Forfivo

Description

FORFIVO XL (bupropion hydrochloride) is an antidepressant belonging to the aminoketone class, which is chemically distinct from tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, and other known antidepressant agents. The chemical designation is (±)-2-(tert-Butylamino)-3'-chloropropiophenone hydrochloride. It has a molecular weight of 276.2 and an empirical formula of C13H18ClNO·HCl. The bupropion hydrochloride powder appears white or almost white, crystalline, and is soluble in water. It has a bitter taste and can induce a sensation of local anesthesia on the oral mucosa.

FORFIVO XL is available in the form of extended-release tablets for oral administration, each containing 450 mg of bupropion hydrochloride. The tablets are white to off-white and film-coated. Inactive ingredients in each tablet include carboxymethyl cellulose sodium, colloidal silicon dioxide, hydrochloric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 8000, polyethylene oxide, a blend of polyvinyl pyrrolidone and polyvinyl acetate, stearic acid, talc, titanium dioxide, and triacetin.

Uses and Indications

FORFIVO XL is indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of FORFIVO XL was established through two 4-week clinical trials and one 6-week trial utilizing a bupropion immediate-release formulation, as well as one maintenance trial involving a bupropion sustained-release formulation.

Healthcare professionals are advised to periodically re-evaluate the long-term usefulness of FORFIVO XL for each individual patient to ensure continued appropriateness of therapy.

No teratogenic or nonteratogenic effects have been reported in relation to the use of FORFIVO XL.

Dosage and Administration

Patients should take one tablet of FORFIVO XL (450 mg) once daily, without regard to food. The tablet must be swallowed whole; it should not be chewed, divided, or crushed to ensure proper release and absorption of the medication.

It is important to note that treatment with FORFIVO XL should not be initiated directly. Instead, healthcare professionals should use another bupropion formulation for initial dose titration. FORFIVO XL can be prescribed to patients who have been receiving 300 mg/day of another bupropion formulation for a minimum of two weeks and require an increase to a dosage of 450 mg/day.

For patients currently treated with other bupropion products at a dosage of 450 mg/day, a direct switch to the equivalent dose of FORFIVO XL once daily is appropriate.

Contraindications

Use of FORFIVO XL is contraindicated in the following situations:

• Patients with a seizure disorder due to the increased risk of seizures.

• Individuals currently using other bupropion products, as this may lead to an overdose.

• Patients with a current or prior diagnosis of bulimia or anorexia nervosa, as these conditions increase the risk of seizures.

• Individuals who have abruptly discontinued alcohol, benzodiazepines, barbiturates, or antiepileptic drugs, which may precipitate seizures.

• Patients taking Monoamine Oxidase Inhibitors (MAOIs) intended for psychiatric disorders, or those who have stopped MAOIs within the last 14 days. Additionally, FORFIVO XL should not be initiated in patients receiving linezolid or intravenous methylene blue.

• Individuals with known hypersensitivity to bupropion or any other ingredients in FORFIVO XL.

Warnings and Precautions

The use of FORFIVO XL necessitates careful consideration of several warnings and precautions to ensure patient safety and effective treatment outcomes.

Increased Risk of Suicidal Thoughts and Behaviors Healthcare professionals should be aware of the increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants, including FORFIVO XL. It is essential to monitor these patients closely for any worsening of symptoms or the emergence of suicidal thoughts and behaviors.

Neuropsychiatric Adverse Events During Smoking Cessation Postmarketing reports have indicated that patients attempting to quit smoking while on FORFIVO XL may experience serious neuropsychiatric adverse events. These can include mood changes (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Patients should be observed for these symptoms, and if any occur, they should be instructed to discontinue FORFIVO XL and contact a healthcare provider immediately.

Seizure Risk The risk of seizures associated with FORFIVO XL is dose-dependent. If a seizure occurs, the medication should be discontinued promptly.

Hypertension FORFIVO XL has the potential to increase blood pressure. It is recommended that blood pressure be monitored before initiating treatment and periodically throughout the course of therapy.

Activation of Mania/Hypomania Patients should be screened for bipolar disorder prior to treatment initiation. Continuous monitoring for symptoms of mania or hypomania is advised during treatment.

