PRODUCT MONOGRAPH

PAROXETINE

Paroxetine (as Paroxetine Hydrochloride) Tablets 10 mg, 20 mg and 30 mg

ACTIONS AND CLINICAL PHARMACOLOGY

Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant and anxiolytic action in the treatment of depression, obsessive-compulsive disorder (OCD), panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (a1, a2, b), dopaminergic, serotonergic (5HT1, 5HT2), or histaminergic receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine receptor was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.

Human Pharmacokinetics

Paroxetine is well absorbed after oral administration. In healthy volunteers, the absorption of a single 30 mg oral dose of paroxetine was not appreciably affected by the presence or absence of food. Owing to the extensive distribution of paroxetine into the tissues, less than 1% of the total drug in the body is believed to reside in the systemic circulation. Paroxetine is subject to a biphasic process of metabolic elimination which involves presystemic (first-pass) and systemic pathways. First-pass metabolism is extensive, but may be partially saturable, accounting for the increased bioavailability observed with multiple dosing. The metabolism of paroxetine is accomplished in part by cytochrome P450(IID6). Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). The majority of the dose appears to be oxidized to a catechol intermediate which is converted to highly polar glucuronide and sulphate metabolites through methylation and conjugation reactions. The glucuronide and sulphate conjugates of paroxetine are about >10,000 and 3,000 times less potent, respectively, than the parent compound as inhibitors of 5-HT reuptake in rat brain synaptosomes. Approximately 64% of an administered dose of paroxetine is eliminated by the kidneys and 36% in the faeces. Less than 2% of the dose is recovered in the form of the parent compound. A wide range of interindividual variation is observed for the pharmacokinetic parameters. Following the single or multiple dose administration of paroxetine at doses of 20 to 50 mg, the mean elimination half-life value for healthy subjects appears to be about 24 hours, although a range of 3 to 65 hours has been reported. Both the rate of absorption and the terminal elimination half-life appear to be independent of dose. Steady-state plasma concentrations of paroxetine are generally achieved in 7 to 14 days. No correlation has been established between paroxetine plasma concentrations and therapeutic efficacy or the incidence of adverse reactions. No clear dose relationship has been demonstrated for the antidepressant effects of paroxetine at doses above 20 mg/day. The results of fixed-dose studies comparing paroxetine and placebo in the treatment of depression, panic disorder, generalized anxiety disorder and posttraumatic stress disorder revealed a dose dependency for some adverse events. In healthy young volunteers receiving a 20 mg daily dose of paroxetine for 15 days, the mean maximal plasma concentration was 41 ng/mL at steady state (see Table 1). Peak plasma levels generally occurred within 3 to 7 hours. In elderly subjects, increased steady-state plasma concentrations and prolongation of the elimination half life were observed relative to younger adult controls (Table 1). Elderly patients should, therefore, be initiated and maintained at the lowest daily dosage of paroxetine which is associated with clinical efficacy. The results from a multiple dose pharmacokinetic study in subjects with severe hepatic dysfunction suggest that the clearance of paroxetine is markedly reduced in this patient group (see Table 1). As the elimination of paroxetine is dependent upon extensive hepatic metabolism, its use in patients with hepatic impairment should be undertaken with caution (see DOSAGE AND ADMINISTRATION). In a single dose pharmacokinetic study in patients with mild to severe renal impairment, plasma levels of paroxetine tended to increase with deteriorating renal function (see Table 2). As multiple-dose pharmacokinetic studies have not been performed in patients with renal disease, paroxetine should be used with caution in such patients. At therapeutic concentrations, the plasma protein binding of paroxetine is approximately 95%. After the administration of a single 50 mg oral dose to lactating women, the concentrations of paroxetine detected in breast milk were similar to those in plasma.

a

Creatinine clearance = 13-27 mL/min.

b

Creatinine clearance = 32-46 mL/min.

c

Creatinine clearance > 100 mL/min.

