Medications: Paxil^® – paroxetine

INDICATION AND USES:

Paxil is indicated for:

• Major Depressive Disorder
• Obsessive Compulsive Disorder
• Panic Disorder
• Social Anxiety Disorder
• Generalized Anxiety Disorder
• Posttraumatic Stress Disorder

DOSAGE AND ADMINISTRATION

Major Depressive Disorder:

Usual Initial Dosage: PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of PAXIL in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with PAXIL should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Systematic evaluation of the efficacy of PAXIL has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.

Obsessive Compulsive Disorder:

Usual Initial Dosage: PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of PAXIL in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL in the treatment of OCD. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Panic Disorder:

Usual Initial Dosage: PAXIL should be administered as a single daily dose with or without food, usually in the morning. The target dose of PAXIL in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of PAXIL. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Social Anxiety Disorder:

Usual Initial Dosage: PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of PAXIL has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials).

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Generalized Anxiety Disorder:

Usual Initial Dosage: PAXIL should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.

Maintenance Therapy: Systematic evaluation of continuing PAXIL for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking PAXIL during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Posttraumatic Stress Disorder:

Usual Initial Dosage: PAXIL should be administered as a single daily dose with or without food, usually in the morning. The recommended starting dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of PAXIL was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at intervals of at least 1 week.

Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with PAXIL should remain on it. Although the efficacy of PAXIL beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

SIDE EFFECTS:

• Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer.
• Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.
• Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.
• Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis.
• Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia.
• Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.
• Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany.
• Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome.
• Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration.
• Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.
• Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect.
• Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.
• Postmarketing Reports: Voluntary reports of adverse events in patients taking PAXIL that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of PAXIL and phenytoin coadministration. There has been a case report of severe hypotension when PAXIL was added to chronic metoprolol treatment.

DRUG INTERACTIONS:

• Tryptophan: As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered.
• Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.
• Pimozide: Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and PAXIL is contraindicated (see CONTRAINDICATIONS).
• Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when PAXIL is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort (see WARNINGS: Serotonin Syndrome).
• The concomitant use of PAXIL with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS).
• The concomitant use of PAXIL with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan).
• Thioridazine: See CONTRAINDICATIONS and WARNINGS.
• Warfarin: (see PRECAUTIONS: Drugs That Interfere With Hemostasis).
• Triptans: (see WARNINGS: Serotonin Syndrome).
• Drugs Affecting Hepatic Metabolism: The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
• Cimetidine: When these drugs are administered concurrently, dosage adjustment of PAXIL after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied.
• Phenobarbital: No initial dosage adjustment of PAXIL is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.
• Phenytoin: No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).
• Drugs Metabolized by CYP2D6: Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with PAXIL. In 1 study, daily dosing of PAXIL (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of PAXIL with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either PAXIL or the other drug. Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, 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 coadministered (see CONTRAINDICATIONS and WARNINGS). Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Tricyclic Antidepressants [TCAs]).
• Drugs Metabolized by Cytochrome CYP3A4: An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome 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 cyclosporine. 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 is not likely to be of clinical significance.
• Tricyclic Antidepressants (TCAs): Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with PAXIL (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6).
• Drugs Highly Bound to Plasma Protein: Because paroxetine is highly bound to plasma protein, administration of PAXIL 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.
• Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
• Alcohol: Although PAXIL does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking PAXIL.
• Lithium: A multiple-dose study has shown that there is no pharmacokinetic interaction between PAXIL and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when PAXIL is coadministered with lithium.
• Digoxin: The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.
• Diazepam: Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.
• Procyclidine: Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC_{0­ 24}, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced.
• Beta-Blockers: In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports).
• Theophylline: Reports of elevated theophylline levels associated with treatment with PAXIL 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.
• Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
• Electroconvulsive Therapy (ECT): There are no clinical studies of the combined use of ECT and PAXIL