Sandoz Paroxetine

Paroxetine Hydrochloride Film-Coated Tablets 10, 20 and 30 mg Manufacturer's Standard Anti-depressant - Antiobsessional - Antipanic - Anxiolytic Agent - Social Phobia (Social Anxiety Disorder) - Posttraumatic Stress Disorder Therapy Sandoz Canada Inc. Date of Revision: 145 Jules-Leger July 23, 2008 Boucherville, QC J4B 7K8

Control Number: 120718

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 13 DRUG INTERACTIONS. 23 DOSAGE AND ADMINISTRATION 28 OVERDOSAGE 30 SYMPTOMS OF OVERDOSAGE 31 ACTION AND CLINICAL PHARMACOLOGY 31 STORAGE AND STABILITY 34 DOSAGE FORMS, COMPOSITION AND PACKAGING 34

PART II: SCIENTIFIC INFORMATION 36

PHARMACEUTICAL INFORMATION 36 CLINICAL TRIALS 37 DETAILED PHARMACOLOGY 40 TOXICOLOGY 42 REFERENCES 45

PART III: CONSUMER INFORMATION 50

Sandoz Paroxetine

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Hypersensitivity:

Sandoz Paroxetine is contraindicated in patients who are known to be hypersensitive to the drug or any of its components. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Monoamine Oxidase Inhibitors:

In patients receiving serotonin reuptake inhibitors (SSRIs) 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 SSRI treatment and have begun treatment on a MAO inhibitor. Some cases presented with features resembling serotonin syndrome or neuroleptic malignant syndrome (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome). Therefore, Sandoz Paroxetine should not be used in combination with MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) or within a minimum of 2 weeks of terminating treatment with MAO inhibitors. Treatment with Sandoz 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 Sandoz 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 SSRIs such as paroxetine, fluoxetine and fluvoxamine, will elevate plasma levels of thioridazine. Therefore, Sandoz Paroxetine should not be used in combination with thioridazine or within a minimum of 2 weeks of terminating treatment with thioridazine. At least 2 weeks should be allowed after discontinuing Sandoz Paroxetine therapy before initiating treatment with thioridazine.

Pimozide:

The concomitant use of Sandoz Paroxetine and pimozide is contraindicated as paroxetine hydrochloride has been shown to increase plasma pimozide levels. Elevation of pimozide blood concentration may result in QT interval prolongation and severe arrhythmias including torsade de pointes (see DRUG INTERACTIONS).

WARNINGS AND PRECAUTIONS GENERAL

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 behavioral and emotional changes, including an increased risk of suicidal ideation and behavior 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.

Adult 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 behavior is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioral changes.

Discontinuation Symptoms: Patients currently taking Sandoz 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.

Discontinuation of Treatment with Sandoz Paroxetine

When discontinuing treatment, regardless of the indication for which Sandoz Paroxetine is being prescribed, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, sleep disturbances including abnormal dreams, sensory disturbances (including paresthesias electric shock sensations and tinnitus), agitation, anxiety, headache, tremor, confusion, diarrhea, nausea, vomiting and sweating or other symptoms which may be of clinical significance [see ADVERSE REACTIONS, Adverse Events following Discontinuation of Treatment (or Dose Reduction), Post-marketing)]. 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).

Paroxetine Treatment during Pregnancy Effects on Newborns

Epidemiological studies of pregnancy outcomes following maternal exposure to anti- depressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. If a patient becomes pregnant while taking Sandoz Paroxetine, consideration should be given to switching to other treatment options. Treatment with Sandoz Paroxetine should only be continued for an individual pregnant patient if the potential benefits outweigh the potential risks. Initiation of paroxetine, for women who intend to become pregnant, or are in their first trimester of pregnancy, should be considered only after other treatment options have been evaluated (see WARNINGS AND PRECAUTIONS, SPECIAL POPULATIONS). Post-marketing reports indicate that some neonates exposed to paroxetine hydrochloride, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with Sandoz Paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see WARNINGS AND PRECAUTIONS, SPECIAL POPULATIONS, DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS, Treatment of Pregnant Women during the Third Trimester).