Abbreviations:

Cmax = maximum plasma concentration; Tmax = time to reach Cmax

AUCss = area under the plasma concentration time curve between dosing intervals (i.e. 24 hrs) at steady-state. AUC[?] = area under the plasma concentration time curve at infinity.

t1/2 = terminal elimination half-life; ss = steady state.

Clinical Trials

Depression

The efficacy of paroxetine as a treatment for depression has been established in six placebo- controlled clinical trials of 6 weeks in duration performed in patients with depression (ages 18 to 73). In these studies, paroxetine was shown to be significantly more effective than placebo in treating depression according to the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI) - severity of illness.

Obsessive-Compulsive Disorder

Three double-blind, placebo-controlled clinical trials of 12 weeks in duration have been performed to investigate the efficacy of paroxetine in obsessive-compulsive disorder: two flexible dose studies (20-60 mg/day) and one fixed dose study (20, 40 & 60 mg/day). Results for the fixed dose study and one of the flexible dose studies showed statistically significant differences from placebo in favour of paroxetine in terms of mean change from baseline to endpoint on the Yale- Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive- Compulsive Scale. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at endpoint according to a Clinical Global Impression of Improvement was 15% (13/88) in the placebo group, 20% (17/85) in the 20 mg/day group, 36% (30/83) in the 40 mg/day group, and 37% (31/83) in the 60 mg/day group. In the two flexible dose studies, placebo response rates according to this criterion were 28% (28/99) and 25% (19/75), while paroxetine response rates were 45% (89/198) and 35% (28/79), respectively.

Panic Disorder

One fixed dose and three flexible dose placebo-controlled clinical trials of 10 to 12 weeks in duration have been performed to investigate the efficacy of paroxetine in panic disorder. The fixed dose study and two of the three flexible dose studies were supportive of differences from placebo in favour of paroxetine for measures of panic attack frequency. At endpoint, in the fixed dose study, the proportion of patients who were free of panic attacks was 44% (29/66) for the placebo group, 56% (33/59) for the 10 mg/day paroxetine group, 57% (35/61) for the 20 mg/day paroxetine group, and 76% (47/62) for the 40 mg/day paroxetine group.

Social Phobia (Social Anxiety Disorder)

One fixed dose and two flexible dose placebo-controlled clinical trials of 12 weeks in duration have been performed to investigate the efficacy of paroxetine in social phobia (social anxiety disorder). These studies showed statistically significant differences from placebo in favour of paroxetine in terms of mean change from baseline to endpoint on the Liebowitz Social Anxiety Scale and the percentage of therapeutic responders according to the Clinical Global Impression of Improvement. In the fixed dose study, the proportion of patients who were considered to be much or very much improved at week 12 of treatment according to the Clinical Global Impression of Improvement was 28.3% (26/92) in the placebo group, 44.9% (40/89) in the 20 mg/day group, 46.6% (41/88) in the 40 mg/day group, and 42.9% (39/91) in the 60 mg/day group. In the two flexible dose (20-50 mg/day) studies, placebo response rates according to this criterion were 23.9% (22/92) and 32.4% (47/145), while paroxetine response rates were 54.9% (50/91) and 65.7% (90/137), respectively.

Generalized Anxiety Disorder

The effectiveness of paroxetine in the treatment of Generalized Anxiety Disorder (GAD) (DSM IV) was demonstrated in two 8-week, multicentre, placebo-controlled studies. One trial was a flexible dose (20-50 mg/day) study while the other was a multiple fixed dose (20 or 40 mg/day) study. In both studies paroxetine demonstrated statistically significant superiority over placebo on the primary outcome measure - the Hamilton Rating Scale for Anxiety (HAM-A) total score, and on a number of secondary outcomes including the HAM-A anxiety and tension items, the Clinical Global Impression (CGI) responder criterion and the Sheehan Disability Scale (SDS). An additional 8-week flexible dose study did not demonstrate a significant difference between paroxetine (20-50 mg/day), and placebo on the primary outcome measure. However, paroxetine (20-50 mg/day) was more effective than placebo on many secondary study outcomes.

