1. PAXIL HISTORY

How was Paxil discovered?
Paxil was introduced into the U.S. market in 1992 by SmithKline Beecham, now known as Glaxo SmithKline Corporation and has become one of the best-selling drugs in the country.

GlaxoSmithKline (GSK) is a world leading research-based pharmaceutical company with a powerful combination of skills and resources that provides a platform for delivering strong growth in today's rapidly changing healthcare environment.

GSK's mission is to improve the quality of human life by enabling people to do more, feel better and live longer.

Headquartered in the UK and with operations based in the US, the new company is one of the industry leaders, with an estimated seven per cent of the world's pharmaceutical market.

GSK also has leadership in four major therapeutic areas - anti-infectives, central nervous system (CNS), respiratory and gastro-intestinal/metabolic. In addition, it is a leader in the important area of vaccines and has a growing portfolio of oncology products.

Note: World-drugs.net sells generic version of Paxil

2. PAXIL FACTS

Paxil is doctor prescribed medication that has been approved for use in the United States to treat depression, panic disorder, social phobia, and obsessive-compulsive disorder. Patients can usually detect effects of Paxil within one to four weeks.

Paxil is a drug known as an SSRI (selective serotonin reuptake inhibitor). "SSRI" stands for selective serotonin reuptake inhibitor. Serotonin is one of hundreds of chemicals that affect brain function. It is not known how SSRIs really work, but because it was once thought that depressed people have low serotonin levels, it was thought that increasing the levels of serotonin may relieve a depressed condition. Serotonin has long been associated with violence and suicide, leaving SSRIs questionable to how they really work.

3. ABOUT PAXIL MEDICATION

What is depression?
Depression is a medical illness, like diabetes or high blood pressure. People don't choose to be depressed. It's not because they're weak or "crazy." Depression affects more than 17 million people in the United States each year. It's twice as common in women as in men. Symptoms of depression include the following:

• Feeling sad most of the day, nearly every day, for 2 weeks or longer
• Loss of interest in things you used to enjoy
• Lack of energy
• Sleep and appetite disturbances
• Weight changes
• Feelings of hopelessness, helplessness and worthlessness
• Not being able to make decisions
• Thoughts of death and suicide

What causes depression?
The exact cause of depression is not known. Doctors think it may be caused by a chemical imbalance in the brain. The imbalance could be caused by your genes or by events in your life. Sometimes there aren't enough chemical messengers (called neurotransmitters) in the brain. Two primary messengers, called serotonin (say "seer-o-tone-in") and norepinephrine (say "nor-ep-in-ef-rin"), are responsible for your moods (how you feel).

Symptoms of Depression You feel miserable and sad. You feel exhausted a lot of the time with no energy. You feel as if even the smallest tasks are sometimes impossible. You seldom enjoy the things that you used to enjoy-you may be off sex or food or may 'comfort eat' to excess. You feel very anxious sometimes. You don't want to see people or are scared to be left alone. Social activity may feel hard or impossible. You find it difficult to think clearly You feel like a failure and/or feel guilty a lot of the time. You feel a burden to others. You sometimes feel that life isn't worth living. You can see no future. There is a loss of hope. You feel all you've ever done is make mistakes and that's all that you ever will do. You feel irritable or angry more than usual. You feel you have no confidence. You spend a lot of time thinking about what has gone wrong, what will go wrong or what is wrong about yourself as a person. You may also feel guilty sometimes about being critical of others (or even thinking critically about them). You feel that life is unfair. You have difficulty sleeping or wake up very early in the morning and can't sleep again. You seem to dream all night long and sometimes have disturbing dreams. You feel that life has/is 'passing you by.' You may have physical aches and pains, which appear to have no physical cause, such as back pain. Symptoms of depression

What are antidepressants?
Antidepressants are medicines used to help people who have depression. Most people with depression get better with treatment with antidepressants.

How do antidepressants work?
Most antidepressants are believed to work by slowing the removal of certain chemicals from the brain. These chemicals are called neurotransmitters. Neurotransmitters are needed for normal brain function. Antidepressants help people with depression by making these natural chemicals more available to the brain.

How long will you have to take an antidepressant?
Antidepressants are typically taken for at least 4 to 6 months. In some cases, patients and their doctors may decide that antidepressants are needed for a longer time.

What are the different kinds of antidepressants?
Antidepressants are put into groups based on which chemicals in the brain they affect. There are many different kinds of antidepressants, including:

Selective serotonin reuptake inhibitors (SSRIs)

• citalopram
• escitalopram
• fluoxetine
• paroxetine
• sertraline

These medicines tend to have fewer side effects than other antidepressants. Some of the side effects that can be caused by SSRIs include dry mouth, nausea, nervousness, insomnia, sexual problems and headache.