Psychomotor Impairment

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 Sandoz Paroxetine does not affect them adversely.

The following additional precautions are listed alphabetically. CARCINOGENESIS AND MUTAGENESIS

See TOXICOLOGY for animal data.

CARDIOVASCULAR

Paroxetine hydrochloride 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.

CONCOMITANT ILLNESSES

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

DEPENDENCE LIABILITY

Paroxetine hydrochloride has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Sandoz Paroxetine.

ENDOCRINE AND METABOLISM

Serum Cholesterol Elevation:

Several public domain studies have shown increased LDL-cholesterol levels of ~10% in volunteers and patients taking paroxetine for 8 to

12 weeks, which generally normalized after paroxetine discontinuation. In addition, of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, total serum levels of cholesterol showed a mean increase of ~1.5 mg/dL in n=653 paroxetine-treated patients, compared to a mean decrease of ~5.0 mg/dL in placebo-treated patients (n=379). Increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of placebo-treated patients (see MONITORING AND LABORATORY TESTS, Serum Cholesterol Elevation). These data should be taken into consideration when treating patients with underlying cardiac risk factors.

HEMATOLOGIC

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 (including upper gastrointestinal bleeding) 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.

HEPATIC/BILIARY/PANCREATIC

Hepatic Impairment:

Pharmacokinetic studies of paroxetine hydrochloride 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. Sandoz Paroxetine should be used with caution and dosages restricted to the lower end of the range in patients with clinically significant hepatic impairment (see DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS, ACTIONS AND CLINICAL PHARMACOLOGY, Hepatic Insufficiency).

NEUROLOGIC

Epilepsy:

As with other anti-depressants, Sandoz 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 hydrochloride. 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.

Serotonin Syndrome/Neuroleptic Malignant Syndrome:

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of paroxetine, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs. As these syndromes may result in potentially

life-threatening conditions, treatment with Sandoz Paroxetine should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome Sandoz Paroxetine should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium, tramadol, St. John's Wort, most tricyclic anti-depressants) or neuroleptics/antipsychotics (see CONTRAINDICATIONS and DRUG INTERACTIONS).

OPHTHALMOLOGIC

Glaucoma:

As with other SSRIs, paroxetine hydrochloride can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.

PSYCHIATRIC

Suicide:

The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking anti-depressant medications. Notwithstanding, 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

Sandoz 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 AND PRECAUTIONS, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

Activation of Mania/Hypomania:

During clinical testing in a patient population comprised primarily of unipolar depressed patients, approximately 1% of paroxetine hydrochloride treated patients experienced manic reactions. When bipolar patients were considered as a subgroup the incidence of mania was 2%. As with all drugs effective in the treatment of depression, Sandoz Paroxetine should be used with caution in patients with a history of mania.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with anti-depressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.

Electroconvulsive Therapy (ECT):

The efficacy and safety of the concurrent use of paroxetine hydrochloride and ECT have not been studied.

RENAL

Hyponatremia:

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

Renal Impairment: Since paroxetine hydrochloride 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 hydrochloride should therefore be used with caution and the dosage restricted to the lower end of the range in patients with clinically significant renal impairment (See DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS, ACTIONS AND CLINICAL PHARMACOLOGY, Renal Insufficiency).

SPECIAL POPULATIONS

Pregnant Women and Newborns

Risk of Cardiovascular Malformations Following First Trimester Exposure to SSRIs:

Epidemiological studies of pregnancy outcomes following maternal exposure to anti-depressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is approximately 1/50 (2%), compared with an expected rate for such defects of approximately 1/100 (1%) infants in the general population. In general, septal defects range from those that are symptomatic and may require surgery, to those that are asymptomatic and may resolve spontaneously. Information about the severity of the septal defects reported in the studies is not available.

