetine (as hydrochloride hemihydrate) 20 mg;
excipients: calcium phosphate dibasic (dihydrate), sodium starch glycolate (type A), magnesium stearate, Opadry White YS-1R-7003 (hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80).
Dosage form
Film-coated tablets.
Main physicochemical properties: white, film-coated, oval biconvex tablets marked "20" on one side and a score line on the other.
Pharmacotherapeutic group
Antidepressants. ATX code N06A B05.
Pharmacological properties
Pharmacodynamics
Paxil is a potent selective 5-hydroxytryptamine (5-HT, serotonin) reuptake inhibitor. Its antidepressant action and efficacy in the treatment of obsessive-compulsive and panic disorders are due to the specific inhibition of 5-hydroxytryptamine uptake by brain neurons. In terms of its chemical structure, Paxil differs from tricyclic, tetracyclic and other known antidepressants.
The drug has low affinity for muscarinic cholinergic receptors. Unlike tricyclic antidepressants, it has low affinity for alpha1-, alpha2- and beta-adrenergic receptors, dopamine (D2), 5-HT1-like, 5-HT2- and histamine (H1-) receptors; it does not affect psychomotor function and does not enhance the depressive effect of ethanol.
Paxil does not affect the activity of the cardiovascular system; it does not cause clinically significant changes in blood pressure, heart rate, and ECG parameters.
Paxil, unlike antidepressants that inhibit norepinephrine uptake, has a much smaller effect on the hypotensive effect of guanethidine.
Pharmacokinetics
After oral administration, it is rapidly absorbed and undergoes transformation in the liver.
The main metabolites of the active ingredient Paxil (paroxetine) are polar and conjugated oxidation and methylation products, which are rapidly excreted from the body.
Approximately 64% of an administered dose of paroxetine is excreted in the urine, with less than 2% of the dose excreted unchanged. Approximately 36% of the administered dose of paroxetine is excreted in the feces as metabolites.
Paroxetine metabolites are eliminated in two stages - first by first-pass metabolism through the liver, and then by systemic elimination of paroxetine.
The half-life is on average approximately 1 day.
Steady-state blood concentrations are achieved 7–14 days after the start of treatment, and during subsequent long-term treatment, the pharmacokinetics of the drug almost does not change.
No correlation was found between paroxetine plasma concentrations and clinical effect (efficacy and adverse reactions).
Due to the breakdown of the drug in the liver, the amount of paroxetine circulating in the blood is less than the amount absorbed from the gastrointestinal tract. With an increase in a single dose or with repeated dosing, the effect of partial saturation of the metabolic pathway of the first pass through the liver occurs and a decrease in plasma clearance is observed. This leads to a disproportionate increase in the concentration of paroxetine in the blood plasma and changes in pharmacokinetic parameters with the appearance of a nonlinear relationship. However, such nonlinearity is mostly insignificant and is observed only in patients in whom low doses achieve a low concentration of the drug in the blood plasma.
Paroxetine is widely distributed in body tissues. Calculated pharmacokinetic parameters indicate that only 1% of the administered dose remains in the blood plasma.
When used in therapeutic concentrations, approximately 95% of paroxetine binds to plasma proteins.
In elderly patients and patients with renal or hepatic insufficiency, an increase in the concentration of paroxetine in the blood plasma is observed, but it does not exceed the concentration fluctuations in healthy adults.
Indication
Adults
Major depressive disorder. Treatment of major depressive disorder.
Obsessive-compulsive disorder. Treatment of symptoms and prevention of relapses of obsessive-compulsive disorder.
Panic disorder. Treatment of symptoms and prevention of relapses of panic disorder with or without concomitant agoraphobia.
Social phobias/social anxiety disorders. Treatment of social phobias/social anxiety disorders.
Generalized anxiety disorder. Treatment of symptoms and prevention of relapse of generalized anxiety disorder.
Post-traumatic stress disorder. Treatment of post-traumatic stress disorder.
Contraindication
Paxil should not be administered concomitantly with monoamine oxidase inhibitors (MAOIs), including linezolid, an antibiotic that is a reversible non-selective inhibitor of monoamine oxidase, and methylthioninium chloride (methylene blue), and within 2 weeks of discontinuation of treatment with MAOIs. Similarly, MAOIs may be administered no earlier than 2 weeks after discontinuation of treatment with Paxil (see section "Interaction with other medicinal products and other forms of interaction").
