Appbutamone
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Questions & Answers
Side Effects & Adverse Reactions
WARNINGS
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
| Age Range |
Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
| |
Increases Compared to Placebo |
| less than18 |
14 additional cases |
| 18-24 |
5 additional cases |
| |
Decreases Compared to Placebo |
| 25-64 | 1 fewer case |
| greaterthan are equal to65 |
6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
Bupropion hydrochloride, bupropion hydrochloride, the sustained-release formulation, and bupropion hydrochloride, the extended-release forumlation, are not approved for smoking cessation treatment, but bupropion under the name ZYBAN (bupropion hydrochloride) Sustained-Release Tablets is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking bupropion who continued to smoke. When symptoms were reported, most were during bupropion treatment, but some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.
Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of ZYBAN.
Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that bupropion hydrochloride tablets is not approved for use in treating bipolar depression.
Bupropion-Containing Products
Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that bupropion hydrochloride tablets should not be used in combination with ZYBAN, or any other medications that contain bupropion, such as Wellbutrin SR (bupropion hydrochloride), the sustained-release formulation or Wellbutrin XL (bupropion hydrochloride), the extended-release formulation.
Seizures
Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted. The estimated seizure incidence for bupropion hydrochloride tablets increases almost tenfold between 450 and 600 mg/day, which is twice the usually required daily dose (300 mg) and one and one-third the maximum recommended daily dose (450 mg). Given the wide variability among individuals and their capacity to metabolize and eliminate drugs this disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
During the initial development, 25 among approximately 2,400 patients treated with bupropion hydrochloride tablets experienced seizures. At the time of seizure, 7 patients were receiving daily doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); 6 additional patients had seizures at daily doses between 600 and 900 mg (2.8% incidence).
A separate, prospective study was conducted to determine the incidence of seizure during an 8-week treatment exposure in approximately 3,200 additional patients who received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond 8 weeks if clinically indicated. Eight seizures occurred during the initial 8-week treatment period and 5 seizures were reported in patients continuing treatment beyond 8 weeks, resulting in a total seizure incidence of 0.4%.
The risk of seizure appears to be strongly associated with dose. Sudden and large increments in dose may contribute to increased risk. While many seizures occurred early in the course of treatment, some seizures did occur after several weeks at fixed dose. Bupropion hydrochloride tablets should be discontinued and not restarted in patients who experience a seizure while on treatment.
The risk of seizure is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride tablets.
- Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold.
- Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
- Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure
Retrospective analysis of clinical experience gained during the development of bupropion hydrochloride tablets suggests that the risk of seizure may be minimized if • the total daily dose of bupropion hydrochloride tablets does not exceed 450 mg,
- the daily dose is administered 3 times daily, with each single dose not to exceed 150 mg to avoid high peak concentrations of bupropion and/or its metabolites, and
- the rate of incrementation of dose is very gradual.
Bupropion hydrochloride tablets should be administered with extreme caution to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.
Hepatic Impairment
Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
Potential for Hepatotoxicity
In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.
Legal Issues
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Manufacturer Warnings
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FDA Labeling Changes
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Uses
INDICATIONS AND USAGE
Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder. A physician considering bupropion hydrochloride tablets for the management of a patient’s first episode of depression should be aware that the drug may cause generalized seizures in a dose-dependent manner with an approximate incidence of 0.4% (4/1,000). This incidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted (see WARNINGS).
The efficacy of bupropion hydrochloride tablets has been established in 3 placebo-controlled trials, including 2 of approximately 3 weeks’ duration in depressed inpatients and one of approximately 6 weeks’ duration in depressed outpatients. The depressive disorder of the patients studied corresponds most closely to the Major Depression category of the APA Diagnostic and Statistical Manual III.
Major Depression implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicidal ideation or attempts.
Effectiveness of bupropion hydrochloride tablets in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use bupropion hydrochloride tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
INDICATIONS FOR USE AppTrim is intended for the clinical nutritional management of the metabolic processes in patients with obesity, morbid obesity, and metabolic syndrome. • To control appetite and carbohydrate cravings in obese patients who are undergoing a medically supervised weight loss program. • To control appetite and carbohydrate cravings in patients who are being treated for metabolic syndrome. • To control appetite and carbohydrate cravings in patients preparing for bariatric surgery. • To control appetite and carbohydrate cravings in patients following bariatric surgery.
History
There is currently no drug history available for this drug.
Other Information
DESCRIPTION
Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18CINO-HCI. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. It has the following structural formula:
Each bupropion hydrochloride tablet intended for oral administration contains 75 mg or 100 mg bupropion hydrochloride. In addition, each bupropion hydrochloride tablet contains the following inactive ingredients: FDandC Blue No. 2 aluminum lake, FDandC Red No. 40 aluminum lake, hydroxypropyl methylcellulose, microcrystalline cellulose, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triethyl citrate.
