Carboplatin Merck

Carboplatin Merck may be available in the countries listed below.

Ingredient matches for Carboplatin Merck

Carboplatin

Carboplatin is reported as an ingredient of Carboplatin Merck in the following countries:

• Tunisia

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Kotozole

Kotozole may be available in the countries listed below.

Ingredient matches for Kotozole

Clotrimazole

Clotrimazole is reported as an ingredient of Kotozole in the following countries:

• Japan

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Vétécardiol

Vétécardiol may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Vétécardiol

Heptaminol

Heptaminol acefyllinate (a derivative of Heptaminol) is reported as an ingredient of Vétécardiol in the following countries:

• France

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Lotencin

Lotencin may be available in the countries listed below.

Ingredient matches for Lotencin

Terazosin

Terazosin hydrochloride (a derivative of Terazosin) is reported as an ingredient of Lotencin in the following countries:

• Philippines

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Fludeoxyglucose F 18

Ingredient matches for Fludeoxyglucose F-18

Fludeoxyglucose (18F)

Fludeoxyglucose F-18 (USAN) is also known as Fludeoxyglucose (18F) (Rec.INN)

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Glossary

Rec.INN	Recommended International Nonproprietary Name (World Health Organization)
USAN	United States Adopted Name

Click for further information on drug naming conventions and International Nonproprietary Names.

becaplermin topical

Generic Name: becaplermin topical (be KAP ler min TOP ik al)

Brand Names: Regranex

What is becaplermin topical?

Becaplermin contains a human growth factor that helps your body heal. It works by promoting the growth of cells that aid in wound healing.

Becaplermin topical (for the skin) is used to treat diabetic foot ulcers.

Becaplermin topical may also be used for purposes not listed in this medication guide.

What is the most important information I should know about becaplermin topical?

You should not use this medication if you are allergic to becaplermin or parabens, or if you have skin cancer affecting your feet. Do not apply becaplermin over any wound or surgical incision that has been closed with stitches, staples, or surgical tape.

A becaplermin dose is measured by the length of a ribbon of gel squeezed from the medicine tube. Ask your doctor, pharmacist, or wound care counselor if you have any questions about how to measure your becaplermin dose.

You will need to recalculate your dose about every week or two as the size of your ulcer changes. Follow your doctor's instructions.

Do not apply becaplermin gel more than once per day and never use more than your prescribed dose. Using more of the medication will not make it work faster and may cause unwanted side effects.

Use this medication for the full prescribed length of time. Call your doctor if your symptoms do not improve, or if they get worse while using becaplermin topical.

Becaplermin topical is only part of a complete ulcer care treatment program that may also include routine foot exams and avoiding weight on the affected foot. Follow your doctor's instructions very closely.

Some people who used 3 or more courses of treatment with becaplermin topical have developed cancer. However, it is not known whether this medication actually causes cancer. Talk with your doctor about your own specific cancer risk.

What should I discuss with my healthcare provider before using becaplermin topical?

You should not use this medication if you are allergic to becaplermin or parabens, or if you have skin cancer affecting your feet. Do not apply becaplermin over any wound or surgical incision that has been closed with stitches, staples, or surgical tape. FDA pregnancy category C. It is not known whether becaplermin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether becaplermin topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Do not use this medication on a child younger than 16 years old.

Some people who used 3 or more courses of treatment with becaplermin topical have developed cancer. However, it is not known whether this medication actually causes cancer. Talk with your doctor about your own specific cancer risk.

How should I use becaplermin topical?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Using more of this medication will not make it work faster and may cause unwanted side effects.

A becaplermin dose is measured by the length of a ribbon of gel squeezed from the medicine tube. To calculate the proper dose, measure the length and width of your ulcer and use one of the following formulas:

• 
  

  When using a 15-gram tube of becaplermin gel: multiply length x width x 0.6. For example, 2 inches x 1 inch x 0.6 = 1.25 inches of gel.

  
  


• 
  

  When using a 2-gram tube of becaplermin gel: multiply length x width x 1.3. For example, 2 inches x 1 inch x 1.3 = 2.75 inches of gel.

  
  


• 
  

  To measure the dose in centimeters: Multiply length x width and divide by 4 if using a 15-gram tube, or divide by 2 if using a 2-gram tube. For example, 4 centimeters x 2 centimeters / 4 = 2 centimeters of gel from the 15-gram tube; or 4 centimeters x 2 centimeters / 2 = 4 centimeters of gel from the 2-gram tube.