The drug should not be used in combination with thioridazine because, like other drugs that inhibit the hepatic enzyme CYP450 2D6, Paxil may increase thioridazine levels (see section "Interaction with other medicinal products and other forms of interaction"). The use of thioridazine may cause prolongation of the QT interval with associated severe ventricular arrhythmia (e.g. torsades de pointes) and sudden death. Paxil should not be prescribed in combination with pimozide (see section "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other types of interactions
Serotonergic drugs
As with other selective serotonin reuptake inhibitors, concomitant use with serotonergic drugs may lead to a 5-HT-associated effect (serotonin syndrome).
Use of Paxil with serotonergic drugs such as L-tryptophan, triptans, tramadol, other serotonin reuptake inhibitors, lithium, fentanyl and St. John's wort Hypericum perforatum should be done with caution and with mandatory close monitoring of the patient's clinical condition. The concomitant use of paroxetine and MAO inhibitors (including linezolid, an antibiotic that is a reversible non-selective MAO inhibitor, and methylthioninium chloride (methylene blue)) is contraindicated (see section "Contraindications").
Pimozide
In a study of the co-administration of a single low dose of pimozide (2 mg) and paroxetine, an increase in pimozide levels was observed. This was explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its potential to prolong the QT interval, the concomitant use of pimozide and paroxetine is contraindicated (see section 4.3).
Enzymes involved in drug metabolism
The metabolism and pharmacokinetic parameters of paroxetine may be altered by induction or inhibition of enzymes involved in drug metabolism.
When paroxetine is used concomitantly with enzyme-inhibiting drugs, it is recommended to use the lowest effective dose. When used concomitantly with enzyme-inducing drugs (carbamazepine, rifampicin, phenobarbital, phenytoin), there is no need to change the initial dose of paroxetine. The dose should be adjusted during further treatment according to the clinical effect (tolerability and efficacy).
Muscle relaxants
Selective serotonin reuptake inhibitors may reduce plasma cholinesterase activity, leading to a prolongation of the neuromuscular blocking effect of mivacurium and suxamethonium.
Fosamprenavir/ritonavir
Co-administration of fosamprenavir/ritonavir with paroxetine significantly reduces plasma levels of paroxetine. Dosage adjustments during subsequent treatment should be based on clinical response (tolerability and efficacy).
Procyclidine
Daily use of paroxetine significantly increases serum procyclidine levels. If anticholinergic effects occur, the procyclidine dose should be reduced.
Anticonvulsants
Carbamazepine, phenytoin, sodium valproate. When used together with these drugs, no effect on the pharmacokinetics/pharmacodynamics of the drug is observed in patients with epilepsy.
The ability of paroxetine to inhibit the CYP2D6 enzyme
Paxil, like other antidepressants that are serotonin reuptake inhibitors, inhibits the activity of the cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma concentrations of concomitantly administered drugs that are metabolized by this enzyme. Such drugs include some tricyclic antidepressants (e.g., amitriptyline, nortriptyline, imipramine, and desipramine), phenothiazine neuroleptics (e.g., perphenazine and thioridazine), risperidone, atomoxetine, some type 1c antiarrhythmics (e.g., propafenone and flecainide), and metoprolol.
Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and is an important component of tamoxifen's efficacy. Irreversible inhibition of CYP2D6 by paroxetine results in decreased plasma concentrations of endoxifen (see section 4.4).
CYP3A4
In clinical studies, it was found that the absorption or pharmacokinetics of Paxil are not affected or are almost not affected (i.e. do not require a change in dosage) by the following factors: food, antacids, digoxin, propranolol, alcohol.
Paxil does not increase the impairment of mental and motor reactions caused by alcohol, however, drinking alcoholic beverages during treatment with Paxil is not recommended.
Oral anticoagulants
When oral anticoagulants are used concomitantly with paroxetine, a pharmacodynamic interaction is possible, which may lead to increased anticoagulant activity and risk of bleeding. Therefore, paroxetine should be prescribed with caution to patients treated with oral anticoagulants.
Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and antiplatelet agents.
