The P-I-E-N-O Parkinsn's List Drug Database
paroxetine / PaxilTM , AropaxTM
ANTIDEPRESSANT:
SSRI: LOW RISK
Description: Paroxetine is an oral antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) type, a group that includes fluoxetine and sertraline. Paroxetine is structurally distinct from tricyclic antidepressants and monoamine oxidase inhibitors. Paroxetine has no active metabolites and has the highest specificity for serotonin of all the SSRIs. It is efficacious in depression resistant to other antidepressants and in depression complicated by anxiety.¥ Paroxetine was approved by the FDA in December 1992 for the treatment of major depression. It is currently under investigation for the treatment of panic disorder and has been studied for the treatment of obsessive-compulsive disorder (OCD).
Mechanism of Action: Paroxetine potentiates serotonin (5-HT) in the CNS. Paroxetine does not affect norepinephrine as do many tricyclic antidepressants. The precise action of SSRIs is not fully understood, but it is believed that paroxetine and related agents inhibit reuptake of serotonin at the neuronal membrane. According to rat brain in vitro studies, paroxetine is several fold more potent than sertraline and significantly more potent than fluoxetine in ability to inhibit 5-HT reuptake.¥ SSRIs have less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs due to dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors. Monoamine oxidase is not inhibited by any of the SSRIs. Anticholinergic activity is virtually absent.
Pharmacokinetics: Paroxetine is administered orally and is completely absorbed. There appears to be individual patient variation in response, but steady-state concentrations are achieved in about 10 days. The onset of action, however, may require 1-4 weeks of therapy. The drug is widely distributed, including into the CNS, and it is 93-95% bound to plasma protein.
Paroxetine is extensively metabolized to several metabolites, none of which shows any appreciable pharmacological activity. Metabolism is partly achieved by cytochrome P-450 isoenzymes, predominantly 2D6. Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. Excretion is mainly renal (about 62%), mostly as metabolites and about 2% as unchanged drug. About 36% is excreted in the feces, mainly via the bile as metabolites. The elimination half-life is approximately 21 hours. The elderly or patients with renal or hepatic impairment are predisposed to increased plasma concentrations. Severe renal dysfunction increases paroxetine half-life to 55 hours while cirrhosis has been shown to prolong half-life to 30 hours.¥
CONTRAINDICATIONS/PRECAUTIONS: Paroxetine should be used with caution in patients with a history of seizure disorder, as well as in debilitated patients or those taking multiple medications, because of the possibility of drug- induced seizure. Paroxetine should be used with caution in patients with severe renal impairment because excretion of metabolites can be reduced. Lower doses or less frequent dosing may be necessary.
All effective antidepressants can transform depression into mania in predisposed individuals. The usual presentation of this switch is the sudden appearance of insomnia. The antidepressant should be held and appropriate therapy to treat the manic symptoms initiated. Therapeutic doses of lithium (and possibly carbamazepine or valproate) are effective in suppressing the switch process.
Paroxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date. Some clinicians have reported that in rare instances the induced seizure was prolonged.
All antidepressants should be used with caution in depressed patients because of the possibility of suicidal ideation. Close monitoring of the patient is essential during the initial stages of therapy. Paroxetine should be prescribed in the smallest quantity appropriate for the patient.
Paroxetine should be used with caution in patients with hepatic disease or severe heart failure because metabolism can be delayed. Either lower doses or a longer dosing interval may be necessary. Initial starting dose should be reduced to 10 mg PO once daily.
Paroxetine can cause a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) that presents as serum and urine hypoosmolarity, and hyponatremia. Elderly patients and those receiving diuretics appear to be more at risk.
Paroxetine should be used with caution in breast-feeding mothers because of the excretion of the drug into breast milk. Patients should advise their physician of their intention to breast-feed. Because of the drug's slow elimination, consideration should be given to the possible presence of the drug for a prolonged period after discontinuation of therapy.