  
  


• 
  

  Ask your doctor, pharmacist, or wound care counselor if you have any questions about how to measure your becaplermin dose.

  
  

Make sure you are aware of which tube size you are using when calculating your becaplermin topical dose. Always check your refills to make sure you have received the correct tube size prescribed by your doctor. Ask the pharmacist if you have any questions about the medicine you receive at the pharmacy.

You will need to recalculate your dose about every week or two as the size of your ulcer changes. Follow your doctor's instructions.

Wash your hands before and after using this medication.

To apply becaplermin topical gel:

• 
  

  Squeeze a ribbon of gel (in the correct length for your ulcer) onto a clean, firm surface that will not absorb the gel such as wax paper.

  
  


• 
  

  To keep the tip of the medicine tube from getting contaminated, do not allow the tip to touch any surface, including your fingers, the firm surface, or the ulcer you are treating.

  
  


• 
  

  Use a cotton swab, tongue depressor, or other disposable applicator to lift the gel from the firm surface

  
  


• 
  

  Spread the gel evenly in a thin layer (about 1/16 of an inch thick) over the ulcerated skin area.

  
  


• 
  

  Cover the treated skin area with a cotton gauze bandage that has been moistened with saline. Leave this gauze dressing on for the next 12 hours.

  
  


• 
  

  After 12 hours have passed, remove the gauze and rinse the ulcer with saline or water to remove the gel. Moisten a new gauze bandage with saline and cover the ulcer without applying any becaplermin gel.

  
  

Do not apply becaplermin gel more than once per day and never use more than your prescribed dose.

Use this medication for the full prescribed length of time. Call your doctor if your symptoms do not improve, or if they get worse while using becaplermin topical.

Becaplermin topical is only part of a complete ulcer care treatment program that may also include routine foot exams and avoiding weight on the affected foot. Follow your doctor's instructions very closely.

Store in the refrigerator, do not freeze. Keep the medicine tube tightly capped when not in use. Do not use becaplermin gel past the expiration date on the tube.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while using becaplermin topical?

Avoid getting this medication in your eyes, nose, or mouth. If it does get into any of these areas, rinse with water.

Avoid using other medications on the areas you treat with becaplermin unless you doctor tells you to.

Becaplermin topical side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using becaplermin topical and call your doctor at once if you have severe itching, redness, blistering, peeling, or other skin irritation.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect becaplermin topical?

It is not likely that other drugs you take orally or inject will have an effect on topically applied becaplermin. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More becaplermin topical resources

• Becaplermin topical Side Effects (in more detail)
• Becaplermin topical Use in Pregnancy & Breastfeeding
• Becaplermin topical Support Group
• 0 Reviews · Be the first to review/rate this drug

• Regranex Prescribing Information (FDA)


• Regranex Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Regranex MedFacts Consumer Leaflet (Wolters Kluwer)

Where can I get more information?

• Your pharmacist can provide more information about becaplermin topical.

See also: becaplermin side effects (in more detail)

Kupramickin

Kupramickin may be available in the countries listed below.

Ingredient matches for Kupramickin

Amikacin

Amikacin is reported as an ingredient of Kupramickin in the following countries:

• Vietnam

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Dermisan

Dermisan may be available in the countries listed below.

Ingredient matches for Dermisan

Hexachlorophene

Hexachlorophene is reported as an ingredient of Dermisan in the following countries:

• Indonesia

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Bromocriptine Capsules

Dosage Form: capsule
Bromocryptine Mesylate

   

     

      Bromocriptine Mesylate

      Capsules, USP

      Rx only

      Prescribing Information

DESCRIPTION

Bromocriptine mesylate is an ergot derivative with potent dopamine receptor agonist activity. Each bromocriptine mesylate capsule for oral administration contains 5 mg bromocriptine (as the mesylate). Bromocriptine mesylate is chemically designated as Ergotaman-3′,6′,18-trione, 2-bromo-12′-hydroxy-2′- (1-methylethyl)-5′-(2-methylpropyl)-, (5′α)-monomethanesulfonate (salt).