Psychosis and Other Neuropsychiatric Reactions In the event of psychosis or other neuropsychiatric reactions, discontinuation of FORFIVO XL is warranted.

Angle-Closure Glaucoma Patients with untreated anatomically narrow angles may be at risk for angle-closure glaucoma when treated with antidepressants. Caution is advised in these cases.

Laboratory Tests Regular monitoring of blood pressure is essential before starting treatment with FORFIVO XL and at periodic intervals thereafter.

Patients should be instructed to seek emergency medical help and discontinue FORFIVO XL if they experience any neuropsychiatric adverse events. Additionally, they should stop taking the medication and contact their healthcare provider if a seizure occurs or if psychosis or other neuropsychiatric reactions develop.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions reported include dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitations, sweating, tinnitus, myalgia, anorexia, urinary frequency, and rash.

Serious warnings include an increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults taking antidepressants. It is essential to monitor these patients for any worsening or emergence of suicidal thoughts and behaviors.

Postmarketing reports have indicated that serious or clinically significant neuropsychiatric adverse events may occur during smoking cessation. These events include changes in mood (such as depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempts, and completed suicides.

The risk of seizures is dose-dependent; therefore, the medication should be discontinued if a seizure occurs. Additionally, FORFIVO XL has been associated with increased blood pressure, necessitating monitoring before and periodically during treatment.

Patients should be screened for bipolar disorder, as activation of mania or hypomania may occur. If psychosis or other neuropsychiatric reactions develop, discontinuation of the medication is advised. Angle-closure glaucoma has also been reported in patients with untreated anatomically narrow angles who are treated with antidepressants.

In cases of overdosage, serious reactions have been documented, including hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes (such as conduction disturbances or arrhythmias), clonus, myoclonus, hyperreflexia, fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure. Deaths associated with overdoses of bupropion alone have been reported, often preceded by multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest.

Drug Interactions

Coadministration of FORFIVO XL with ticlopidine or clopidogrel is not recommended due to the potential for increased bupropion exposure.

When FORFIVO XL is used in conjunction with CYP2B6 inducers such as ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, or phenytoin, a dose increase may be necessary to achieve desired clinical exposure.

Bupropion, the active ingredient in FORFIVO XL, is a known inhibitor of CYP2D6. This inhibition can lead to elevated concentrations of various medications, including antidepressants (e.g., venlafaxine, nortriptyline), antipsychotics (e.g., haloperidol, risperidone), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone). Clinicians should monitor patients closely for signs of increased drug effects or toxicity when these medications are used concurrently.

Extreme caution is advised when dosing FORFIVO XL alongside drugs that lower the seizure threshold, as this combination may heighten the risk of seizures.

Concomitant use of FORFIVO XL with dopaminergic drugs, such as levodopa and amantadine, may result in CNS toxicity.

The risk of hypertensive reactions is increased when FORFIVO XL is administered with monoamine oxidase inhibitors (MAOIs).

Additionally, it is important to note that FORFIVO XL can cause false-positive results in urine tests for amphetamines, which may lead to misinterpretation of drug screening results.

Packaging & NDC

The table below lists all NDC Code configurations of Forfivo (bupropion hydrochloride), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of FORFIVO XL in the pediatric population have not been established. When considering the use of FORFIVO XL in children or adolescents, healthcare professionals should carefully balance the potential risks with the clinical need.

Geriatric Use

Clinical trials involving bupropion hydrochloride sustained-release tablets included approximately 6,000 patients, of whom 275 were aged 65 years and older, and 47 were aged 75 years and older. Additionally, several hundred patients aged 65 years and older participated in clinical trials utilizing the immediate-release formulation of bupropion hydrochloride for depression.

No overall differences in safety or effectiveness were observed between elderly patients and younger patients in these studies. However, while clinical experience has not identified significant differences in responses between these age groups, it is important to note that greater sensitivity to the drug may be present in some older individuals.

