Bupropion Hydrochloride (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 mg and 150 mg per kg per day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 mg to 300 mg per kg per day (approximately 2 to 7 times the MRHD on a mg per m2 basis); lower doses were not tested. 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 the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study in rats at doses up to 300 mg per kg per day revealed no evidence of impaired fertility.

14 CLINICAL STUDIES

The efficacy of bupropion hydrochloride tablets in the treatment of major depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 4) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in Table 4). In the first trial, the dose range of bupropion hydrochloride tablets was 300 mg to 600 mg per day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of bupropion hydrochloride tablets as measured by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (Item 1), and the Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of bupropion hydrochloride tablets (300 mg and 450 mg per day) and placebo. This trial demonstrated the effectiveness of bupropion hydrochloride tablets for only the 450 mg per day dose. The efficacy results were statistically significant for the HDRS total score and the CGI-S score, but not for HDRS Item 1. In the third trial, outpatients were treated with 300 mg per day of bupropion hydrochloride tablets. This trial demonstrated the efficacy of bupropion hydrochloride tablets as measured by the HDRS total score, the HDRS Item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score. Effectiveness of bupropion hydrochloride tablets in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials.

Table 4. Efficacy of Bupropion Hydrochloride Tablets for the Treatment of Major Depressive Disorder

Trial number Treatment Group Primary Efficacy Measure: HDRS
Mean Baseline Score (SD) LS Mean Score at Endpoint Visit (SE) Placebo-subtracted Differencea (95% CI)
Trial 1 Bupropion Hydrochloride Tablets300 to 600 mg/dayb (n = 48) 28.5 (5.1) 14.9 (1.3) -4.7 (-8.8, -0.6)
Placebo (n = 27) 29.3 (7) 19.6 (1.6)
Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI)
Trial 2 Bupropion Hydrochloride Tablets300 mg/day (n = 36) 32.4 (5.9) -15.5 (1.7) -4.1
Bupropion Hydrochloride Tablets450 mg/dayb (n = 34) 34.8 (4.6) -17.4 (1.7) -5.9 (-10.5, -1.4)
Placebo (n = 39) 32.9 (5.4) -11.5 (1.6)
Trial 3 Bupropion Hydrochloride Tablets300 mg/dayb (n = 110) 26.5 (4.3) -12 (NA) -3.9 (-5.7, -1)
Placebo (n = 106) 27 (3.5) -8.7 (NA)

n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval included for doses that were demonstrated to be effective; NA: not available.

a Difference (drug minus placebo) in least-squares estimates with respect to the primary efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it refers to the mean change from baseline to the endpoint visit.

b Doses that are demonstrated to be statistically significantly superior to placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING


Bupropion hydrochloride tablets USP, 75 mg are light orange colored, round, biconvex film coated tablets debossed with ‘L295’ on one side and plain on other side.

Bottles of 100 NDC # 46708-118-31

Bottles of 1000 NDC # 46708-118-91

Bupropion hydrochloride tablets USP, 100 mg are light yellow colored, round, biconvex film coated tablets debossed with ‘L296’ on one side and plain on other side.

Bottles of 100 NDC # 46708-127-31

Bottles of 500 NDC # 46708-127-71
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride tablets and counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Bupropion Hydrochloride Tablets?” is available for bupropion hydrochloride tablets. 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 tablets.

Suicidal Thoughts and Behaviors
Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. 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. Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. 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.

Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment
Although bupropion hydrochloride tablet is 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 and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions (5.2), Adverse Reactions (6.2)].
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and to discontinue bupropion hydrochloride tablets if they have a severe allergic reaction.

Seizure
Instruct patients to discontinue and not restart bupropion hydrochloride tablets if they experience a seizure while on treatment. Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.

Angle-Closure Glaucoma
Patients should be advised that taking bupropion hydrochloride tablets 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.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.7)].

Bupropion-Containing Products
Educate patients that bupropion hydrochloride tablets contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is 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, the sustained-release formulation and WELLBUTRIN XL or FORFIVO XL, the extended-release formulations, and APLENZIN, the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.

Potential for Cognitive and Motor Impairment
Advise patients that any CNS-active drug like bupropion hydrochloride tablets 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 tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion hydrochloride tablets may lead to decreased alcohol tolerance.

Concomitant Medications
Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because bupropion hydrochloride tablets and other drugs may affect each others’ metabolisms.

Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.

Precautions for Nursing Mothers
Advise patients that bupropion hydrochloride tablets are present in human milk in small amounts.

Storage Information
Instruct patients to store bupropion hydrochloride tablets at room temperature, between 15° to 25°C (59° to 77°F) and keep the tablets dry and out of the light.

Administration Information
Instruct patients to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day, with doses separated by at least 6 hours to minimize the risk of seizure. 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 tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets can be taken with or without food.
Trademarks are owned by or licensed to the GSK group of companies. The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.

Manufactured by:
Alembic Pharmaceuticals Limited (Formulation Division),
Village Panelav, P. O. Tajpura, Near Baska,
Taluka-Halol, Panchmahal 389350, Gujarat, India.
Revised: 10/2023

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