Tricyclics

• amitriptyline
• desipramine
• imipramine
• nortriptyline

Common side effects caused by these medicines include dry mouth, blurred vision, constipation, difficulty urinating, worsening of glaucoma, impaired thinking and tiredness. These antidepressants can also affect a person's blood pressure and heart rate.

Serotonin and norepinephrine reuptake inhibitors (SNRIs)

• venlafaxine
• duloxetine

Some common side effects caused by these medicines include nausea and loss of appetite, anxiety and nervousness, headache, insomnia and tiredness. Dry mouth, constipation, weight loss, sexual problems, increased heart rate and increased cholesterol levels can also occur.

Norepinephrine and dopamine reuptake inhibitors (NDRIs)

• bupropion

Some of the common side effects in people taking NDRIs include agitation, nausea, headache, loss of appetite and insomnia. It can also cause increase blood pressure in some people.

Combined reuptake inhibitors and receptor blockers

• trazodone
• nefazodone
• maprotiline
• mirtazpine

Common side effects of these medicines are drowsiness, dry mouth, nausea and dizziness. If you have liver problems, you should not take nefazodone. If you have seizures, you should not take maprotiline.

Monamine oxidase inhibitors (MAOIs)

• isocarboxazid
• phenelzine
• tranlcypromine
• MAOIs are used less commonly than the other antidepressants. They can have serious side effects, including weakness, dizziness, headaches and trembling. Taking an MAOI antidepressant while you're taking another antidepressant or certain over-the-counter medicines for colds and flu can cause a dangerous reaction. Your doctor will also tell you what foods and alcoholic beverages you should avoid while you are taking an MAOI. You should not take an MAOI unless you clearly understand what medications and foods to avoid. If you are taking an MAOI and your doctor wants you to start taking one of the other antidepressants, he or she will have you stop taking the MAOI for a while before you start the new medicine. This gives the MAOI time to clear out of your body.

How will my doctor choose an antidepressant for me?
Your doctor will probably think about the following 10 points when choosing an antidepressant medicine for you:

• If you were depressed before and a certain antidepressant worked well, that antidepressant might be the right choice of medicine for you again.
• If any of your brothers or sisters, parents, uncles or aunts had depression and a certain antidepressant worked well for them, that medicine might work for you too.
• The choice of an antidepressant depends on your health. If a certain antidepressant would have a bad effect on a health problem you have, that medicine wouldn't be the right choice for you.
• Antidepressants may cause side effects. The right medicine for you may be the one that gives you the fewest side effects.
• The choice of an antidepressant depends on how often you have to take it. The less often you have to take the medicine, the easier it is for you to take all the doses you need to treat your depression.
• Some antidepressants cost more than others. Your doctor will choose an antidepressant that works for you and that you can afford.
• Your doctor will want to choose a medicine he or she has experience prescribing.
• Your doctor will choose an antidepressant that will help you with symptoms like sleeplessness, anxiety and lack of energy.
• If you're taking other medicines, your doctor will consider how an antidepressant will work with these other medicines.
• Some antidepressants don't work well with certain foods. If your doctor gives you one of these antidepressants, he or she will let you know which foods you should stop eating.
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Will antidepressants affect my other medicines?
Antidepressants can have an effect on many other medicines. If you're going to take an antidepressant, tell your doctor about all the other medicines you take, including over-the-counter medicines and herbal health products (such as St. John's wort). Ask your doctor and pharmacist if any of your regular medicines can cause problems when combined with an antidepressant.

4. PAXIL EFFECTIVENESS

When is Paxil best taken?
Paxil (Paroxetine hydrochloride) is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n=15) received 30 mg tablets daily for 30 days, steady-state Paxil concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C max, T max, C min and T 1/2 were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%) and 21.0 hr. (CV 32%), respectively. The steady-state C max and C min values were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUC 0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that one of the enzymes that metabolizes Paxil is readily saturable.

In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 to 40 mg daily for the elderly and 20 to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C min values after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled.

The effects of food on the bioavailability of Paxil were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the C max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.

Paxil is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of Paxil is accomplished in part by cytochrome P 450 IID 6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of Paxil kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in Paxil metabolism also suggests potential drug-drug interactions.

Approximately 64% of a 30 mg oral solution dose of Paxil was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.

Distribution : Paxil distributes throughout the body, including the CNS, with only 1% remaining in the plasma.

Protein Binding: Approximately 95% and 93% of Paxil is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, Paxil concentrations would normally be less than 400 ng/mL. Paxil does not alter the in vitro protein binding of phenytoin or warfarin.