Bupropion is extensively metabolized in the liver to active metabolites, which are subsequently metabolized and excreted by the kidneys. Given that elderly patients are more likely to have decreased renal function, the risk of adverse reactions may be heightened in this population. Therefore, it is advisable to consider renal function when selecting a dose for geriatric patients, and monitoring of renal function may be beneficial to ensure safety and efficacy.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at National Pregnancy Registry for AntidepressantsNational Pregnancy Registry for Antidepressants.

Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall. However, there are risks to the mother associated with untreated depression. A prospective, longitudinal study involving 201 pregnant women with a history of major depressive disorder indicated that those who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression compared to those who continued treatment. Therefore, healthcare providers should consider the risks of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.

Animal studies have shown that when bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. In contrast, when given to pregnant rabbits during organogenesis, non-dose-related increases in the incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were noted at doses twice the MRHD and greater.

The estimated background risk for major birth defects and miscarriage in the indicated population is unknown; however, all pregnancies have a background rate of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data from the international bupropion Pregnancy Registry, which included 675 first-trimester exposures, and a retrospective cohort study using the United Healthcare database, which included 1,213 first-trimester exposures, did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. Notably, the prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester was 1.3%, which is similar to the background rate of approximately 1%.

Study findings regarding bupropion exposure during the first trimester and the risk for left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD) are inconsistent and do not allow for definitive conclusions regarding a possible drug association. In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the MRHD on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk. In a lactation study involving ten women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure, assuming a daily consumption of 150 mL/kg, was found to be 2% of the maternal weight-adjusted dose.

There are no data available regarding the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in breastfed infants. However, it is important to note that postmarketing reports have described seizures in breastfed infants, although the relationship between bupropion exposure and these seizures remains unclear.

The developmental and health benefits of breastfeeding should be considered alongside the lactating mother's clinical need for FORFIVO XL and any potential adverse effects on the breastfed child from FORFIVO XL or from the underlying maternal condition.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring of these patients.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In cases of bupropion overdose, significant clinical manifestations can occur, necessitating immediate medical attention. Overdoses of 30 g or more have been documented, with seizures reported in approximately one third of these instances.

Clinical Manifestations Serious reactions associated with bupropion overdose may include hallucinations, loss of consciousness, alterations in mental status, and changes in electrocardiogram (ECG) readings. Additional symptoms that have been observed include fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure, particularly in scenarios involving multiple drug overdoses.

Mortality Risks There have been reports of fatalities linked to bupropion overdose, often characterized by multiple uncontrolled seizures and various cardiac complications preceding death.

Management Recommendations Currently, there are no known antidotes for bupropion. Therefore, the primary approach to managing an overdose involves supportive care and vigilant medical supervision. Healthcare professionals are advised to consult a Certified Poison Control Center for further guidance in overdose situations. The Poison Control Center can be reached at 1-800-222-1222 or through their website at www.poison.org.

Nonclinical Toxicology

Lifetime carcinogenicity studies were conducted in rats and mice with bupropion hydrochloride at doses of up to 300 mg/kg/day and 150 mg/kg/day, respectively. These doses correspond to approximately 7 and 2 times the maximum recommended human dose (MRHD) on a mg/m² basis. In the rat study, an increase in nodular proliferative lesions of the liver was observed at doses ranging from 100 to 300 mg/kg/day, which is approximately 2 to 7 times the MRHD on a mg/m² basis; lower doses were not evaluated. The potential for these lesions to serve as precursors to liver neoplasms remains unresolved. Conversely, similar liver lesions were not detected in the mouse study, and no increase in malignant tumors of the liver or other organs was noted in either species.

Bupropion demonstrated a positive response in 2 of 5 strains in one Ames bacterial mutagenicity assay, resulting in a mutation rate that was 2 to 3 times higher than the control. However, it yielded negative results in another assay. Additionally, an increase in chromosomal aberrations was reported in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study conducted in rats at doses up to 300 mg/kg/day indicated no evidence of impaired fertility.

Postmarketing Experience

Some patients have reported experiencing changes in mood, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic. Suicidal ideation and suicide attempts have also been noted in individuals attempting to quit smoking while taking bupropion.

New or exacerbated mental health issues, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions, have been documented. These symptoms have been observed in some individuals upon initiation of bupropion therapy, while others developed them after several weeks of treatment or following discontinuation of the medication.