      The structural formula is:

5 mg Capsules

Active Ingredient: bromocriptine mesylate, USP

      Inactive Ingredients: colloidal silicon dioxide, gelatin, lactose, magnesium stearate, red iron oxide, silicon dioxide, sodium lauryl sulfate, starch, titanium dioxide, yellow iron oxide, and another ingredient

CLINICAL PHARMACOLOGY

Bromocriptine mesylate is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, bromocriptine significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces long lasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors.

      Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients.

      In about 75% of cases of amenorrhea and galactorrhea, bromocriptine therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles.

      Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6-8 weeks. However, some patients respond within a few days, and others may take up to 8 months.

      Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks. Some patients may fail to respond even after 12 months of therapy.

      In many acromegalic patients, bromocriptine produces a prompt and sustained reduction in circulating levels of serum growth hormone.

      Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson’s disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population.

Pharmacokinetics

The pharmacokinetics and metabolism of bromocriptine in human subjects were studied with the help of radioactively labeled drug. Twenty-eight percent of an oral dose was absorbed from the gastrointestinal tract. The blood levels following a 2½mg dose were in the range of 2-3 ng equivalents/mL. Plasma levels were in the range of 4-6 ng equivalents/mL indicating that the red blood cells did not contain appreciable amounts of drug and/or metabolites. In vitro experiments showed that the drug was 90%-96% bound to serum albumin.

      When tablets or standard capsules are administered to healthy volunteers, the absorption half-life is 0.2 to 0.5 hours, and the peak plasma levels of bromocriptine are reached within 1 to 3 hours. An oral dose of 5 mg of bromocriptine results in a Cmax of 0.465 ng/mL. The prolactin-lowering effect begins within 1 to 2 hours of ingestion, reaches its maximum, i.e., a reduction of prolactin in the plasma by more than 80%, within 5 to 10 hours and remains close to maximum for 8 to 12 hours.

      Bromocriptine undergoes extensive first-pass biotransformation in the liver, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces. It shows a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constitute a main metabolic pathway. Inhibitors and/or potent substrates for CYP3A4 might therefore be expected to inhibit the clearance of bromocriptine and lead to increased levels. Bromocriptine is also a potent inhibitor of CYP3A4 with a calculated IC50 value of 1.69 µM. However, given the low therapeutic concentrations of free bromocriptine in patients, a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected.

      The elimination of the parent drug from plasma is biphasic, with a terminal half-life of about 15 hours (range 8 to 20 hours). Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney.

      In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase requiring dose adjustment.

     

INDICATIONS AND USAGE

Hyperprolactinemia-Associated Dysfunctions

Bromocriptine mesylate is indicated for the treatment of dysfunctions associated with hyperprolactinemia including amenorrhea with or without galactorrhea, infertility or hypogonadism. Bromocriptine treatment is indicated in patients with prolactin-secreting adenomas, which may be the basic underlying endocrinopathy contributing to the above clinical presentations. Reduction in tumor size has been demonstrated in both male and female patients with macroadenomas. In cases where adenectomy is elected, a course of bromocriptine therapy may be used to reduce the tumor mass prior to surgery.

Acromegaly

Bromocriptine therapy is indicated in the treatment of acromegaly. Bromocriptine therapy, alone or as adjunctive therapy with pituitary irradiation or surgery, reduces serum growth hormone by 50% or more in approximately ½ of patients treated, although not usually to normal levels.

      Since the effects of external pituitary radiation may not become maximal for several years, adjunctive therapy with bromocriptine offers potential benefit before the effects of irradiation are manifested.

Parkinson’s Disease

Bromocriptine Capsules are indicated in the treatment of the signs and symptoms of idiopathic or postencephalitic Parkinson’s disease. As adjunctive treatment to levodopa (alone or with a peripheral decarboxylase inhibitor), bromocriptine therapy may provide additional therapeutic benefits in those patients who are currently maintained on optimal dosages of levodopa, those who are beginning to deteriorate (develop tolerance) to levodopa therapy, and those who are experiencing “end of dose failure’’ on levodopa therapy. Bromocriptine therapy may permit a reduction of the maintenance dose of levodopa and, thus may ameliorate the occurrence and/or severity of adverse reactions associated with long-term levodopa therapy such as abnormal involuntary movements (e.g., dyskinesias) and the marked swings in motor function (“on-off’’ phenomenon). Continued efficacy of bromocriptine therapy during treatment of more than 2 years has not been established.