While on Sandoz Paroxetine: Pregnancy, or Intent to Become Pregnant:

If a patient becomes pregnant while taking Sandoz Paroxetine, or intends to become pregnant, she should be informed of the current estimate of increased risk to the fetus with Sandoz Paroxetine over other anti-depressants. Examinations of additional databases, as well as updated analyses, may result in changes to the current risk estimates. Consideration should be given to switching to other treatment options, including another anti-depressant or non-pharmaceutical treatment such as cognitive behavioral therapy. Treatment with Sandoz Paroxetine should only be continued for an individual patient, if the potential benefits outweigh the potential risks. Due to the potential for discontinuation symptoms, if a decision is taken to discontinue Sandoz Paroxetine treatment, a gradual reduction in the dose rather than an abrupt cessation is recommended (see WARNINGS AND PRECAUTIONS, Discontinuation of Treatment With Sandoz Paroxetine, ADVERSE REACTIONS, Adverse Reactions Following Discontinuation of Treatment, and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment).

Initiation of Paroxetine:

For women who intend to become pregnant, or are in their first trimester of pregnancy, initiation of paroxetine should be considered only after other treatment options have been evaluated.

Complications Following Late Third Trimester Exposure to SSRIs:

Post-marketing reports indicate that some neonates exposed to paroxetine hydrochloride, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer anti-depressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS AND PRECAUTIONS, Neurologic-Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with Sandoz Paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS, Treatment of Pregnant Women during the Third Trimester).

Risk of PPHN and Exposure to SSRIs (including paroxetine):

In one epidemiological case-control study on persistent pulmonary hypertension (PPHN) with n=377 infants with PPHN and n=836 matched control infants, PPHN was six times more common in babies whose mothers took an SSRI anti-depressant after the 20th week of pregnancy compared to babies whose mothers did not take an anti-depressant. The study was too small to determine relative risks among the specific SSRIs. This information is considered to be preliminary at this time. The absolute risk of PPHN in the general population is reported to be 1-2 per 1 000 (see ADVERSE REACTIONS, Post-market Adverse Drug Reactions).

Nursing Women

The concentrations of paroxetine detected in the breast milk of lactating women are similar to those in the mother's 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.

Pediatrics (<18 years of age)

Sandoz Paroxetine is not indicated for use in patients below the age of 18 years (

see

WARNINGS AND PRECAUTIONS, Potential Association with Behavioral and Emotional Changes, Including Self Harm). See also INDICATIONS, Pediatrics, DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS, Children). Controlled clinical studies in depression failed to demonstrate efficacy and do not support the use of paroxetine in the treatment of children under the age of 18 years with depression. Moreover, a higher incidence of adverse events related to behavioral and emotional changes, including self-harm, was reported with paroxetine treatment compared to placebo during controlled clinical trials in depression, OCD and social anxiety disorder (see ADVERSE DRUG REACTIONS, CLINICAL TRIAL ADVERSE DRUG REACTIONS, Pediatrics).

Geriatrics (>=65 years of age)

Administration of paroxetine hydrochloride to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adults. (See ACTION AND CLINICAL PHARMACOLOGY). Elderly patients should be initiated and maintained at the lowest daily dose of paroxetine which is associated with clinical efficacy (see DOSAGE AND ADMINISTRATION). Evaluation of approximately 800 elderly patients (>=65 years) treated with paroxetine hydrochloride (10-40 mg daily) in worldwide pre-marketing clinical trials revealed no unusual pattern of adverse events relative to the clinical experience in younger patients. However, it is not possible to rule out potential age-related differences in safety and effectiveness during chronic use, particularly in elderly patients who have concomitant systemic illnesses or who are receiving concomitant drugs.

MONITORING AND LABORATORY TESTS

Serum Cholesterol Elevation:

Of the patients in placebo-controlled clinical trials for whom baseline and on-treatment measurements were taken, increases from baseline of 45 mg/dL or greater were recorded in 6.6% of paroxetine-treated patients compared to 2.6% of

placebo-treated patients (see ADVERSE REACTIONS, Laboratory Changes - Cholesterol and WARNINGS AND PRECAUTIONS, ENDOCRINE AND METABOLISM). These data should be taken into consideration when treating patients with underlying cardiac risk factors.