Paroxetine should be used cautiously during pregnancy because full evaluation of its effects has not been conducted. Paroxetine is classified as FDA category B. DRUG INTERACTIONS: Paroxetine potentiates serotonin by inhibiting its neuronal reuptake. Since serotonin is deaminated by monoamine oxidase type A, administration of drugs that can inhibit this enzyme concurrently with paroxetine can lead to a serious reaction known as "serotonin syndrome." This reaction may include confusion, seizures, and severe hypertension as well as less severe symptoms. Most MAOIs are non-specific inhibitors of MAO (e.g., furazolidone, pargyline, phenelzine, tranylcypromine) and, since they affect MAO type A, should not be used with paroxetine. In addition, selegiline, although selective for MAO type B at usual doses, may inhibit MAO type A at higher doses and should also be avoided in patients receiving paroxetine. Finally, procarbazine, an antineoplastic agent, is a weak MAOI and should also be avoided. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of paroxetine therapy, or vice versa.
Paroxetine impairs metabolism of the hepatic CYP2D6 (cytochrome P- 450 isoenzyme 2D6) pathway at therapeutic doses. This action can cause substantial increases in concentrations of other antidepressants metabolized via the same pathway. Plasma concentrations of certain tricyclic antidepressants, and maprotiline and trazodone can double when used concomitantly with fluoxetine, an agent closely related to paroxetine.When certain tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine) have been used concomitantly with paroxetine, symptoms of tricyclic toxicity (such as sedation, decreased energy, lightheadedness, psychomotor retardation, xerostomia, constipation, and memory impairment) have been reported. Concomitant use of trazodone with paroxetine can lead to excessive sedation and unstable gait. The clinical need for antidepressant polypharmacy is unknown, and it should be undertaken only after careful consideration of alternatives and with careful monitoring.
Paroxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isoenzyme 2D6) pathway at therapeutic doses. This action can substantially increase serum concentrations of benzodiazepines metabolized via the same pathway. Fluoxetine, an agent related to paroxetine, has been reported to affect the clearance and plasma concentrations of alprazolam and diazepam, but fluoxetine had no effect on clonazepam or triazolam. The effects of paroxetine on these benzodiazepines are not known. Diazepam does not appear to affect the pharmacokinetics of paroxetine.
Paroxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isoenzyme 2D6) pathway at therapeutic doses. This can result in substantial increases in concentrations of antipsychotics metabolized via the same pathway. Paroxetine can increase the possible risk of adverse effects if used with haloperidol, loxapine, molindone, phenothiazines, pimozide, or thiothixene.
Paroxetine impairs metabolism of the CYP2D6 (cytochrome P-450 isoenzyme 2D6) pathway at therapeutic doses. Paroxetine should be used cautiously in patients receiving type 1C antiarrhythmics (such as propafenone, flecainide, or encainide) and quinidine. Competition for hepatic CYP2D6 (cytochrome P-450 isoenzyme 2D6) by paroxetine may potentiate the toxicity of these antiarrhythmics.
Cimetidine, which is known to inhibit cytochrome P-450 isoenzymes, exerts unpredictable effects on paroxetine pharmacokinetics. In a study of 10 healthy volunteers, there was no net change in mean paroxetine AUC, however the AUC for paroxetine was increased in 6 of these subjects. In another study of volunteers, cimetidine increased paroxetine AUC by 51%. Patients should be monitored carefully for an increased response to paroxetine if cimetidine is coadministered. The effect of paroxetine on cimetidine has not been reported, although clinicians should note that paroxetine itself is a potent inhibitor of cytochrome 2D6.
Phenobarbital, which induces many cytochrome P-450 isoenzymes, can reduce paroxetine half-life by 38%. A similar drug interaction with other barbiturates should also be expected for paroxetine. Since primidone is metabolized to phenobarbital, primidone may also affect paroxetine pharmacokinetics.
Paroxetine plasma concentrations and half-life may be reduced when phenytoin is used concurrently. Paroxetine may need to be administered in higher doses in patients receiving phenytoin. Initial studies suggest no effect of paroxetine on phenytoin serum concentrations, however, clinicians should keep in mind that paroxetine itself is a potent inhibitor of cytochrome 2D6.
Paroxetine used concomitantly with tryptophan can cause "serotonin syndrome" (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behaviors, nausea, abdominal cramps, diarrhea, palpitations, or chills). Discontinuation of tryptophan usually resolves symptoms. Since sumatriptan is also an agonist at serotonin receptors, it is theoretically possible that a similar reaction could occur if sumatriptran was administered to patients receiving this type of antidepressant.