      Data are insufficient to evaluate potential benefit from treating newly diagnosed Parkinson’s disease with bromocriptine. Studies have shown, however, significantly more adverse reactions (notably nausea, hallucinations, confusion and hypotension) in bromocriptine treated patients than in levodopa/carbidopa-treated patients. Patients unresponsive to levodopa are poor candidates for bromocriptine therapy.

CONTRAINDICATIONS

Hypersensitivity to bromocriptine or to any of the excipients of bromocriptine mesylate, uncontrolled hypertension and sensitivity to any ergot alkaloids. In patients being treated for hyperprolactinemia bromocriptine mesylate should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that bromocriptine is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When bromocriptine is being used to treat acromegaly, prolactinoma, or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine is considered to be medically contraindicated.

      The drug should not be used during the postpartum period in women with a history of coronary artery disease and other severe cardiovascular conditions unless withdrawal is considered medically contraindicated. If the drug is used in the postpartum period the patient should be observed with caution.

WARNINGS

Since hyperprolactinemia with amenorrhea/galactorrhea and infertility has been found in patients with pituitary tumors, a complete evaluation of the pituitary is indicated before treatment with bromocriptine mesylate.

      If pregnancy occurs during bromocriptine administration, careful observation of these patients is mandatory. Prolactin-secreting adenomas may expand and compression of the optic or other cranial nerves may occur, emergency pituitary surgery becoming necessary. In most cases, the compression resolves following delivery. Reinitiation of bromocriptine treatment has been reported to produce improvement in the visual fields of patients in whom nerve compression has occurred during pregnancy. The safety of bromocriptine treatment during pregnancy to the mother and fetus has not been established.

      Bromocriptine has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. Patients must be informed of this and advised not to drive or operate machines during treatment with bromocriptine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must not drive or operate machines. Furthermore, a reduction of dosage or termination of therapy may be considered.

      Symptomatic hypotension can occur in patients treated with bromocriptine for any indication. In postpartum studies with bromocriptine, decreases in supine systolic and diastolic pressures of greater than 20 mm and 10 mm Hg, respectively, have been observed in almost 30% of patients receiving bromocriptine. On occasion, the drop in supine systolic pressure was as much as 50-59 mm of Hg.

      Since, especially during the first days of treatment, hypotensive reactions may occasionally occur and result in reduced alertness, particular care should be exercised when driving a vehicle or operating machinery.

        While hypotension during the start of therapy with bromocriptine occurs in some patients, in postmarketing experience in the U.S. in postpartum patients 89 cases of hypertension have been reported, sometimes at the initiation of therapy, but often developing in the second week of therapy; seizures have been reported in 72 cases (including 4 cases of status epilepticus), both with and without the prior development of hypertension; 30 cases of stroke have been reported mostly in postpartum patients whose prenatal and obstetric courses had been uncomplicated. Many of these patients experiencing seizures and/or strokes reported developing a constant and often progressively severe headache hours to days prior to the acute event. Some cases of strokes and seizures were also preceded by visual disturbances (blurred vision, and transient cortical blindness). Nine cases of acute myocardial infarction have been reported.

      Although a causal relationship between bromocriptine administration and hypertension, seizures, strokes, and myocardial infarction in postpartum women has not been established, use of the drug for prevention of physiological lactation, or in patients with uncontrolled hypertension is not recommended. In patients being treated for hyperprolactinemia bromocriptine should be withdrawn when pregnancy is diagnosed (see PRECAUTIONS, Hyperprolactinemic States). In the event that bromocriptine is reinstituted to control a rapidly expanding macroadenoma (see PRECAUTIONS, Hyperprolactinemic States) and a patient experiences a hypertensive disorder of pregnancy, the benefit of continuing bromocriptine must be weighed against the possible risk of its use during a hypertensive disorder of pregnancy. When bromocriptine is being used to treat acromegaly or Parkinson’s disease in patients who subsequently become pregnant, a decision should be made as to whether the therapy continues to be medically necessary or can be withdrawn. If it is continued, the drug should be withdrawn in those who may experience hypertensive disorders of pregnancy (including eclampsia, preeclampsia, or pregnancy-induced hypertension) unless withdrawal of bromocriptine is considered to be medically contraindicated. Because of the possibility of an interaction between bromocriptine and other ergot alkaloids, the concomitant use of these medications is not recommended. Periodic monitoring of the blood pressure, particularly during the first weeks of therapy is prudent. If hypertension, severe, progressive, or unremitting headache (with or without visual disturbance), or evidence of CNS toxicity develops, drug therapy should be discontinued and the patient should be evaluated promptly. Particular attention should be paid to patients who have recently been treated or are on concomitant therapy with drugs that can alter blood pressure. Their concomitant use in the puerperium is not recommended.