DRUG INTERACTIONS

Serious Drug Interactions

Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS

Thioridazine: See CONTRAINDICATIONS

Pimozide: See CONTRAINDICATIONS

OVERVIEW

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 hydrochloride (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. Consideration should be given to decreasing the dose of the CYP2D6 metabolized drug or paroxetine and/or monitoring of drug plasma levels, especially when paroxetine hydrochloride is co-administered with drugs with a narrow therapeutic index. Paroxetine hydrochloride co-administration has been associated with elevated levels of the anticholinergic procyclidine, certain neuroleptics/antipsychotics (e.g. perphenazine, risperidone), tricyclic anti-depressants (e.g. desipramine), atomoxetine, type 1C antiarrhythmics (e.g. propafenone), and theophylline. Co-administration of phenobarbitol or phenytoin with paroxetine hydrochloride has been associated with decreased levels of Paroxetine. When co-administered with cimetidine, paroxetine hydrochloride levels were elevated. The concomitant use of paroxetine hydrochloride and alcohol has not been studied.

DRUG-DRUG INTERACTIONS

Monoamine Oxidase Inhibitors:

Combined use of paroxetine hydrochloride and monoamine oxidase inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Serotonin

Syndrome/Neuroleptic Malignant Syndrome).

Thioridazine:

Combined use of paroxetine hydrochloride and thioridazine is contraindicated due to a potential for elevated thioridazine plasma levels. Thioridazine treatment alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death (see CONTRAINDICATIONS).

Pimozide: In an open-label study of healthy volunteers, co-administration of a single dose of 2 mg pimozide, under steady-state conditions of paroxetine hydrochloride (titrated to 60 mg daily) was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. This is likely explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide, and its known ability to prolong the QT interval, and produce severe cardiac arrhythmias including torsade de pointes, concomitant use of pimozide and paroxetine hydrochloride is contraindicated (see CONTRAINDICATIONS). Drugs Metabolized by Cytochrome P450 (CYP2D6): In two studies, daily dosing of paroxetine hydrochloride (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 hydrochloride 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 anti-depressants or paroxetine hydrochloride, if these drugs are to be used in combination. Plasma tricyclic anti- depressant concentrations may need to be monitored in such instances. Concomitant use of paroxetine hydrochloride with other drugs metabolized by CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine hydrochloride or the other drug. Drugs metabolized by CYP2D6 include certain tricyclic anti-depressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), selective serotonin reuptake inhibitors (e.g. fluoxetine), phenothiazine neuroleptics (e.g. perphenazine), risperidone, atomoxetine, 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 hydrochloride and thioridazine should not be co-administered (see CONTRAINDICATIONS). Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy). Drugs Metabolized by Cytochrome P450 (CYP3A4): An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine hydrochloride and terfenadine, a substrate for CYP3A4, revealed no effect of paroxetine hydrochloride 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.

Microsomal Enzyme Inhibition/Induction:

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

Drugs Highly Bound to Plasma Protein:

Paroxetine is highly bound to plasma protein, therefore administration of paroxetine hydrochloride 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.

Alcohol:

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

Anti-cholinergic Drugs:

Paroxetine hydrochloride has been reported to increase significantly 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.

Antiretroviral

: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine (by ~60% in one study). Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Phenobarbital:

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 hydrochloride were reduced by an average of 25% and 38% respectively compared to paroxetine hydrochloride administered alone. The effect of paroxetine hydrochloride on phenobarbital pharmacokinetics was not studied. No initial paroxetine hydrochloride dosage adjustment is considered necessary when co-administered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

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 hydrochloride (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 hydrochloride 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 hydrochloride with anticonvulsants may be associated with an increased incidence of adverse experiences.

Antipsychotic Drugs/Neuroleptic Malignant Syndrome:

As with other SSRIs, paroxetine should be used with caution in patients already receiving antipsychotics/ neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome cases have been reported with this combination (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Serotonergic Drugs:

Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is co-administered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol, or St. John's Wort (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome). Concomitant use of Sandoz Paroxetine and MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated (see CONTRAINDICATIONS).