5. PAXIL EFFECTS ON SPECIAL POPULATION

How do different people react to Paxil?
Elderly Patients : In a multiple-dose study in the elderly at daily Paxil doses of 20, 30 and 40 mg, C min concentrations were about 70% to 80% greater than the respective C min concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced.

Nursing Mothers
Like many other drugs, Paxil is secreted in human milk, and caution should be exercised when Paxil (paroxetine hydrochloride) is administered to a nursing woman.

Pediatric Use
Safety and effectiveness in the pediatric population have not been established.

Geriatric Use
In worldwide premarketing Paxil clinical trials, 17% of Paxil-treated patients (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients.

6. PAXIL EFFECTS ON MEDICAL CONDITIONS

How does Paxil affect your existing condition/ailment?
Renal and Liver Disease : Increased plasma concentrations of Paxil occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, C max).

The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and upward titration, if necessary, should be at increased intervals.

7. OTHER/ALTERNATE USES OF PAXIL

What else does Paxil treat?
Paxil is indicated only for the management of depression, obsessive-compulsive disorders, panic disorders, and premenstrual dysphoric disorder.

8. ADVERSE/SIDE EFFECTS of PAXIL

What are the side effects of Paxil?
Twenty percent (1,199/6,145) of Paxil patients in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735) and 11.7% (79/676) of Paxil patients in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD and PTSD, respectively, discontinued treatment due to an adverse event. The most common events associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for Paxil compared to placebo) included the following:

	Major Depressive Disorder		OCD		Panic Disorder		Social Anxiety Disorder		Generalized Anxiety Disorder		PTSD
	Paxil	Placebo	Paxil	Placebo	Paxil	Placebo	Paxil	Placebo	Paxil	Placebo	Paxil	Placebo
CNS
Somnolence	2.3%	0.7%	--		1.9%	0.3%	3.4%	0.3%	2.0%	0.2%	2.8%	0.6%
Insomnia	--	--	1.7%	0%	1.3%	0.3%	3.1%	0%			--	--
Agitation	1.1%	0.5%	--								--	--
Tremor	1.1%	0.3%	--				1.7%	0%			1.0%	0.2%
Anxiety	--	--	--				1.1%	0%			--	--
Dizziness	--	--	1.5%	0%			1.9%	0%	1.0%	0.2%	--	--
Gastrointestinal
Constipation	--		1.1%	0%							--	--
Nausea	3.2%	1.1%	1.9%	0%	3.2%	1.2%	4.0%	0.3%	2.0%	0.2%	2.2%	0.6%
Diarrhea	1.0%	0.3%	--
Dry mouth	1.0%	0.3%	--								--	--
Vomiting	1.0%	0.3%	--				1.0%	0%			--	--
Flatulence							1.0%	0.3%			--	--
Other
Asthenia	1.6%	0.4%	1.9%	0.4%			2.5%	0.6%	1.8%	0.2%	1.6%	0.2%
Abnormal    ejaculation 1	1.6%	0%	2.1%	0%			4.9%	0.6%	2.5%	0.5%	--	--
Sweating	1.0%	0.3%	--				1.1%	0%	1.1%	0.2%	--	--
Impotence 1	--		1.5%	0%							--	--
Libido Decreased							1.0%	0%			--	--
Where numbers are not provided the incidence of the adverse events in Paxil patients was not >1% or was not greater than or equal to two times the incidence of placebo.

Commonly Observed Adverse Events
Major Depressive Disorder
The most commonly observed adverse events associated with the use of Paxil were: asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance and other male genital disorders.

Obsessive Compulsive Disorder
The most commonly observed adverse events associated with the use of Paxil were: nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence and abnormal ejaculation.

Panic Disorder
The most commonly observed adverse events associated with the use of Paxil were: asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders and impotence.

Social Anxiety Disorder
The most commonly observed adverse events associated with the use of Paxil were: sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders and impotence.

Generalized Anxiety Disorder
The most commonly observed adverse events associated with the use of Paxil were: asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

Posttraumatic Stress Disorder
The most commonly observed adverse events associated with the use of Paxil were: asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence.

Other Events Observed During the Premarketing Evaluation of Paxil
During its premarketing assessment in major depressive disorder, multiple doses of Paxil were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to Paxil varied greatly and included open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, generalized anxiety disorder and posttraumatic stress disorder, 542, 469, 522, 735 and 676 patients, respectively, received multiple doses of Paxil . Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

It is important to emphasize that although the events reported occurred during treatment with Paxil; they were not necessarily caused by it.

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, 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.