Posttraumatic Stress Disorder

The efficacy of paroxetine in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12 week, multicenter placebo controlled studies (Study 1 and Study 2) in adult patients who met the DSM-IV criteria for PTSD. Study outcome was assessed by (i) the Clinician Administered PTSD Scale Part (CAPS-2) score and (ii) the Clinical Global Impression Global Improvement Item (CGI-I). The CAPS-2 is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of: reexperiencing/intrusion, avoidance/numbing and hyperarousal. The two primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12 week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo. Paroxetine 20 mg and 40 mg were demonstrated to be significantly superior to placebo for the CAPS-2 total score, and on proportion of responders on the CGI-I. Study 2 was a 12-week flexible-dose study comparing paroxetine (20 mg to 50 mg daily) to placebo. Paroxetine was demonstrated to be significantly superior to placebo for the CAPS-2 total scorer, and on proportion of responders on the CGI-I. The majority (66-68%) of patients in these trials were women. Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years or older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively.

Comparative Bioavailability

Two comparative bioavailability studies were conducted in healthy human volunteers - one under fasting conditions and one under fed conditions. The rate and extent of absorption of paroxetine were measured and compared following oral administration of 30 mg paroxetine (one tablet of either PAROXETINE or Paxil). The results from measured data are summarized as follows:

INDICATIONS AND CLINICAL USE

Depression

PAROXETINE (paroxetine) is indicated for symptomatic relief of depressive illness. Clinical trials have provided evidence that continuation treatment with paroxetine in patients with moderate to moderately severe depressive disorder is effective for at least 6 months.

Obsessive-Compulsive Disorder

PAROXETINE (paroxetine) is indicated for the symptomatic treatment of obsessive-compulsive disorder (OCD). The obsessions or compulsions must be experienced as intrusive, markedly distressing, time-consuming, or interfering significantly with the person's social or occupational functioning.

Panic Disorder

PAROXETINE (paroxetine) is indicated for the symptomatic treatment of panic disorder, with or without agoraphobia.

Social Phobia (Social Anxiety Disorder)

PAROXETINE is indicated for the symptomatic relief of generalized social phobia (social anxiety disorder), a disorder characterized by marked and persistent fear, anxious anticipation, or avoidance of multiple social situations (eg. interacting with strangers, attending social gatherings, dealing with authority figures) and/or performance situations (eg. eating, writing, working while being observed, or public speaking). A diagnosis of social phobia/social anxiety disorder should not be made unless the fear, anxious anticipation, or avoidance of social and/or performance situations interferes significantly with the person's normal routine, occupational functioning, or social life, or causes marked distress.

Generalized Anxiety Disorder

PAROXETINE is indicated for the symptomatic relief of anxiety causing significant distress in patients with Generalized Anxiety Disorder (GAD).

Posttraumatic Stress Disorder

PAROXETINE is indicated for the symptomatic treatment of posttraumatic stress disorder (PTSD). PTSD as defined by DSM-IV requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to clues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A diagnosis of PTSD requires that the symptoms are present for at least one month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Long-Term Use of Paroxetine

The effectiveness of paroxetine in long-term use (i.e. more than 8 weeks for GAD and 12 weeks for other indications) has not yet been established in controlled trials for OCD, panic disorder, social phobia (social anxiety disorder), generalized anxiety disorder and posttraumatic stress disorder. Therefore, the physician who elects to use PAROXETINE for extended periods in these indications should periodically re-evaluate the long-term usefulness of the drug for individual patients.

CONTRAINDICATIONS

Hypersensitivity

: PAROXETINE (paroxetine) is contraindicated in patients who are known to be hypersensitive to the drug or any of its components.

Monoamine Oxidase Inhibitors

: In patients receiving another serotonin reuptake inhibitor drug in combination with a MAO inhibitor, there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have begun treatment on a MAO inhibitor. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, PAROXETINE should not be used in combination with MAO inhibitors or within 2 weeks of terminating treatment with MAO inhibitors. Treatment with PAROXETINE should then be initiated cautiously and dosage increased gradually

until optimal response is reached. MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with PAROXETINE.

