Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert- butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P enzymes are not involved in the formation of threohydrobupropion.
Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized.
However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance, because the plasma concentrations of the metabolites are as high or higher than those of bupropion. At steady state, peak plasma concentration of hydroxybupropion occurred approximately 7 hours after administration of bupropion hydrochloride extended-release tablets XL , and it was approximately 7 times the peak level of the parent drug.
The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion. Only 0. Factors or conditions altering metabolic capacity e.
The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function, because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion. Renal Impairment.
There is limited information on the pharmacokinetics of bupropion in subjects with renal impairment. An inter-trial comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug C max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.
A second study, comparing normal subjects and subjects with moderate-to-severe renal impairment GFR Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys.
The elimination of the major metabolites of bupropion may be reduced by impaired renal function. The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild to severe cirrhosis.
The differences in half-life for bupropion and the other metabolites in the 2 groups were minimal. The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers.
Left Ventricular Dysfunction. During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction history of CHF or an enlarged heart on x-ray , there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy volunteers. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that in younger subjects.
These data suggest that there is no prominent effect of age on bupropion concentration; however, another single-and multiple-dose pharmacokinetic study suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations 8. A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
In addition, pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The effects of cigarette smoking on the pharmacokinetics of bupropion hydrochloride were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single mg dose of bupropion, there was no statistically significant difference in C max , half-life, T max , AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.
In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
The exposures of hydroxybupropion were decreased. Cimetidine: Following oral administration of bupropion mg with and without cimetidine mg in 24 healthy young male volunteers, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites. Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In a study of 8 healthy male volunteers, following a day administration of bupropion mg three times per day, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.
In vitro, bupropion and hydroxybupropion are CYP2D6 inhibitors. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied. Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response 2 to 3 times control mutation rate in 2 of 5 strains in one Ames bacterial mutagenicity assay, but was negative in another. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
The efficacy of bupropion in the treatment of major depressive disorder was established with the immediate-release formulation of bupropion hydrochloride in two 4-week, placebo-controlled trials in adult inpatients with MDD and in one 6-week, placebo-controlled trial in adult outpatients with MDD. The second study included 2 fixed doses of bupropion mg and mg per day and placebo. This trial demonstrated the efficacy of bupropion for only the mg dose.
In the third study, outpatients were treated with bupropion mg per day. A longer-term, placebo-controlled, randomized withdrawal trial demonstrated the efficacy of bupropion HCl sustained-release in the maintenance treatment of MDD. The trial included adult outpatients meeting DSM-IV criteria for MDD, recurrent type, who had responded during an 8-week open-label trial of bupropion mg per day. Responders were randomized to continuation of bupropion mg per day or placebo for up to 44 weeks of observation for relapse.
Response during the open-label phase was defined as a CGI-Improvement Scale score of 1 very much improved or 2 much improved for each of the final 3 weeks.
Patients in the bupropion group experienced significantly lower relapse rates over the subsequent 44 weeks compared to those in the placebo group. Although there are no independent trials demonstrating the efficacy of bupropion hydrochloride extended-release tablets XL in the acute treatment of MDD, studies have demonstrated similar bioavailability between the immediate-, sustained-, and extended-release formulations of bupropion HCl under steady-state conditions i.
The efficacy of bupropion hydrochloride extended-release tablets XL in the prevention of seasonal major depressive episodes associated with SAD was established in 3 randomized, double-blind, placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined by DSM-IV criteria.
Bupropion treatment was initiated prior to the onset of symptoms in the autumn September to November. Treatment was discontinued following a 2-week taper that began during the first week of spring fourth week of March , resulting in a treatment duration of approximately 4 to 6 months for the majority of patients.
Patients were randomized to treatment with bupropion hydrochloride extended-release tablets XL or placebo. The initial bupropion dose was mg once daily for 1 week, followed by up-titration to mg once daily. Patients who were deemed by the investigator to be unlikely or unable to tolerate mg once daily were allowed to remain on, or had their dose reduced to, mg once daily.
The mean bupropion doses in the 3 trials ranged from mg to mg per day. The SIGH-SAD consists of the HAMD17 plus 7 items specifically assessing core symptoms of seasonal affective disorder: social withdrawal, weight gain, increased appetite, increased eating, carbohydrate craving, hypersomnia, and fatigability.
The primary efficacy endpoint was the onset of a seasonal major depressive episode. The primary analysis was a comparison of depression-free-rates between the bupropion and placebo groups. In these 3 trials, the percentage of patients who were depression-free did not have an episode of MDD at the end of treatment was significantly higher in the bupropion group than in the placebo group: For the 3 trials combined, the depression-free rate was Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets XL and counsel them in its appropriate use.
Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients regarding the following issues and to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets XL. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Although bupropion hydrochloride extended-release tablets XL are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN which is approved for this use. Inform patients that some patients have experienced changes in mood including depression and mania , psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking bupropion.
Instruct patients to discontinue bupropion hydrochloride extended-release tablets XL and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions 5. Educate patients on the symptoms of hypersensitivity and to discontinue bupropion hydrochloride extended-release tablets XL if they have a severe allergic reaction. Instruct patients to discontinue and not restart bupropion hydrochloride extended-release tablets XL if they experience a seizure while on treatment.
Advise patients to minimize or avoid the use of alcohol. Patients should be advised that taking bupropion hydrochloride extended-release tablets XL can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma.
Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure e. In addition, there are a number of generic bupropion HCl products for the immediate, sustained, and extended-release formulations. Advise patients that any CNS-active drug like bupropion hydrochloride extended-release tablets XL may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that bupropion hydrochloride extended-release tablets XL do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Bupropion hydrochloride extended-release tablets XL treatment may lead to decreased alcohol tolerance. Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with bupropion hydrochloride extended-release tablets XL. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to bupropion hydrochloride extended-release tablets XL during pregnancy [see Use in Specific Populations 8.
Instruct patients to swallow bupropion hydrochloride extended-release tablets XL whole so that the release rate is not altered. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that bupropion hydrochloride extended-release tablets XL should be swallowed whole and not crushed, divided, or chewed.
Distributed by: Actavis Pharma, Inc. This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness also called manic-depressive illness or suicidal thoughts or actions.
How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider right away if you or your family member has any of the following symptoms especially if they are new, worse, or worry you:. It is not known if bupropion hydrochloride extended-release tablets XL are safe and effective in children under the age of This section of the Medication Guide is only about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.
Although bupropion hydrochloride extended-release tablets XL are not a treatment for quitting smoking, it contains the same active ingredient bupropion hydrochloride as ZYBAN which is used to help patients quit smoking. When you try to quit smoking, with or without bupropion you may have symptoms that may be due to nicotine withdrawal, including:. Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.
Some people have had serious side effects while taking bupropion to help them quit smoking, including:. New or worse mental health problems , such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions.
Some people had these symptoms when they began taking bupropion, and others developed them after several weeks of treatment, or after stopping bupropion. These symptoms happened more often in people who had a history of mental health problems before taking bupropion than in people without a history of mental health problems.
Stop taking bupropion hydrochloride extended-release tablets XL and call your healthcare provider right away if you, your family, or caregiver notice any of these symptoms. Work with your healthcare provider to decide whether you should continue to take bupropion hydrochloride extended-release tablets XL. In many people, these symptoms went away after stopping bupropion hydrochloride extended-release tablets XL , but in some people symptoms continued after stopping bupropion hydrochloride extended-release tablets XL.
It is important for you to follow-up with your healthcare provider until your symptoms go away. Before taking bupropion hydrochloride extended-release tablets XL , tell your healthcare provider if you have ever had depression or other mental health problems.
You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion. The chance of having seizures increases with higher doses of bupropion hydrochloride extended-release tablets XL.
Do not take any other medicines while you are taking bupropion hydrochloride extended-release tablets XL unless your healthcare provider has said it is okay to take them. If you have a seizure while taking bupropion hydrochloride extended-release tablets XL , stop taking the tablets and call your healthcare provider right away.
Do not take bupropion hydrochloride extended-release tablets XL again if you have a seizure. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Severe allergic reactions. Some people can have severe allergic reactions to bupropion hydrochloride extended-release tablets XL. Stop taking bupropion hydrochloride extended-release tablets XL and call your healthcare provider right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing.
These could be signs of a serious allergic reaction. What are bupropion hydrochloride extended-release tablets XL? Bupropion hydrochloride extended-release tablets XL are the prescription medicine used to treat adults with a certain type of depression called major depressive disorder. Who should not take bupropion hydrochloride extended-release tablets XL?
Do not take bupropion hydrochloride extended-release tablets XL if you:. Do not take bupropion hydrochloride extended-release tablets XL if you :. What should I tell my healthcare provider before using bupropion hydrochloride extended-release tablets XL? Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, or other mental health problems.
You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion hydrochloride extended-release tablets XL. Tell your healthcare provider about all the medicines you take , including prescription, over-the-counter medicines, vitamins, and herbal supplements. Many medicines increase your chances of having seizures or other serious side effects if you take them while you are taking bupropion hydrochloride extended-release tablets XL.
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