Plisil (Tablets) Instructions for Use

Marketing Authorization Holder

Pliva Hrvatska, d.o.o. (Croatia)

ATC Code

N06AB05 (Paroxetine)

Active Substance

Paroxetine (Rec.INN registered by WHO)

Dosage Form

Plisil

Film-coated tablets, 20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from yellow to orange in color, round, with the engraving “POT 20” on one side and a score on both sides.

Excipients : anhydrous calcium hydrogen phosphate, sodium carboxymethyl starch, magnesium stearate.

Film coating composition lactose monohydrate, hypromellose, titanium dioxide (E171), macrogol 4000, yellow iron oxide (E172), red iron oxide (E172).

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Antidepressant. Paroxetine is a potent and selective inhibitor of serotonin (5-hydroxytryptamine, 5-HT) reuptake by neurons in the brain, which determines its antidepressant effect and efficacy in the treatment of obsessive-compulsive and panic disorders.

The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are rapidly eliminated from the body, have weak pharmacological activity and do not affect the therapeutic action. The metabolism of paroxetine does not disrupt its induced selective uptake of 5-HT by neurons.

Paroxetine has low affinity for m-cholinergic receptors.

Having a selective action, unlike tricyclic antidepressants, Paroxetine is characterized by low affinity for α₁, α₂, β-adrenergic receptors, as well as for dopamine, 5-HT₁-like, 5-HT₂-like and histamine H₁ receptors.

Paroxetine does not impair psychomotor functions and does not potentiate the depressant effect of ethanol on them.

According to behavioral and EEG studies, paroxetine exhibits weak activating properties when administered at doses higher than those required to inhibit 5-HT uptake. In healthy volunteers, it does not cause significant changes in blood pressure, heart rate, or EEG.

Unlike antidepressants that inhibit norepinephrine uptake, Paroxetine is much weaker in suppressing the antihypertensive effects of guanethidine.

Pharmacokinetics

Absorption

After oral administration, Paroxetine is well absorbed from the gastrointestinal tract. It undergoes metabolism during the “first pass” through the liver.

Distribution

Steady-state concentration (C_ss) is reached by day 7-14 after the start of treatment, and the pharmacokinetics do not change during long-term treatment.

The clinical effects of paroxetine (side effects and efficacy) do not correlate with its plasma concentration.

Paroxetine is extensively distributed in tissues, and pharmacokinetic calculations show that only 1% of it is present in plasma.

At therapeutic concentrations, the binding of paroxetine to plasma proteins is 95%.

Metabolism

Since the metabolism of paroxetine involves the “first pass” through the liver, the amount determined in the systemic circulation is less than that absorbed from the gastrointestinal tract. When the dose of paroxetine is increased or with repeated administration, when the load on the body increases, there is a partial saturation of the “first pass” effect through the liver and a decrease in the plasma clearance of paroxetine. As a result, an increase in the plasma concentration of paroxetine and fluctuations in pharmacokinetic parameters are possible, which can only be observed in those patients in whom low doses of the drug achieve low plasma concentrations of paroxetine.

Elimination

The half-life (T_1/2) varies but is usually about 16-21 hours. The elimination of paroxetine metabolites from the body is biphasic, first as a result of metabolism during the first pass through the liver, and then it is controlled by systemic elimination.

Paroxetine is excreted mainly in the form of metabolites: 64% of metabolites are excreted in the urine and 36% through the intestines, probably with bile. Less than 2% is excreted unchanged in the urine and less than 1% in the bile.

Indications

• Depression of all types (including reactive, severe endogenous depression and depression accompanied by anxiety);
• Obsessive-compulsive disorder;
• Panic disorder, including with agoraphobia;
• Social anxiety disorder/social phobia;
• Generalized anxiety disorder;
• Post-traumatic stress disorder.

ICD codes

Dosage Regimen

The drug is taken orally once a day, in the morning, with meals. The tablet should be swallowed whole with water. The dose is selected individually during the first 2-3 weeks after the start of therapy and subsequently adjusted if necessary.

For depression, the drug is prescribed at a dose of 20 mg once a day. If necessary, the dose is gradually increased by 10 mg per day, the maximum daily dose is 50 mg, depending on the patient’s response.

For obsessive-compulsive disorders, the initial therapeutic dose is 20 mg/day, with a subsequent weekly increase of 10 mg. The recommended average therapeutic dose is 40 mg/day; if necessary, the dose can be increased to 60 mg/day.

For panic disorders, the drug is prescribed at an initial dose of 10 mg/day (to reduce the possible risk of exacerbation of panic symptoms), with a subsequent weekly increase of 10 mg. The average therapeutic dose is 40 mg/day. The maximum dose is 50 mg/day.

For social anxiety disorders/social phobia, the initial dose is 20 mg/day; if there is no effect for at least 2 weeks, the dose may be increased to a maximum of 50 mg/day. The dose should be increased by 10 mg at intervals of at least 1 week according to the clinical effect.

For post-traumatic mental disorders, for most patients, the initial and therapeutic doses are 20 mg/day. In some cases, an increase in the dose of paroxetine to a maximum of 50 mg/day is recommended. The dose should be increased by 10 mg each week according to the clinical effect.

For generalized anxiety disorders, the initial and recommended doses are 20 mg/day.

In renal and/or hepatic impairment, the recommended daily dose is 20 mg.

For elderly patients, the daily dose should not exceed 40 mg.

The dose of the drug should be assessed and adjusted if necessary within 2-3 weeks at the beginning of therapy, and then as needed. Patients should continue treatment for a period sufficient for the symptoms to disappear, at least 4-6 months after recovery from depression and longer in the presence of obsessive-compulsive and panic disorders.