Thioridazine

: Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose-related.

An in vivo study suggests that drugs which inhibit P450 2D6, including certain SSRI's such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, paroxetine should not be used in combination with thioridazine.

WARNINGS

POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM.

Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

Adults and Pediatrics: Additional data

There are clinical trial and post-marketing reports with SSRIs and other newer anti- depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

Discontinuation Symptoms

Patients currently taking PAROXETINE should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

PRECAUTIONS

Suicide

: The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Therefore, high risk patients should be closely supervised throughout therapy with appropriate consideration to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescriptions for PAROXETINE (paroxetine) should be written for the smallest quantity of drug consistent with good patient management.

Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders. (see WARNINGS: POTENTIAL ASSOCIATION WITH BEHAVIOURAL AND EMOTIONAL CHANGES, INCLUDING SELF-HARM).

Epilepsy

: As with other antidepressants, paroxetine should be used with caution in patients with epilepsy.

Seizures

: During clinical trials, the overall incidence of seizures was 0.15% in patients treated with paroxetine. However, patients with a history of convulsive disorders were excluded from these studies. Caution is recommended when the drug is administered to patients with a history of seizures. The drug should be discontinued in any patient who develops seizures.

Activation of Mania/Hypomania

: During clinical testing in depressed patients, approximately 1% of paroxetine-treated patients experienced manic reactions. When bipolar patients were considered as a sub-group the incidence of mania was 2%. As with other Selective Serotonin Reuptake Inhibitors (SSRIs), PAROXETINE should be used with caution in patients with a history of mania.

Discontinuation of Treatment with PAROXETINE

: When discontinuing treatment, regardless of the indication for which PAROXETINE is being prescribed, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, nausea, vomiting and sweating or other symptoms which may be of clinical significance, see ADVERSE REACTIONS). A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. (See ADVERSE REACTIONS and DOSAGE and ADMINISTRATION).

Occupational Hazards

: Although paroxetine did not cause sedation or interfere with psychomotor performance in placebo-controlled studies in normal subjects, patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that PAROXETINE does not affect them adversely.

Use in Patients with Concomitant Illness

General

: Clinical experience with paroxetine in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using paroxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiac Conditions

: PAROXETINE has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. The usual precautions should be observed in patients with cardiac conditions.

Electroconvulsive Therapy (ECT)

: The efficacy and safety of the concurrent use of PAROXETINE and ECT have not been studied.

Use in Elderly

: Administration of paroxetine to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adults (see Human Pharmacokinetics). Elderly patients should be initiated and maintained at the lowest daily dose of paroxetine which is associated with clinical efficacy.

Approximately 800 elderly patients (>= 65 years) have been treated with paroxetine in worldwide premarketing clinical trials. The pattern of adverse experiences in the elderly was comparable to that in younger patients.

Children

: The safety and effectiveness of PAROXETINE in children under 18 years of age have not been established.

Pregnancy and Lactation

: Although animal studies have not shown any teratogenic or selective embryotoxic effects, the safety of paroxetine in human pregnancy has not been established. PAROXETINE should not be used during pregnancy unless the potential benefit to the patient outweighs the possible risk to the fetus.

The concentrations of paroxetine detected in the breast milk of lactating women are similar to those in plasma. Lactating women should not nurse their infants while receiving paroxetine unless in the opinion of the treating physician, breast feeding is necessary, in which case the infant should be closely monitored.

Renal Impairment

: Since paroxetine is extensively metabolized by the liver, excretion of unchanged drug in urine is a minor route of elimination. However, single dose pharmacokinetic studies in subjects with clinically significant renal impairment suggest that plasma levels of paroxetine are elevated in such subjects. Paroxetine should therefore be used with caution and the dosage restricted to the lower end of the range in patients with clinically significant renal impairment.