When NSAIDs/acetylsalicylic acid are used concomitantly with paroxetine, a pharmacodynamic interaction may occur, which may lead to an increased risk of bleeding. Paroxetine should be administered with caution in conjunction with drugs that affect platelet function or increase the risk of bleeding.
Pravastatin
The interaction between paroxetine and pravastatin observed in studies suggests that concomitant use of paroxetine and pravastatin may lead to an increase in blood glucose levels. Diabetic patients receiving both paroxetine and pravastatin may require dosage adjustments of oral hypoglycemic agents and/or insulin (see section 4.4).
Application features
Children and adolescents
Antidepressant treatment is associated with an increased risk of suicidal behaviour and thoughts in children and adolescents with major depressive disorder and other psychiatric disorders. In clinical trials, adverse events related to suicidality (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and irritability) were observed more frequently in children and adolescents treated with Paxil than in the placebo group (see section 4.8). There are no data on the safety of the drug in children and adolescents with regard to growth, development, cognitive and behavioural characteristics.
Clinical deterioration and suicide risk in adults
Young adults, especially those with major depressive disorder, may be at increased risk of suicidal behavior while taking Paxil. In an analysis of placebo-controlled clinical trials in adults with psychiatric disorders, young adults (approximately 18–24 years of age) were at increased risk of suicidal behavior compared with placebo (17 of 776 (2.19%) versus 5 of 542 (0.92%)), although this difference was not statistically significant. This increased risk was not observed in older patients (25–64 years of age and 65 years of age and older). In patients with major depressive disorder (of any age) treated with Paxil, there was a statistically significant increase in the incidence of suicidal behavior compared with placebo (11 of 3455 (0.32%) compared with 1 of 1978 (0.05%), all of which were suicide attempts). However, the majority of such attempts (8 of 11) during treatment with Paxil occurred in young adults aged 18–30 years. These data on the treatment of major depressive disorder suggest that the higher risk of these complications observed in the group of young patients with psychiatric disorders may extend to patients aged 24 years and older.
Patients with depressive disorders may experience worsening of depressive symptoms and/or suicidal ideation and behavior (suicidality) whether or not they are taking antidepressants. This risk persists until significant remission occurs. It is a general clinical experience with all courses of antidepressants that the risk of suicide may increase in the early stages of recovery.
Other psychiatric disorders for which Paxil is prescribed may be associated with an increased risk of suicidal behavior, and such disorders may also be associated with major depressive disorder. In addition, patients with a history of suicidal behavior and related intentions, young patients, and patients with a persistent suicidal ideation prior to the start of treatment are at increased risk for suicide attempts and suicidal thoughts. All patients should be closely monitored for clinical worsening (including the development of new symptoms) and suicidality during treatment, particularly at the beginning of treatment or during changes in dosage (both increases and decreases).
A change in therapeutic regimen, including discontinuation of the drug, should be considered for patients with clinical worsening (including development of new symptoms) and/or emergence of suicidal ideation/behavior, especially if these symptoms are severe, sudden in onset, or not part of the patient's previous symptom complex.
Akathisia
Rarely, the use of Paxil or other selective serotonin reuptake inhibitors may be associated with the development of akathisia, a condition characterized by a feeling of inner restlessness and psychomotor agitation, such as an inability to sit or stand still, combined with a subjective feeling of discomfort. This is most likely to occur during the first weeks of treatment.
Serotonin syndrome/neuroleptic malignant syndrome
In isolated cases, treatment with Paxil may be associated with the development of serotonin syndrome or symptoms characteristic of neuroleptic malignant syndrome, especially when used concomitantly with other serotonergic and/or neuroleptic drugs. Since these syndromes can cause life-threatening conditions, treatment with Paxil should be discontinued in the event of such phenomena (characterized by a combination of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid changes in the main indicators of the functional state of the body, changes in mental status, including confusion, irritability, borderline agitation with progression to delirium and coma) and supportive symptomatic therapy should be prescribed. Paxil should not be used in combination with serotonin precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonin syndrome (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions").