As with many other psychotropic drugs, abrupt discontinuation of the drug is not recommended.

The use of paroxetine in children is not recommended, as its safety and efficacy in this population have not been established.

Adverse Reactions

From the central nervous system: drowsiness, tremor, asthenia, insomnia, dizziness, fatigue, convulsions, extrapyramidal disorders, hallucinations, mania, confusion, agitation, anxiety, depersonalization, panic attacks, nervousness, paresthesia, decreased ability to concentrate, serotonin syndrome.

From the musculoskeletal system: arthralgia, myalgia, myopathy, myasthenia.

From the sensory organs: visual disturbances, taste changes.

From the genitourinary system: urinary retention, increased urination, sexual dysfunction, including impotence and ejaculation disorders, decreased libido, anorgasmia.

From the digestive system: decreased appetite, nausea, vomiting, dry mouth, constipation or diarrhea; very rarely – hepatitis.

From the cardiovascular system: orthostatic hypotension.

Dermatological reactions: ecchymoses, increased sweating.

Allergic reactions: rash, urticaria, itching, angioedema.

Other: impaired ADH secretion, hyperprolactinemia/galactorrhea, hyponatremia, withdrawal syndrome upon abrupt discontinuation of the drug.

Contraindications

• Concomitant use of MAO inhibitors and the period up to 14 days after their discontinuation;
• Pregnancy;
• Period of lactation (breastfeeding);
• Children and adolescents under 18 years of age (efficacy and safety not established);
• Hypersensitivity to the components of the drug.

With caution, the drug should be prescribed for hepatic and renal impairment, closed-angle glaucoma, prostatic hyperplasia, mania, cardiac pathology, epilepsy (in unstable epilepsy, the use of the drug should be avoided), convulsive conditions, during electroconvulsive therapy, when taking drugs that increase the risk of bleeding, in the presence of risk factors for increased bleeding and diseases that increase the risk of bleeding; elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

In renal and/or hepatic impairment, the recommended daily dose is 20 mg.

Use in Renal Impairment

In renal and/or hepatic impairment, the recommended daily dose is 20 mg.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age (efficacy and safety not established).

Geriatric Use

With caution, the drug should be prescribed to elderly patients.

Special Precautions

The drug should be prescribed with caution to patients receiving antipsychotic drugs (neuroleptics) to avoid the development of neuroleptic malignant syndrome (NMS).

Plisil should be prescribed no earlier than 2 weeks after discontinuation of MAO inhibitors.

During the first few weeks of taking the drug, the patient’s condition should be carefully monitored due to possible suicide attempts, since adequate therapeutic action of paroxetine is not yet achieved at this time.

Treatment with Plisil should be discontinued if seizures develop, as well as at the first symptoms of mania.

During treatment, in patients with diabetes mellitus, in some cases, correction of the dose of insulin and/or oral hypoglycemic drugs may be required.

In elderly patients, hyponatremia is possible.

Effect on the ability to drive vehicles and operate machinery

Plisil does not impair cognitive and psychomotor functions; nevertheless, as with treatment with other psychotropic drugs, patients should refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms: nausea, vomiting, tremor, dry mouth, dilated pupils, fever, changes in blood pressure, headache, involuntary muscle contractions, agitation, anxiety, sinus tachycardia, sweating, drowsiness, nystagmus, bradycardia, nodal rhythm.

In very rare cases, when taken simultaneously with other psychotropic drugs and/or alcohol, changes in the ECG and coma are possible.

Treatment: gastric lavage, administration of activated charcoal. If necessary, symptomatic therapy should be carried out. There is no specific antidote.

Drug Interactions

Food and antacid intake do not affect the absorption and pharmacokinetic parameters of the drug.

Paroxetine is incompatible with MAO inhibitors and thioridazine.

When co-administered with paroxetine, the concentration of procyclidine increases.

During treatment, the patient should refrain from consuming alcohol due to the possible enhancement of the toxic effect of ethanol.

With simultaneous use with inducers/inhibitors of liver enzymes, changes in the metabolism and pharmacokinetics of paroxetine are possible.

Due to the inhibition of cytochrome P450 isoenzymes by paroxetine, it is possible to enhance the effect of barbiturates, phenytoin, indirect anticoagulants, tricyclic antidepressants (nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine), phenothiazine neuroleptics (thioridazine) and class 1C antiarrhythmics (including propafenone), metoprolol and increase the risk of side effects when these drugs are co-administered.

When co-administered with drugs that inhibit liver enzymes, a reduction in the dose of paroxetine may be required.

Paroxetine increases bleeding time while taking warfarin, while prothrombin time does not change.

When paroxetine is co-administered with atypical antipsychotics, phenothiazines, tricyclic antidepressants, acetylsalicylic acid, and NSAIDs, caution is recommended due to possible coagulation disorders.

When co-administered with serotonergic drugs (tramadol, sumatriptan), an enhancement of the serotonergic effect is possible.

With simultaneous use, a mutual enhancement of the action of tryptophan, lithium preparations and paroxetine has been noted (as with the administration of other selective serotonin reuptake inhibitors). Concomitant use with lithium preparations should be carried out under the control of their plasma lithium concentration. Concomitant administration with preparations containing tryptophan is not recommended.

When using paroxetine (like other selective serotonin reuptake inhibitors) with neuroleptics, the development of neuroleptic malignant syndrome (NMS) is possible.

When paroxetine is co-administered with phenytoin and other anticonvulsants, a decrease in the plasma concentration of paroxetine and an increase in the frequency of side effects are possible.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.