Hepatic Impairment

: Pharmacokinetic studies of paroxetine in subjects with clinically significant hepatic impairment suggest that prolongation of the elimination half-life and increased plasma levels can be expected in this patient group. PAROXETINE should be used with caution and dosages restricted to the lower end of the range in patients with clinically significant hepatic impairment.

Hyponatremia

: Several cases of hyponatremia have been reported. The hyponatremia appeared to be reversible when paroxetine was discontinued. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

Abnormal Bleeding

: There have been several reports of abnormal bleeding (mostly ecchymosis) associated with paroxetine treatment, including a report of impaired platelet aggregation. While a causal relationship to paroxetine is unclear, impaired platelet aggregation may result from platelet serotonin depletion and contribute to such occurrences.

Skin and mucous membrane bleedings have been reported following treatment with paroxetine. Paroxetine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal anti-inflammatories and ASA) and in patients with a known tendency for bleeding or those with predisposing conditions.

Glaucoma

: As with other SSRIs, paroxetine infrequently causes mydriasis and should be used with caution in patients with narrow angle glaucoma.

Neuroleptic Malignant Syndrome

: As with other SSRIs, paroxetine should be used with caution in patients already receiving neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination.

Drug Interactions

Monoamine Oxidase Inhibitors

: See CONTRAINDICATIONS.

Thioridazine:

See CONTRAINDICATIONS.

Drugs Metabolized by Cytochrome P450 (CYP2D6): Like some other selective serotonin reuptake inhibitors, paroxetine inhibits the specific hepatic cytochrome P450 isozyme CYP2D6 which is responsible for the metabolism of debrisoquine and sparteine. Poor metabolizers of debrisoquine/sparteine represent approximately 5 - 10% of Caucasians. The median Cmin (ss) for paroxetine (20 mg daily) at steady state in poor metabolizers (n=8) was almost triple that reported for extensive metabolizers (n=9). Although the full clinical significance of this effect has not been established, inhibition of CYP2D6 can lead to elevated plasma levels of co-administered drugs which are metabolized by this isozyme. In two studies, daily dosing of paroxetine (20 mg qd) under steady state conditions increased the following mean pharmacokinetic parameters for a single (100 mg) dose of desipramine in extensive metabolizers: Cmax (2 fold), AUC (6 fold), and t1/2 (3-5 fold). Concomitant steady-state paroxetine treatment did not result in any further impairment of desipramine elimination in poor metabolizers. Insufficient information is available to provide recommendations on the necessary dosage adjustments for tricyclic antidepressants or paroxetine, if these drugs are to be used in combination. Plasma tricyclic antidepressant concentrations may need to be monitored in such instances. Concomitant use of PAROXETINE with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either PAROXETINE or the other drug. Drugs metabolized by cytochrome P450 CYP2D6 include certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), selective serotonin reuptake inhibitors (e.g. fluoxetine), phenothiazine neuroleptics (e.g. perphenazine), Type IC antiarrhythmics (e.g. propafenone and flecainide), and metoprolol. Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be co-administered (see CONTRAINDICATIONS). Drugs Metabolized by Cytochrome P450 (CYP3A4): An in vivo interaction study involving the co- administration under steady state conditions of paroxetine and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam and cyclosporin. Based on the assumption that the relationship between paroxetine's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity would not be expected to be of clinical significance.

Serotonergic Drugs

: As with other SSRIs, co-administration with serotonergic drugs (e.g. MAO inhibitors (see CONTRAINDICATIONS), L-tryptophan) may lead to an incidence of 5-HT associated effects (Serotonergic Syndrome; see ADVERSE REACTIONS).

CNS Drugs

: Experience in a limited number of healthy subjects has shown that paroxetine does not increase the sedation and drowsiness associated with haloperidol, amylbarbitone or oxazepam, when given in combination. Since the effects of concomitant administration of paroxetine with neuroleptics have not been studied, the use of PAROXETINE with these drugs should be approached with caution.

Food/Antacids

: The absorption and pharmacokinetics of PAROXETINE are not affected by food or antacids.