      Among patients on bromocriptine, particularly on long-term and high-dose treatment, pleural and pericardial effusions, as well as pleural and pulmonary fibrosis and constrictive pericarditis, have occasionally been reported. Patients with unexplained pleuropulmonary disorders should be examined thoroughly and discontinuation of bromocriptine therapy should be considered. In those instances in which bromocriptine treatment was terminated, the changes slowly reverted towards normal.

      In a few patients on bromocriptine, particularly on long-term and high-dose treatment, retroperitoneal fibrosis has been reported. To ensure recognition of retroperitoneal fibrosis at an early reversible stage it is recommended that its manifestations (e.g., back pain, edema of the lower limbs, impaired kidney function) should be watched in this category of patients. Bromocriptine medication should be withdrawn if fibrotic changes in the retroperitoneum are diagnosed or suspected.

PRECAUTIONS

General

Safety and efficacy of bromocriptine mesylate have not been established in patients with renal or hepatic disease. Care should be exercised when administering bromocriptine therapy concomitantly with other medications known to lower blood pressure.

      The drug should be used with caution in patients with a history of psychosis or cardiovascular disease. If acromegalic patients or patients with prolactinoma or Parkinson’s disease are being treated with bromocriptine during pregnancy, they should be cautiously observed, particularly during the postpartum period if they have a history of cardiovascular disease.

      Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hyperprolactinemic States

Visual field impairment is a known complication of macroprolactinoma. Effective treatment with bromocriptine leads to a reduction in hyperprolactinemia and often to a resolution of the visual impairment. In some patients, however, a secondary deterioration of visual fields may subsequently develop despite normalized prolactin levels and tumor shrinkage, which may result from traction on the optic chiasm which is pulled down into the now partially empty sella. In these cases the visual field defect may improve on reduction of bromocriptine dosage while there is some elevation of prolactin and some tumor re-expansion. Monitoring of visual fields in patients with macroprolactinoma is therefore recommended for an early recognition of secondary field loss due to chiasmal herniation and adaptation of drug dosage.

      The relative efficacy of bromocriptine versus surgery in preserving visual fields is not known. Patients with rapidly progressive visual field loss should be evaluated by a neurosurgeon to help decide on the most appropriate therapy.

      Since pregnancy is often the therapeutic objective in many hyperprolactinemic patients presenting with amenorrhea/galactorrhea and hypogonadism (infertility), a careful assessment of the pituitary is essential to detect the presence of a prolactin-secreting adenoma. Patients not seeking pregnancy, or those harboring large adenomas, should be advised to use contraceptive measures, other than oral contraceptives, during treatment with bromocriptine. Since pregnancy may occur prior to reinitiation of menses, a pregnancy test is recommended at least every 4 weeks during the amenorrheic period, and, once menses are reinitiated, every time a patient misses a menstrual period. Treatment with Bromocriptine Capsules should be discontinued as soon as pregnancy has been established. Patients must be monitored closely throughout pregnancy for signs and symptoms that may signal the enlargement of a previously undetected or existing prolactin-secreting tumor. Discontinuation of bromocriptine treatment in patients with known macroadenomas has been associated with rapid regrowth of tumor and increase in serum prolactin in most cases.

      In some patients with prolactin-secreting adenomas treated with bromocriptine, cerebrospinal fluid rhinorrhea has been observed. The data available suggest that this may result from shrinkage of invasive tumors.

Acromegaly

Cold sensitive digital vasospasm has been observed in some acromegalic patients treated with bromocriptine. The response, should it occur, can be reversed by reducing the dose of bromocriptine and may be prevented by keeping the fingers warm. Cases of severe gastrointestinal bleeding from peptic ulcers have been reported, some fatal. Although there is no evidence that bromocriptine increases the incidence of peptic ulcers in acromegalic patients, symptoms suggestive of peptic ulcer should be investigated thoroughly and treated appropriately. Patients with a history of peptic ulcer or gastrointestinal bleeding should be observed carefully during treatment with bromocriptine.