Cyproheptadine is an antagonist of serotonin in the CNS, and this pharmacologic action opposes the pharmacologic actions of paroxetine. Clinically, cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine, an agent related to paroxetine, but more data are needed to confim a direct drug-drug interaction. Cyproheptadine should probably be avoided in patients receiving paroxetine whenever possible. Ondansetron, granisetron, and methysergide also antagonize serotonin (5-HT) receptors, although no drug-drug interactions have been reported with paroxetine.
Both paroxetine and fluoxetine have been shown to interfere with dextromethorphan metabolism leading to clinical toxicity. Dextromethorphan should be used in lower doses in patients receiving either of these antidepressant since both are potent inhibitors of cytochrome 2D6, the enzyme responsible for metabolism of dextromethorphan.
Although a study in healthy volunteers demonstrated no effect of paroxetine on carbamazepine plasma concentrations, clinicians should be aware that metabolism of carbamazepine could be impaired by the concomitant administration of paroxetine, leading to ocular changes, vertigo, or tremor. Paroxetine is a potent inhibitor of cytochrome 2D6. Carbamazepine plasma concentrations should be monitored at least weekly after the addition of paroxetine and the dose of carbamazepine adjusted to compensate for the interaction. Close monitoring should be maintained until a new steady-state has been achieved, which theoretically can require up to 4 weeks following the final paroxetine or carbamazepine dosage adjustment.
The effect of coadministering buspirone with paroxetine is unknown. However, use of buspirone with another SSRI (fluoxetine) in a patient with major depression, generalized anxiety disorder, and panic disorder was reported to have caused increased anxiety. In some patients with obsessive-compulsive disorder, fluoxetine and buspirone have been reported to improve efficacy. Until more data are available, careful monitoring should be undertaken when buspirone and paroxetine are used together.
Fluoxetine, an agent closely related to paroxetine, can increase or decrease lithium concentrations. Because paroxetine is related to fluoxetine, close monitoring of lithium concentrations is advisable if paroxetine is added to stabilized lithium therapy. A pharmacodynamic interaction between paroxetine and lithium is also possible. Administration of paroxetine to bipolar patients with inadequate lithium concentrations (<0.6 mEq/L) can predispose the bipolar patient to switch into mania.
Anticholinergic effects can be additive if procyclidine is used concurrently with paroxetine, possibly due to inhibition of procyclidine metabolism. If this occurs, dosage reduction of procyclidine should be considered.
Paroxetine may slightly decrease mean digoxin area under the curve (AUC) values. Until more clinical data is known, patients should be monitored for loss of digoxin clinical effect if paroxetine is added.
Although propranolol concentrations were not altered by the addition of paroxetine, paroxetine is known to inhibit hepatic pathways which are responsible for the metabolism of other drugs. Until more data is available, paroxetine should be used cautiously in patients receiving œ-blockers. The effect of propranolol on paroxetine concentrations was not evaluated.
ADVERSE REACTIONS: Adverse CNS effects due to paroxetine include headache, dizziness, tremor, paresthesias, hypotension, lethargy, and CNS stimulation. Headache is reported in 18%, similar incidence to placebo. Tremor causes drug discontinuation in 1.3% of patients. Some CNS effects may diminish with therapy, since they may also be associated with a depressed state. In severe cases discontinuation of the drug may be necessary. Somnolence is reported most commonly (23%), and patients should exercise caution in activities requiring mental alertness until the effects in them are known. Approximately 10% of the patients that experience somnolence (2.3% of all patients) require discontinuation of paroxetine. Dizziness and insomnia are the next most common adverse effects experienced with rates of ~13%. Insomnia requires drug discontinuation in 2% of patients. Paroxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date. Some clinicians have reported that in rare instances the induced seizure was prolonged in the presence of another SSRI (fluoxetine). To date, seizures have not been reported with paroxetine despite overdoses as high as 850 mg and concomitant ingestion of ethanol. Extrapyramidal symptoms are rare with paroxetine.
Psychiatric side effects occur in most patients receiving paroxetine and include, insomnia, somnolence, agitation, nervousness, anxiety, and confusion. All effective antidepressants can precipitate mania in predisposed individuals suffering from depression. The usual presentation of this switch is the sudden appearance of insomnia. The antidepressant should be held and appropriate therapy to treat the manic symptoms initiated. Therapeutic doses of lithium (and possibly carbamazepine or valproate) are effective in suppressing the switch process. Because of the growing evidence relating brain serotonin concentrations to eating disorders, it is possible that paroxetine may be associated with either weight gain or weight loss. On average weight loss was a minimal change of approximately 1 pound, which is not significantly different compared to placebo.