Cardiovascular Drugs

: Multiple dose treatment with paroxetine 30 mg/day has little or no effect on the steady-state pharmacokinetics of digoxin (0.25 mg qd) or propanolol (80 mg bid).

Microsomal Enzyme Inhibition/Induction

: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolizing enzymes.

Steady state levels of paroxetine (30 mg daily) were elevated by about 50% when cimetidine (300 mg tid), a known drug metabolizing enzyme inhibitor, was co-administered to steady-state. Consideration should be given to using doses of paroxetine towards the lower end of the range when co-administered with known drug metabolizing enzyme inhibitors.

Anticonvulsants

: In a limited number of patients with epilepsy on long-term treatment with anticonvulsants (carbamazepine 600-900 mg/day, n=6; phenytoin 250-400 mg/day, n=6; sodium valproate 300-2500 mg/day, n=8) the co-administration of paroxetine (30 mg/day for 10 days) had no significant effect on the plasma concentrations of these anticonvulsants. In healthy volunteers, co-administration of paroxetine with phenytoin has been associated with decreased plasma levels of paroxetine and an increased incidence of adverse experiences. However, no initial dosage adjustment of paroxetine is considered necessary when the drug is to be co- administered with known drug metabolizing enzyme inducers (e.g. carbamazepine, phenytoin, sodium valproate) and any subsequent dosage adjustment should be guided by clinical effect.

Co-administration of paroxetine with anticonvulsants may be associated with an increased incidence of adverse experiences.

Alcohol

: The concomitant use of PAROXETINE and alcohol has not been studied and is not recommended. Patients should be advised to avoid alcohol while taking PAROXETINE.

Tryptophan

can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of PAROXETINE together with tryptophan may result in adverse reactions consisting primarily of headache, nausea, sweating and dizziness as well as serotonin syndrome (see ADVERSE REACTIONS, Postmarketing Reports). Consequently, concomitant use of PAROXETINE with tryptophan is not recommended.

Chronic daily dosing with phenobarbital (100 mg qid for 14 days) decreased the systemic availability of a single 30 mg dose of paroxetine in some subjects. The AUC and t1/2 of paroxetine were reduced by an average of 25% and 38% respectively compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. No initial PAROXETINE dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Anti-cholinergic Drugs

: Paroxetine has been reported to increase the systemic bioavailability of procyclidine. Steady state plasma levels of procyclidine (5 mg daily) were elevated by about 40% when 30 mg paroxetine was co-administered to steady-state. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.

Drugs Highly Bound to Plasma Protein

: Paroxetine is highly bound to plasma protein, therefore administration of PAROXETINE to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

In a study of depressed patients stabilized on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, since there is limited experience in patients, the concurrent administration of PAROXETINE and lithium should be undertaken with caution. A multiple dose study of the interaction between paroxetine and diazepam showed no alteration in the pharmacokinetics of paroxetine that would warrant changes in the dose of paroxetine for patients receiving both drugs. The effects of paroxetine on the pharmacokinetics of diazepam were not evaluated. Sumatriptan: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and the 5HT1 agonist, sumatriptan. If concomitant treatment with sumatriptan and an SSRI (eg., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. The possibility of such interactions should also be considered if other 5HT1 agonists are to be used in combination with SSRIs.

Theophylline

: Reports of elevated theophylline levels associated with paroxetine treatment have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.

St. John's Wort

: In common with other SSRI's, pharmakodynamic interactions between paroxetine and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