Severe allergic reactions to FORFIVO XL have been reported. Patients are advised to discontinue use and contact their healthcare provider immediately if they experience symptoms such as 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 difficulty breathing, as these may indicate a serious allergic reaction.

The risk of seizures is known to increase with higher doses of FORFIVO XL. Additionally, some patients have experienced significant increases in blood pressure while taking this medication, with a heightened risk observed in those also using nicotine replacement therapy to aid in smoking cessation.

Episodes of mania, characterized by greatly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, and rapid speech, have been reported in some individuals. Unusual thoughts or behaviors, including delusions, hallucinations, paranoia, or confusion, have also been noted, prompting patients to seek guidance from their healthcare provider.

Visual disturbances, such as eye pain, changes in vision, and swelling or redness in or around the eye, have been reported, although only a subset of patients may be at risk for these issues.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Medication Guide) thoroughly. Healthcare providers should instruct patients, their families, and/or caregivers to be vigilant for the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, and other unusual changes in behavior, as well as worsening depression and suicidal ideation. These symptoms are particularly important to monitor during the initial stages of antidepressant treatment and when there are adjustments to the dosage.

Families and caregivers should be encouraged to observe the patient on a daily basis for any abrupt changes in behavior. If such symptoms arise, especially if they are severe, sudden, or not part of the patient’s initial presentation, they should be reported to the patient’s prescriber or healthcare professional promptly.

Patients should be informed that some individuals may experience significant mood changes, including depression and mania, as well as psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, along with suicidal thoughts when attempting to quit smoking while taking bupropion. In the event that patients experience any of these symptoms, they should discontinue FORFIVO XL and contact a healthcare professional immediately.

It is essential to educate patients about the signs of hypersensitivity and instruct them to discontinue FORFIVO XL if they experience a severe allergic reaction. Additionally, patients should be advised to stop taking FORFIVO XL and not to restart it if they experience a seizure during treatment.

Patients should be cautioned that excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizures, and they should be advised to avoid alcohol altogether. Furthermore, patients should be informed that taking FORFIVO XL can cause mild pupillary dilation, which may lead to an episode of angle-closure glaucoma in susceptible individuals.

Patients should be made aware that FORFIVO XL contains the same active ingredient (bupropion) found in ZYBAN, which is used for smoking cessation, and that FORFIVO XL should not be used in conjunction with ZYBAN or any other medications containing bupropion hydrochloride.

Healthcare providers should advise patients that any CNS-active drug, including FORFIVO XL, may impair their ability to perform tasks that require judgment or motor and cognitive skills. Until patients are confident that FORFIVO XL does not adversely affect their performance, they should refrain from driving or operating complex, hazardous machinery.

Patients should also be counseled to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter medications, as interactions may affect the metabolism of FORFIVO XL and other drugs. Additionally, patients should inform their healthcare provider if they become pregnant or plan to become pregnant during therapy with FORFIVO XL.

Finally, patients should be instructed to swallow FORFIVO XL tablets whole to ensure the release rate is not altered. They should not chew, divide, or crush the tablets, and FORFIVO XL may be taken with or without food.

Storage and Handling

The product is supplied in accordance with the National Drug Code (NDC) specifications. It should be stored at a controlled room temperature of 20°C to 25°C (68°F to 77°F), as defined by the United States Pharmacopeia (USP) guidelines. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Patients receiving antidepressants for major depressive disorder (MDD) or other indications should be closely monitored by families and caregivers for signs of agitation, irritability, and unusual behavioral changes, as well as the emergence of suicidality. It is crucial that any concerning symptoms are reported immediately to healthcare providers. Clinicians are advised to prescribe FORFIVO XL in the smallest quantity necessary to ensure effective patient management, thereby minimizing the risk of overdose.

Postmarketing experience has revealed serious neuropsychiatric adverse events associated with bupropion use for smoking cessation. These events include mood changes, psychosis, hallucinations, paranoia, delusions, and suicidal ideation, among others. While many patients reported resolution of symptoms following discontinuation of bupropion, some experienced persistent symptoms, necessitating ongoing monitoring and supportive care until resolution occurs.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Forfivo as submitted by Upsher-Smith Laboratories, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)