Nausea/vomiting is the most commonly (~25%) experienced adverse reaction in patients receiving paroxetine. Gastrointestinal effects usually subside after a few weeks of therapy, but nausea is the most common cause of drug discontinuation (3.4%). Xerostomia occurs in 18% of patients and is the cause of drug discontinuation in 1%. Constipation occurs in 14%. Diarrhea occurs in 12% and is the cause of drug discontinuation in 1%. Anorexia may appear in 6% of patients. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction. Other gastrointestinal adverse effects include dyspepsia (1.9%), flatulence (4%), abdominal pain (3.1%, similar to placebo), and appetite stimulation (1.4%).
Pharyngitis, respiratory disorder (appearing like an upper respiratory infection), and oropharynx disorder (mostly "lump in throat" and "tightness in throat") are reported in 2-6% of patients receiving paroxetine. The frequency of these complaints is no higher for paroxetine than for placebo.
Rash (including maculopapular rash, urticaria, erythema nodosum) is reported in 1.7% of patients receiving paroxetine. Pruritus, alopecia, xerosis, and rarely angioedema also can occur.
Palpitations (2.9%), angina (1.4%, similar to placebo), orthostatic hypotension (1.2%), and vasodilation (2.6%) are reported in 1-3% of patients receiving paroxetine. Sinus tachycardia has been reported after overdoses of paroxetine.
Musculoskeletal system disorders (myopathy, myalgia, myasthenia, and myoclonus) are reported in roughly 2% of patients receiving paroxetine.
Taste perversion or dysgeusia is reported in 2.4% of patients and visual impairment is reported in 3.6% of patients receiving paroxetine.
Polyuria and dysuria, which includes difficulty with micturation and urinary hesitancy, occur in roughly 3% of paroxetine-treated patients.
Asthenia is observed in 15% of patients receiving paroxetine, but it does not decrease with continued therapy. Diaphoresis is reported in 11% of patients and is the cause of drug discontinuation in 1.1%. Fever, back pain, and trauma are each reported in 1-2% of patients receiving paroxetine, the frequency of these complaints is no higher for paroxetine than for placebo.
Sexual dysfunction seen with paroxetine includes orgasm dysfunction (anorgasmia), impotence, ejaculation dysfunction (delayed ejaculation), and libido decrease.
PATIENT INFORMATION:
What do paroxetine tablets do?
Paroxetine (PaxilTM ) is an antidepressant. It helps lift your spirits by treating your depression. Paroxetine is one of a new group of medicines that are chemically different from other medicines used for treating depression. If other antidepressants have not helped relieve depression, paroxetine may help. Generic paroxetine tablets are not yet available.
What should my doctor, dentist, or pharmacist know before I take paroxetine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take paroxetine tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take paroxetine with or without food. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children.
Elderly patients may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If you miss a dose that you normally take at bedtime to avoid daytime drowsiness and loss of mental alertness, it may be better to miss that dose. Follow your doctor's advice on missed doses. Do not take double or extra doses.
Which other medicines may interact with paroxetine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking paroxetine?
Serious side effects with paroxetine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with paroxetine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take paroxetine?
Visit your doctor for regular checks on your progress. Continue to take your tablets even if you do not immediately feel better. It can take several weeks before you feel the full effect of paroxetine. If you get suicidal thoughts call your doctor at once.
If you have been taking paroxetine regularly for some time, do not suddenly stop taking it. You must gradually reduce the dose or your symptoms may get worse. Ask your doctor for advice. Even after you stop taking paroxetine it can still affect your body for several weeks; continue to heed all warnings.
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how paroxetine affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase or decrease the effects of paroxetine. Avoid alcoholic drinks.
Do not treat yourself for coughs, colds or allergies without asking your doctor or pharmacist for advice. Some ingredients can increase possible side effects.
Your mouth may get dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help.
If you are going to have surgery, tell your doctor or dentist that you are taking paroxetine.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Keep container tightly closed. Throw away any unused medicine after the expiration date.
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