PHARMACOLOGY

Animal Pharmacology

Paroxetine showed a high potency for the inhibition of 5-HT reuptake in rat hypothalamic synaptosomes (Ki=1.1 nM), but exerted relatively weak effects upon noradrenaline reuptake (Ki=350 nM). The predominant metabolites of paroxetine, a sulphate and a glucuronide conjugate, were essentially inactive as 5-HT reuptake inhibitors. Paroxetine has a low affinity for muscarinic cholinergic receptors (Ki of 89 nM for displacement of [3H]quinuclidinyl benzilate). Animal studies have indicated only weak anticholinergic properties. Radioligand binding techniques in rat brain, in vitro, have indicated that paroxetine has little affinity for a1, a2 and b-adrenoceptors, dopamine (D2), 5-HT1-like, 5-HT2 and histamine (H1) receptors at concentrations below 1 uM. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate a lack of CNS depressant and hypotensive properties. In mice, paroxetine (ED50=0.4 mg/kg p.o.) was associated with potent and prolonged potentiation of the hypermotility induced by the 5-HT precursor, 5-hydroxytryptophan. Similarly, the anticonvulsant effects of 5-hydroxytryptophan in a mouse electroshock model were potentiated by paroxetine (ED50=0.4 mg/kg p.o. ). In rats paroxetine (ED50=0.8 mg/kg p.o.) inhibited the hypermotility induced by p-chloroamphetamine, an agent which depletes neuronal 5-HT stores. Paroxetine, 1 mg/kg i.p., in conscious rats with chronically implanted cortical electrodes, produced essentially no changes in the power spectrum and frequency analysis of the EEG. Electrophysiological measures have demonstrated that paroxetine has a vigilance-increasing activity in animals. Oral doses of paroxetine 0.32 to 18 mg/kg to rats lengthened the waking period and shortened the slow-wave and paradoxical sleep periods in a dose-dependent fashion. As with other selective 5-HT uptake inhibitors, paroxetine, at a dose of 5 mg/kg i.p., causes symptoms of excessive 5-HT receptor stimulation when administered to rats previously given monoamine oxidase (MAO) inhibitors such as tranylcypromine or phenelzine, or the 5-HT precursor L-tryptophan. Behavioural and EEG studies indicate that paroxetine is weakly activating at doses above those generally required to inhibit 5-HT reuptake. The activating properties are not "amphetamine-like" in nature. In rats trained to discriminate d-amphetamine, 1 mg/kg i.p., from saline, no generalization to amphetamine was observed after administration of paroxetine (0.3, 1, 3 or 10 mg/kg i.p. ). Paroxetine caused seizures in mice at a lethal dose of 300 mg/kg p.o. At a dose of 50 mg/kg p.o., paroxetine lowered the threshold for electroshock-induced seizures in mice. Animal studies indicate that paroxetine is well tolerated by the cardiovascular system. When the cardiovascular effects of paroxetine and amitriptyline were compared in the conscious rabbit and anaesthetised cat, intravenous doses of paroxetine approximately 2 to 4 times higher (on a mg/kg basis) than those of amitriptyline were required to produce significant changes in blood pressure, heart rate and electrocardiographic parameters. Similarly, in the pentobarbital anaesthetised dog, i.v. imipramine, amitriptyline and clomipramine (in doses of 10 mg/kg) caused severe atrioventricular block and ventricular arrhythmias, while equivalent doses of paroxetine resulted in only slight prolongation of the PQ interval. In addition, low doses (0.3 to 1 mg/kg) of the tricyclic antidepressants caused marked tachycardia, whereas paroxetine in doses up to 10 mg/kg had no effect on heart rate. Studies in the spontaneous hypertensive rat indicate that, in contrast to antidepressants which inhibit the uptake of noradrenaline, paroxetine at 5 mg/kg i.v. has a much reduced propensity to inhibit the antihypertensive effect of guanethidine. 5-HT is transported into blood platelets and central neurons by a similar active uptake transporter mechanism in the cell membrane. Thus, in common with other selective 5-HT reuptake inhibitors, administration of paroxetine results in depletion of 5-HT from platelets. This has been reported after repeated daily administration of paroxetine at doses of 0.1, 1 and 10 mg/kg i.p. in mice and rats, 1 - 7.5 mg/kg p.o. in monkeys and 10 - 50 mg orally to healthy human volunteers. Similarly, whole blood 5-HT levels were shown to be depleted in depressed patients after paroxetine administration.

Human Pharmacology

Paroxetine 30 mg administered in single doses to healthy non-depressed volunteers did not impair psychomotor function which was measured by psychomotor tasks such as Morse tapping and motor manipulation, assessment of subjective perception and general assessment of arousal. Paroxetine at doses of up to 40 mg daily produces no clinically significant changes in blood pressure, heart rate or ECG after administration to healthy subjects.