Mania and bipolar disorders
A major depressive episode may be the initial manifestation of bipolar disorder. It is generally accepted (although not supported by data from controlled clinical trials) that treatment of such episodes with an antidepressant alone may increase the likelihood of accelerated onset of mixed/manic episodes in patients at increased risk of developing bipolar disorder. Before initiating treatment with antidepressants, patients should be carefully evaluated to identify any risk factors for bipolar disorder. Such evaluation should include a detailed history of the patient, including the presence of suicide attempts, bipolar disorder, and depression in family members. It should be noted that PAXIL is not approved for the treatment of depression in bipolar disorder. As with other antidepressants, PAXIL should be used with caution in patients with a history of mania.
Tamoxifen
Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer recurrence/fatality, may be reduced when co-administered with Paxil, as paroxetine is an irreversible inhibitor of CYP2D6 (see section 4.5). This risk increases with the duration of co-administration. When treating breast cancer with tamoxifen, the patient should be given an alternative antidepressant with little or no CYP2D6 inhibition.
Bone fractures
Epidemiological studies investigating the risk of bone fractures have reported an association with fractures in some antidepressants, including selective serotonin reuptake inhibitors. The risk arises during treatment and is greatest in the initial stages of therapy. When treating patients with Paxil, the possibility of bone fractures should be considered.
Monoamine oxidase inhibitors
Treatment with Paxil should be initiated with caution, no earlier than 2 weeks after discontinuation of MAO inhibitors; the dose should be increased gradually until the optimal response is achieved.
Renal/hepatic failure
It is recommended to use with caution in the treatment of patients with severe renal or hepatic insufficiency.
Diabetes mellitus
In patients with diabetes mellitus, treatment with serotonin reuptake inhibitors may alter the glycemic profile, therefore the dose of insulin and/or oral hypoglycemic agents should be adjusted. In addition, clinical studies indicate that an increase in blood glucose levels may occur with concomitant treatment with paroxetine and pravastatin.
Epilepsy
Paxil, like other antidepressants, should be used with caution in the treatment of patients with epilepsy.
Attacks
In patients treated with Paxil, the overall incidence of seizures is less than 0.1%.
If the patient develops seizures, Paxil should be discontinued.
Electroconvulsive therapy
There is only limited clinical experience with the use of Paxil in combination with electroconvulsive therapy.
Glaucoma
Paxil, like other serotonin reuptake inhibitors, can cause mydriasis and should be used with caution in patients with angle-closure glaucoma.
Hyponatremia has occasionally been reported, mostly in elderly patients. Symptoms of hyponatremia generally resolved after discontinuation of Paxil.
Hemorrhages
After treatment with Paxil, bleeding into the skin and mucous membranes (including gastrointestinal and gynecological bleeding) has been observed. Therefore, Paxil should be used with caution in patients who are simultaneously prescribed drugs that increase the risk of bleeding, as well as patients with frequent bleeding or a tendency to it. Elderly patients may be at increased risk of bleeding that is not associated with menstruation.
Heart disease
When treating patients with concomitant cardiac disease, the usual precautions should be observed.
Symptoms observed in adults when withdrawing Paxil
In clinical trials, adverse reactions to discontinuation of Paxil were reported in 30% of adults compared with 20% of patients receiving placebo. The occurrence of withdrawal symptoms is not the same as the development of addiction or dependence to the drug when abused.
Symptoms such as dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, increased sweating, headache, diarrhoea have been reported. These symptoms are generally mild to moderate in nature, although in some patients they may be more severe. They usually occur within the first few days after discontinuation of the drug, but there have been isolated cases of these symptoms in patients who accidentally missed a dose. These symptoms usually resolve spontaneously within 2 weeks, although in some patients this process may be longer (2-3 months or longer). Therefore, it is recommended that when discontinuing Paxil, the dose be reduced gradually, over several weeks or months, depending on the individual characteristics of the patient (see section "Method of administration and dosage").
Symptoms observed in children and adolescents during Paxil withdrawal
In clinical trials in children and adolescents, adverse reactions upon discontinuation of Paxil treatment occurred in 32% of patients compared with 24% of patients receiving placebo. The following adverse reactions occurred after discontinuation of Paxil (with a frequency of at least 2% of patients and with a frequency of occurrence twice as high as that in the placebo group): emotional lability (including suicidal ideation, suicide attempts, mood swings and tearfulness), nervousness, dizziness, nausea and abdominal pain (see section "Adverse reactions").