PRODUCT DESCRIPTION Primary Ingredients AppTrim consists of a proprietary formulation of amino acids, cocoa, and flavonoids in specific proportions. These ingredients fall into the classification of Generally Recognized as Safe (GRAS) as defined by the Food and Drug Administration (FDA) (Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act). A GRAS substance is distinguished from a food additive on the basis of the common knowledge about the safety of the substance for its intended use. The standard for an ingredient to achieve GRAS status requires not only technical demonstration of non-toxicity and safety, but also general recognition of safety through widespread usage and agreement of that safety by experts in the field. Many ingredients have been determined by the FDA to be GRAS, and are listed as such by regulation, in Volume 21 Code of Federal Regulations (CFR) Sections 182, 184, and 186. Amino Acids Amino Acids are the building blocks of protein and are GRAS listed as they have been safely ingested by humans for thousands of years. The formulations of the amino acids in AppTrim are equivalent to those found in the usual human diet. Obese patients may require an increased amount of certain amino acids that cannot be obtained from normal diet alone. Tryptophan, for example,is an obligatory amino acid. The body cannot make tryptophan and must obtain tryptophan from the diet. Tryptophan is needed to produce serotonin. Serotonin is required to reduce appetite and carbohydrate cravings. Obese and morbidly obese patients frequently have altered serotonin metabolism. Some obese and morbidly obese patients have a resistance to the use of tryptophan that is similar to the mechanism found in insulin resistance. Some obese and morbidly obese patients cannot acquire sufficient tryptophan from the diet without ingesting a prohibitively large amount of calories, particularly calories from protein. Flavonoids Flavonoids are a group of phytochemical compounds found in all vascular plants including fruits and vegetables. They are a part of a larger class of compounds known as polyphenols. Many of the therapeutic or health benefits of colored fruits and vegetables, cocoa, red wine, and green tea are directly related to their flavonoid content. The specially formulated flavonoids found in AppTrim cannot be obtained from conventional foods in the necessary proportions to elicit a therapeutic response. Other Ingredients AppTrim contains the following inactive or other ingredients, as fillers, excipients, and colorings: gelatin, silicon dioxide, vegetable magnesium stearate, FD C blue 1, FD C Red 3, FD C red 40, titanium dioxide. Physical Description AppTrim is a yellow to light brown powder. L-Glutamic Acid, Choline Bitartrate, L-Tyrosine, L-Serine, Whey Protein Hydrolysate, Griffonia Seed Extract (5-HTP), Cocoa Extract (6%Theobromine), Caffeine, and Grape Seed Extract (95% Proanthocyanidins).
Sources
Appbutamone Manufacturers
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Physician Therapeutics Llc
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Appbutamone | Physician Therapeutics Llc
DOSAGE AND ADMINISTRATION
Table 3. Dosing Regimen Treatment Day
General Dosing Considerations
It is particularly important to administer bupropion hydrochloride tablets in a manner most likely to minimize the risk of seizure (see WARNINGS). Increases in dose should not exceed 100 mg/day in a 3-day period. Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. No single dose of bupropion hydrochloride tablets should exceed 150 mg. Bupropion hydrochloride tablets should be administered 3 times daily, preferably with at least 6 hours between successive doses.
Usual Dosage for Adults
The usual adult dose is 300 mg/day, given 3 times daily. Dosing should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose may be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after beginning therapy (see Table 3).
Total Daily Dose
Tablet Strength
Number of Tablets
Number of Tablets
Number of Tablets
Morning
Midday Evening
1
200 mg
100 mg
1
0
1
4
300 mg
100 mg
1
1
1
Increasing the Dosage Above 300 mg/Day
As with other antidepressants, the full antidepressant effect of bupropion hydrochloride tablets may not be evident until 4 weeks of treatment or longer. An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished using the 75 or 100 mg tablets. The 100 mg tablet must be administered 4 times daily with at least 4 hours between successive doses, in order not to exceed the limit of 150 mg in a single dose. Bupropion hydrochloride tablets should be discontinued in patients who do not demonstrate an adequate response after an appropriate period of treatment at 450 mg/day.
Maintenance Treatment
The lowest dose that maintains remission is recommended. Although it is not known how long the patient should remain on bupropion hydrochloride tablets, it is generally recognized that acute episodes of depression require several months or longer of antidepressant drug treatment.
Dosage Adjustment for Patients with Impaired Hepatic Function
Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 75 mg once a day in these patients. Bupropion hydrochloride tablets should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS).
Dosage Adjustment for Patients with Impaired Renal Function
Bupropion hydrochloride tablets should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).DOSAGE AND ADMINISTRATION Recommended Administration For the dietary management of the metabolic processes associated with obesity and metabolic disorders. Take (2) capsules twice daily; once in mid morning and once in mid afternoon. An additional evening dose of (2) capsules may be added to the daily dose if needed. As with most amino acid formulations, AppTrim should be taken without food to increase the absorption of key ingredients.
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