TOXICOLOGY

In relation to the clinical dose, the acute LD50 of paroxetine is very high in both mice and rats (approximately 350 mg/kg). General toxicity studies have been conducted in rhesus monkeys and rats, in both of which the metabolic pathway for paroxetine is the same as in man. The no-toxic effect levels in the rhesus monkeys and rats were 4 - 10 times and 6 - 15 times the recommended range of clinical doses respectively. At higher doses (40 mg/kg for 3 months and 25 mg/kg for 12 months), lipidosis was observed in several tissues of rats (lungs, mesenteric lymph nodes, epididymides, retinal tissues - the latter by electron microscopy only). As paroxetine is a lipophilic amine with both hydrophobic and hydrophilic moieties, it may accumulate in lysosomes leading to an impairment of lipid catabolism and, hence, the accumulation of lipids within the lysosomes. It should be noted that the slight degree of lipidosis seen in the rat was restricted to doses and plasma levels much higher than those observed in man. In a clinical study investigating lamellated inclusion bodies in peripheral white blood cells during long term therapy, no difference between placebo and paroxetine could be detected. No carcinogenic potential was detected in rat (dose levels of 1, 5 and 20 mg/kg/day) and mouse (dose levels of 1, 5 and 25 mg/kg/day) life-span studies. A non dose-related increase in malignant liver cell tumours occurred in male mice at 1 and 5 mg/kg/day which was statistically significant at 5 mg/kg/day. There was no increase at 25 mg/kg/day in female mice and the incidence was within the historical control range. 5-Hydroxytryptamine and compounds modulating this amine are known to affect reproductive function in animals and at high dose levels cause marked overt toxicity. Paroxetine at 15 and 50 mg/kg (hydrochloride salt) has been shown to impair reproductive function in rats. In male rats, chronic administration of a 50 mg/kg dose has been associated with granulomatous reactions in the epididymides accompanied by atrophy and degeneration of the seminiferous tubules. There were no biologically significant effects on fertility of female rats but corpora lutea count was slightly reduced and preimplantation loss slightly increased at 50 mg/kg in association with marked maternal toxicity. Reproduction studies were performed in rats and rabbits at doses up to 42 and 5 times the maximum recommended daily human dose (60 mg) on a mg/kg basis. These are 8.3 (rat) and 1.7 (rabbit) times the maximum recommended human dose on a mg/m2 basis. These studies have revealed no evidence of teratogenic effects or of selective toxicity to the embryo. Specific studies have demonstrated that paroxetine is unlikely to possess the potential for immunotoxicity. Serum samples were obtained from depressed patients who had received 30 mg of paroxetine daily for between six and twelve months, from groups of rats on a repeat dose toxicity study in which daily doses of 1, 5 and 25 mg/kg of paroxetine were administered for 52 weeks, from guinea pigs epicutaneously exposed (topically under an occlusive patch) to paroxetine and from New Zealand White (NZW) rabbits parenterally (i.m. and s.c.) injected with paroxetine in Freund's adjuvant. In addition as a positive control, sera were obtained from NZW rabbits which had been immunized by i.m. and s.c. injections of Freund's adjuvant emulsions containing paroxetine chemically conjugated to bovine gamma globulin (BGG). Serum antibody levels were assessed by enzyme- or radio-immunoassays (ELISA or RIA). No anti-paroxetine antibody activity was detected in serum samples from patients, from rats in the toxicity study, from guinea pigs epicutaneously exposed to paroxetine, or from rabbits parenterally injected with paroxetine. Serum anti-paroxetine antibody was detected in rabbits immunized with Freund's adjuvant emulsions containing paroxetine coupled with BGG, verifying that the RIA system employed was capable of detecting antibodies directed against paroxetine. Paroxetine also did not induce contact sensitivity reactions in guinea pigs following epicutaneous exposure.

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