Lithium:

In a study of depressed patients stabilized on lithium, no pharmacokinetic interaction between paroxetine and lithium was observed. However, due to the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is co-administered with lithium.

Triptans: There have been rare post-marketing 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 triptan and an SSRI (e.g. 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 (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

Tryptophan

: Tryptophan can be metabolized to serotonin. As with other serotonin reuptake inhibitors, the use of paroxetine hydrochloride together with tryptophan may result in adverse reactions consisting primarily of headache, nausea, sweating and dizziness as well as serotonin syndrome. Consequently, concomitant use of paroxetine hydrochloride with tryptophan is not recommended (see WARNINGS AND PRECAUTIONS, Serotonin Syndrome/Neuroleptic Malignant Syndrome).

CNS Drugs:

Experience in a limited number of healthy subjects has shown that paroxetine hydrochloride 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 hydrochloride with neuroleptics have not been studied, the use of paroxetine hydrochloride with these drugs should be approached with caution.

Diazepam:

A multiple dose study of the interaction between paroxetine hydrochloride and diazepam showed no alteration in the pharmacokinetics of paroxetine hydrochloride that would warrant changes in the dose of paroxetine hydrochloride for patients receiving both drugs. The effects of paroxetine hydrochloride on the pharmacokinetics of diazepam were not evaluated.

Cardiovascular Drugs:

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

Theophylline:

Reports of elevated theophylline levels associated with paroxetine hydrochloride 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.

Cimetidine:

Steady-state levels of paroxetine hydrochloride (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 hydrochloride towards the lower end of the range when co-administered with known drug metabolizing enzyme inhibitors.

DRUG-FOOD INTERACTIONS

The absorption and pharmacokinetics of paroxetine hydrochloride are not affected by food or antacids.

DRUG-HERB INTERACTIONS

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.

DRUG-LABORATORY INTERACTIONS

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION DOSING CONSIDERATIONS

General

Sandoz Paroxetine is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

Lower initial doses of Sandoz Paroxetine are recommended for elderly and debilitated patients, and patients with renal or hepatic impairment (see DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS). Sandoz Paroxetine should be administered once daily in the morning and may be taken with or without food. The tablet should be swallowed rather than chewed.

Dose Adjustments:

Based on pharmacokinetic parameters, steady-state paroxetine plasma levels are achieved over a 7-14 day interval. Hence, dosage adjustments in 10 mg increments should be made at 1-2 week intervals or according to clinician judgment.

Maintenance:

During long-term therapy for any indication, the dosage should be maintained at the lowest effective level.

There is no body of evidence available to answer the question of how long a patient should continue to be treated with paroxetine hydrochloride. It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Whether the dose of an anti-depressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of paroxetine hydrochloride has shown that efficacy is maintained for at least 6 months with doses that averaged about 30 mg (See CLINICAL TRIALS, DEPRESSION).

Discontinuation of Treatment:

Symptoms associated with the discontinuation of paroxetine hydrochloride have been reported in clinical trials and post-marketing. Patients should be monitored for these and other symptoms when discontinuing treatment, regardless of the indication for which Sandoz Paroxetine is being prescribed. (See WARNINGS AND PRECAUTIONS, Discontinuation of Treatment with Sandoz Paroxetine and ADVERSE REACTIONS, Adverse Reactions Following Discontinuation of Treatment).

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).

ADULTS

Depression

Usual Adult Dose:

The administration of Sandoz Paroxetine should be initiated at 20 mg daily. For most patients, 20 mg daily will also be the optimum dose. The therapeutic response may be delayed until the third or fourth week of treatment.

Dose Range:

For those patients who do not respond adequately to the 20 mg daily dose, a gradual increase in dosage up to 40 mg daily may be considered. The maximum recommended daily dose is 50 mg.

Obsessive-Compulsive Disorder

Usual Adult Dose:

The administration of Sandoz Paroxetine should be initiated at 20 mg/day. The recommended dose of Sandoz Paroxetine in the treatment of OCD is 40 mg daily.