      Possible tumor expansion while receiving bromocriptine therapy has been reported in a few patients. Since the natural history of growth hormone secreting tumors is unknown, all patients should be carefully monitored and, if evidence of tumor expansion develops, discontinuation of treatment and alternative procedures considered.

Parkinson’s Disease

Safety during long-term use for more than 2 years at the doses required for parkinsonism has not been established.

      As with any chronic therapy, periodic evaluation of hepatic, hematopoietic, cardiovascular, and renal function is recommended. Symptomatic hypotension can occur and, therefore, caution should be exercised when treating patients receiving antihypertensive drugs.

      High doses of bromocriptine may be associated with confusion and mental disturbances. Since parkinsonian patients may manifest mild degrees of dementia, caution should be used when treating such patients.

      Bromocriptine mesylate administered alone or concomitantly with levodopa may cause hallucinations (visual or auditory). Hallucinations usually resolve with dosage reduction; occasionally, discontinuation of bromocriptine is required. Rarely, after high doses, hallucinations have persisted for several weeks following discontinuation of bromocriptine.

      As with levodopa, caution should be exercised when administering bromocriptine to patients with a history of myocardial infarction who have a residual atrial, nodal, or ventricular arrhythmia.

      Retroperitoneal fibrosis has been reported in a few patients receiving long-term therapy (2-10 years) with bromocriptine in doses ranging from 30-140 mg daily.

Information for Patients

During clinical trials, dizziness, drowsiness, faintness, fainting, and syncope have been reported early in the course of bromocriptine therapy. In postmarketing reports, bromocriptine has been associated with somnolence, and episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported very rarely. All patients receiving bromocriptine should be cautioned with regard to engaging in activities requiring rapid and precise responses, such as driving an automobile or operating machinery. Patients being treated with bromocriptine and presenting with somnolence and/or sudden sleep episodes must be advised not to drive or engage in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g., operating machines) until such recurrent episodes and somnolence have resolved.

      Patients receiving bromocriptine mesylate for hyperprolactinemic states associated with macroadenoma or those who have had previous transsphenoidal surgery, should be told to report any persistent watery nasal discharge to their physician. Patients receiving bromocriptine for treatment of a macroadenoma should be told that discontinuation of drug may be associated with rapid regrowth of the tumor and recurrence of their original symptoms.

Drug Interactions

The risk of using bromocriptine in combination with other drugs has not been systematically evaluated, but alcohol may potentiate the side effects of bromocriptine. Bromocriptine may interact with dopamine antagonists, butyrophenones, and certain other agents. Compounds in these categories result in a decreased efficacy of bromocriptine: phenothiazines, haloperidol, metoclopramide, pimozide. Bromocriptine is both a substrate and an inhibitor of CYP3A4. Caution should therefore be used when coadministering drugs that are strong inhibitors and/or substrates of this enzyme (azole antimycotics, HIV protease inhibitors). The concomitant use of macrolide antibiotics such as erythromycin was shown to increase the plasma levels of bromocriptine. The concomitant treatment of acromegalic patients with bromocriptine and octreotide led to increased plasma levels of bromocriptine. Concomitant use of bromocriptine with other ergot alkaloids is not recommended.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 74-week study was conducted in mice using dietary levels of bromocriptine mesylate equivalent to oral doses of 10 and 50 mg/kg/day. A 100-week study in rats was conducted using dietary levels equivalent to oral doses of 1.7, 9.8, and 44 mg/kg/day. The highest doses tested in mice and rats were approximately 2.5 and 4.4 times, respectively, the maximum human dose administered in controlled clinical trials (100 mg/day) based on body surface area. Malignant uterine tumors, endometrial and myometrial, were found in rats as follows: 0/50 control females, 2/50 females given 1.7 mg/kg daily, 7/49 females given 9.8 mg/kg daily, and 9/50 females given 44 mg/kg daily. The occurrence of these neoplasms is probably attributable to the high estrogen/progesterone ratio which occurs in rats as a result of the prolactin-inhibiting action of bromocriptine mesylate. The endocrine mechanisms believed to be involved in the rats are not present in humans. There is no known correlation between uterine malignancies occurring in bromocriptine-treated rats and human risk. In contrast to the findings in rats, the uteri from mice killed after 74 weeks of treatment did not exhibit evidence of drug-related changes.