Sexual dysfunction
Selective serotonin reuptake inhibitors may cause symptoms of sexual dysfunction (see section 4.8). Cases of long-term sexual dysfunction have been reported even after discontinuation of treatment with selective serotonin reuptake inhibitors.
Warnings regarding excipients.
Sodium compounds
1 tablet of the medicinal product contains less than 1 mmol (23 mg) of sodium, i.e. this medicinal product can be considered to be essentially sodium-free.
Ability to influence reaction speed when driving vehicles or other mechanisms
Clinical experience with Paxil suggests that it does not affect cognitive function or psychomotor reactions. However, as with other psychoactive drugs, patients should be warned about the possible impairment of their ability to drive or operate machinery during treatment.
Paxil does not enhance the impairment of mental and motor reactions caused by alcohol, however, the combined use of Paxil and alcohol is not recommended.
Use during pregnancy or breastfeeding
Fertility
Some clinical studies have shown that selective serotonin reuptake inhibitors, including Paxil, may affect sperm quality. These effects are thought to resolve after treatment is discontinued. Changes in sperm quality may affect fertility in some men.
Pregnancy
According to animal studies, no teratogenic or embryotoxic effects were detected.
The physician should consider alternative treatment options for pregnant women or women planning to become pregnant and should only prescribe paroxetine if the expected benefit to the mother outweighs the potential risk to the fetus. If a decision is made to discontinue treatment during pregnancy, the appropriate sections of the Summary of Product Characteristics should be consulted for further information on the dosage and symptoms of discontinuation of paroxetine (see sections 4.2 and 4.4).
There have been reports of premature birth in women treated with Paxil or other selective serotonin reuptake inhibitors, although a causal relationship to the drug has not been established.
Newborns should be monitored if the pregnant woman continues to take PAXIL during the third trimester of pregnancy, as there have been reports of complications in newborns when the mother was treated with PAXIL or other selective serotonin reuptake inhibitors during this period, although a causal relationship to drug use has not been established. The following effects have been reported: respiratory distress, cyanosis, apnea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, shaking, irritability, lethargy, constant crying, and drowsiness. In some reports, symptoms have been described as neonatal manifestations of withdrawal syndrome. In most cases, they occur immediately or shortly (< 24 hours) after delivery.
Epidemiological studies have shown that the use of selective serotonin reuptake inhibitors (including paroxetine) during pregnancy, particularly in late pregnancy, has been associated with an increased risk of persistent pulmonary hypertension of the newborn. In women who used SSRIs in late pregnancy, the risk was 4- to 5-fold higher than in the general population (1-2 cases per 1000 pregnancies in the general population).
Breast-feeding
Small amounts of Paxil are excreted in breast milk. No evidence of effects on the newborn has been found, but Paxil should not be used during breastfeeding unless the expected benefit to the mother outweighs the potential risk to the child.
Method of administration and doses
General recommendations
The drug is intended for oral use, it is recommended to take 1 time per day - in the morning during meals. The tablet should be swallowed without chewing. The tablet has a break line, which allows you to get a dose of 10 mg if necessary.
As with all other antidepressants, the dose should be carefully titrated individually during the first 2–3 weeks of treatment and then adjusted according to clinical response.
The course of treatment should be long enough to ensure the resolution of symptoms. This period may last several months in the treatment of major depressive disorder, and even longer in obsessive-compulsive and panic disorders. As with other drugs for the treatment of psychiatric disorders, abrupt withdrawal of the drug should be avoided.
Major depressive disorder. The recommended dose is 20 mg per day. Some patients may require an increase in dose. This should be done gradually, in 10 mg increments (up to a maximum of 50 mg per day), depending on the clinical response to treatment.
Obsessive-compulsive disorder. The recommended dose is 40 mg per day. Treatment should be started with a dose of 20 mg per day and then increased by 10 mg per day every week. Some patients only improve with a maximum dose of 60 mg per day.
Panic disorder. The recommended dose is 40 mg per day. Treatment should be initiated at 10 mg per day and increased by 10 mg weekly, depending on clinical response. Some patients may only respond to a maximum dose of 60 mg per day.
To reduce the risk of possible worsening of panic disorder symptoms, which is often observed at the beginning of treatment for this disease, it is recommended to start treatment with a low dose of the drug.