Dose Range:

For those patients who do not respond adequately to the 40 mg daily dose, a gradual increase in dosage may be considered. The maximum recommended daily dose is 60 mg.

Panic Disorder

Usual Adult Dose:

The recommended starting dose of Sandoz Paroxetine in the treatment of panic disorder is 10 mg/day. The recommended dose of Sandoz Paroxetine in the treatment of panic disorder is 40 mg daily.

Dose Range:

For those patients who do not respond adequately to the 40 mg daily dose, a

gradual increase in dosage may be considered. The maximum recommended daily dose is 60 mg.

Social Phobia (Social Anxiety Disorder)

Usual Adult Dose:

The recommended initial dosage is 20 mg/day. No clear dose- relationship has been demonstrated over a 20 to 60 mg/day dose range.

Dose Range

: Some patients not responding adequately to a 20 mg dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Generalized Anxiety Disorder

Usual Adult Dose:

The recommended initial dosage is 20 mg/day.

Dose Range:

Some patients not responding adequately to a 20 mg dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

Posttraumatic Stress Disorder

Usual Adult Dose:

The recommended starting dosage is 20 mg/day.

Dose Range:

Some patients not responding adequately to a 20 mg/day dosage may benefit from gradual dosage increases, in 10 mg/day increments, up to a maximum of 50 mg/day.

SPECIAL PATIENT POPULATIONS

Treatment of Pregnant Women

Epidemiological studies of pregnancy outcomes following maternal exposure to anti-depressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. If a patient becomes pregnant while taking sandoz Paroxetine, she should be informed of the current estimate of risk to the fetus (see WARNINGS AND PRECAUTIONS, SPECIAL POPULATIONS) and consideration should be given to switching to other treatment options. Treatment with Sandoz Paroxetine should only be continued for an individual patient, if the potential benefits outweigh the potential risks. For women who intend to become pregnant, or are in their first trimester of pregnancy, initiation of paroxetine should be considered only after other treatment options have been evaluated (see WARNINGS AND PRECAUTIONS, SPECIAL POPULATIONS for more details). Post-marketing reports indicate that some neonates exposed to paroxetine hydrochloride, SSRIs, or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS AND PRECAUTIONS, SPECIAL POPULATIONS). When treating pregnant women with Sandoz Paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering paroxetine hydrochloride in the third trimester.

Geriatrics:

(>65 years): Administration of paroxetine hydrochloride to the elderly is associated with increased plasma levels and prolongation of the elimination half-life relative to younger adults. (See ACTION AND CLINICAL PHARMACOLOGY). The recommended initial dose is 10 mg/day for elderly and/or debilitated patients. The dose may be increased if indicated up to a maximum of 40 mg daily.

Pediatrics: Sandoz Paroxetine is not indicated for use in children under 18 years of age (see INDICATIONS AND CLINICAL USE and WARNINGS AND PRECAUTIONS, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

Renal/Hepatic Impairment:

Sandoz Paroxetine should be used with caution in patients with renal or hepatic impairment. The recommended initial dose is 10 mg/day in patients with clinically significant renal or hepatic impairment. A maximum dose of 40 mg should not be exceeded (See WARNINGS AND PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY).

OVERDOSAGE

The largest known ingestion from which a patient has recovered is 2000 mg. The smallest known dose of paroxetine alone associated with a fatal outcome is approximately 400 mg.

SYMPTOMS OF OVERDOSAGE

The most commonly reported adverse events subsequent to paroxetine-only overdose include: Some of these symptoms may also be seen with clinical use.

somnolence, nausea, tremor, dizziness, vomiting, diarrhea, agitation, aggression, anxiety, confused state, headache, fatigue, insomnia, tachycardia, hyperhydrosis, mydriasis, convulsion, paraethesia, serotonin syndrome, fever, blood pressure changes, involuntary muscle contraction and loss of consciousness. It should be noted that in some cases, patients may have consumed alcohol in addition to taking an overdose of paroxetine.

Events such as coma and ECG changes have also been reported.