Social anxiety disorder/social phobia. The recommended dose is 20 mg per day. For some patients, the dose may be increased gradually by 10 mg per day, depending on the clinical effect of treatment, up to 50 mg per day. The interval between dose increases should be at least 1 week.
Generalized anxiety disorder. The recommended dose is 20 mg per day. For some patients for whom 20 mg is not effective enough, the dose may be increased gradually by 10 mg per day, depending on the clinical effect, up to 50 mg per day.
Post-traumatic stress disorder. The recommended dose is 20 mg per day. For some patients for whom 20 mg is not sufficiently effective, the dose may be gradually increased by 10 mg per day, depending on the clinical effect, up to 50 mg per day.
As with other drugs for the treatment of mental illness, abrupt withdrawal of the drug should be avoided. In clinical trials, a gradual dose reduction regimen was used, which included a reduction in the daily dose by 10 mg per day at intervals of 1 week. After reaching a dosage regimen of 20 mg per day, patients took the drug at this dose for another week before completely withdrawing it. In the event of severe symptoms during dose reduction or after discontinuation of treatment, it is necessary to decide whether to resume treatment at the previous dose. Later, the dose can be continued to be reduced, but more slowly.
Elderly patients: Treatment should be initiated at the usual adult starting dose, which may then be titrated up to 40 mg daily. Increased plasma concentrations of paroxetine have been reported in elderly patients, but the range of concentrations in this group of patients is similar to that in younger patients.
Children: Paxil is not indicated for the treatment of children.
Renal and hepatic impairment: In patients with severe renal impairment (creatinine clearance less than 30 ml/min) or hepatic impairment, increased plasma concentrations of paroxetine have been observed. Therefore, the dose should be reduced to the lower end of the dosing range in such patients.
Children
Paxil is not indicated for the treatment of children.
Controlled clinical trials have not demonstrated efficacy or provided supportive data for the use of Paxil in the treatment of depression in children. The safety and efficacy of the drug in children under 7 years of age have not been studied.
Overdose
In case of overdose with Paxil, in addition to the symptoms listed in the "Adverse Reactions" section, increased body temperature, changes in blood pressure, involuntary muscle contractions, anxiety and tachycardia have been observed.
All these effects in patients mostly passed without serious consequences even after the use of a dose of 2000 mg. Sometimes coma or changes in ECG parameters were observed, very rarely fatal cases were noted, but mainly in such cases Paxil was taken together with other psychotropic drugs and sometimes with alcohol.
Specific antidote unknown
Treatment of overdose should include general therapeutic measures, the same as for overdose with other antidepressants. Supportive treatment with monitoring of vital signs and careful observation of the patient is indicated.
Adverse reactions
The side effects listed below are classified by system organ class and by frequency of occurrence. The frequency is defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), including isolated cases.
Blood and lymphatic system
Uncommon: increased bleeding, mainly of the skin and mucous membranes (including ecchymoses and gynaecological bleeding).
Very rare: thrombocytopenia.
Immune system
Very rare: severe and potentially fatal allergic reactions (including anaphylactoid reactions and angioedema).
Endocrine system
Very rare: syndrome due to inadequate secretion of antidiuretic hormone.
Metabolism and digestive disorders
Common: increased cholesterol levels, decreased appetite.
Uncommon: There have been reports of altered glycemic profiles in patients with diabetes mellitus (see section 4.4).
Uncommon: hyponatraemia. Hyponatraemia is mainly observed in elderly patients and is sometimes associated with the syndrome of inappropriate antidiuretic hormone secretion.
Mental disorders
Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares).
Uncommon: confusion, hallucinations.
Rarely: manic reactions, anxiety, depersonalization, panic attacks, akathisia.
Frequency unknown: suicidal ideation, suicidal behavior and aggression.
These symptoms may also be caused by an underlying disease.
Nervous system
Common: dizziness, tremor, headache.
Uncommon: extrapyramidal disorders.
Rare: convulsions, akathisia, restless legs syndrome.
Very rare: serotonin syndrome (may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, tachycardia and tremor).
Extrapyramidal disorders, including orofacial dystonia, are observed in patients with movement disorders or in patients with