TREATMENT OF OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Center. No specific antidote is known. Treatment should consist of those general measures employed in the management of overdose with any anti-depressant. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal effectively prevents gastrointestinal absorption of paroxetine, and should be considered as the primary means to reduce paroxetine exposure. It is most effective when administered within one hour of ingestion; usual dose is 25 to 100 grams in adults as an aqueous slurry. During the first 24 hours after ingestion of the overdose, 20 to 30 grams of activated charcoal may be administered every 4 to 6 hours. Due to the large volume of distribution of paroxetine, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. Supportive care with frequent monitoring of vital signs and careful observation is indicated. An ECG should be taken and monitoring of cardiac function instituted if there is any evidence of abnormality. In managing overdosage, consider the possibility of multiple drug involvement. A specific caution involves patients taking or recently having taken Sandoz Paroxetine who might ingest by accident or intent excessive quantities of a tricyclic anti-depressant. In such a case, accumulation of the parent tricyclic and its active metabolite may increase the possibility of clinically significant sequel and extend the time needed for close medical observation.

ACTION AND CLINICAL PHARMACOLOGY MECHANISM OF ACTION

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 anti-depressant 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 anti-depressants. 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.

PHARMACOKINETICS

No clear dose relationship has been demonstrated for the anti-depressant 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.

Absorption:

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.

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. 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 4). Peak plasma levels generally occurred within 3 to 7 hours.

Distribution:

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.

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.

Metabolism:

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 (2D6). 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 DRUG INTERACTIONS). 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.

Elimination:

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.

Approximately 64% of an administered dose of paroxetine is eliminated by the kidneys and 36% in the feces. Less than 2% of the dose is recovered in the form of the parent compound.

SPECIAL POPULATIONS AND CONDITIONS

Geriatrics:

In elderly subjects, increased steady-state plasma concentrations and prolongation of the elimination half-life were observed relative to younger adult controls (Table 4). Elderly patients should, therefore, be initiated and maintained at the lowest daily dosage of paroxetine which is associated with clinical efficacy (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: 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 4). 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, SPECIAL PATIENT POPULATIONS). Renal Insufficiency: 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 5). As multiple dose pharmacokinetic studies have not been performed in patients with renal disease, paroxetine should be used with caution in such patients (see DOSAGE AND ADMINISTRATION, SPECIAL PATIENT POPULATIONS).

TABLE 4 Steady-State Pharmacokinetics of Paroxetine After Doses of 20 mg Daily (Mean and Range)

*Galactose elimination capacity 30-70% of normal.

A wide range of interindividual variation is observed for the pharmacokinetic parameters.

TABLE 5 Pharmacokinetics of Paroxetine After a Single 30 mg Dose in Normal Subjects and Those with Renal Impairment

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

AUC[?] = Area under the plasma concentration time curve at infinity T1/2 = terminal elimination half-life

STORAGE AND STABILITY

Store between 15 and 30degC

DOSAGE FORMS, COMPOSITION AND PACKAGING

Sandoz Paroxetine (paroxetine hydrochloride) is available as film-coated, tablets containing paroxetine hydrochloride equivalent to 10 mg (yellow tablets), 20 mg (pink tablets), 30 mg (blue tablets), paroxetine free base. The 10 mg tablets are engraved "10"on one side and "S" on the other side, the 20 mg tablets are engraved "20"on one side and "S" on the other side, and the 30 mg tablets are engraved "30"on one side. and "S" on the other side The 10 and 20mg tablets are scored. Available in package sizes of: 10 mg - Blisters of 30's and Bottles of 100's 20 mg - Blisters of 30's and Bottles of 100's 30 mg - Blisters of 30's and Bottles of 100's

COMPOSITION

Paroxetine hydrochloride, microcrystalline cellulose, mannitol, copovidone, sodium starch glycolate, silica colloidal anhydrous, magnesium stearate, hypermellose, talc, titanium dioxide, lemon yellow #10 (10mg only) sunset yellow # 6 (10mg only), allura red lake # 40 (20 and 30 mg), brilliant blue lake (20 and 30 mg), indigotine lake (20 and 30 mg).