      Bromocriptine mesylate was evaluated for mutagenic potential in the battery of tests that included Ames bacterial mutation assay, mutagenic activity in vitro on V79 Chinese hamster fibroblasts, cytogenetic analysis of Chinese hamster bone marrow cells following in vivo treatment, and an in vivo micronucleus test for mutagenic potential in mice.

      No mutagenic effects were obtained in any of these tests.

      Fertility and reproductive performance in female rats were not influenced adversely by treatment with bromocriptine beyond the predicted decrease in the weight of pups due to suppression of lactation. In males treated with 50 mg/kg of this drug, mating and fertility were within the normal range. Increased perinatal loss was produced in the subgroups of dams, sacrificed on day 21 postpartum (p.p.) after mating with males treated with the highest dose (50 mg/kg).

Pregnancy

Category B: Administration of 10-30 mg/kg of bromocriptine to 2 strains of rats on days 6-15 post coitum (p.c.) as well as a single dose of 10 mg/kg on day 5 p.c. interfered with nidation. Three mg/kg given on days 6-15 were without effect on nidation, and did not produce any anomalies. In animals treated from day 8-15 p.c., i.e., after implantation, 30 mg/kg produced increased prenatal mortality in the form of increased incidence of embryonic resorption. One anomaly, aplasia of spinal vertebrae and ribs, was found in the group of 262 fetuses derived from the dams treated with 30 mg/kg bromocriptine. No fetotoxic effects were found in offspring of dams treated during the peri- or post-natal period.

      Two studies were conducted in rabbits (2 strains) to determine the potential to interfere with nidation. Dose levels of 100 or 300 mg/kg/day from day 1 to day 6 p.c. did not adversely affect nidation. The high dose was approximately 63 times the maximum human dose administered in controlled clinical trials (100 mg/day), based on body surface area. In New Zealand white rabbits, some embryo mortality occurred at 300 mg/kg which was a reflection of overt maternal toxicity. Three studies were conducted in 2 strains of rabbits to determine the teratological potential of bromocriptine at dose levels of 3, 10, 30, 100, and 300 mg/kg given from day 6 to day 18 p.c. In 2 studies with the Yellow-silver strain, cleft palate was found in 3 and 2 fetuses at maternally toxic doses of 100 and 300 mg/kg, respectively. One control fetus also exhibited this anomaly. In the third study conducted with New Zealand white rabbits using an identical protocol, no cleft palates were produced.

      No teratological or embryotoxic effects of bromocriptine were produced in any of 6 offspring from 6 monkeys at a dose level of 2 mg/kg.

      Information concerning 1276 pregnancies in women taking bromocriptine has been collected. In the majority of cases, bromocriptine was discontinued within 8 weeks into pregnancy (mean 28.7 days), however, 8 patients received the drug continuously throughout pregnancy. The mean daily dose for all patients was 5.8 mg (range 1-40 mg).

      Of these 1276 pregnancies, there were 1088 full term deliveries (4 stillborn), 145 spontaneous abortions (11.4%), and 28 induced abortions (2.2%). Moreover, 12 extrauterine gravidities and 3 hydatidiform moles (twice in the same patient) caused early termination of pregnancy. These data compare favorably with the abortion rate (11%-25%) cited for pregnancies induced by clomiphene citrate, menopausal gonadotropin, and chorionic gonadotropin.

      Although spontaneous abortions often go unreported, especially prior to 20 weeks of gestation, their frequency has been estimated to be 15%.

      The incidence of birth defects in the population at large ranges from 2%-4.5%. The incidence in 1109 live births from patients receiving bromocriptine is 3.3%.

      There is no suggestion that bromocriptine contributed to the type or incidence of birth defects in this group of infants.

Nursing Mothers

Bromocriptine should not be used during lactation in postpartum women.

Pediatric Use

The safety and effectiveness of bromocriptine for the treatment of prolactin-secreting pituitary adenomas have been established in patients age 16 to adult. No data are available for bromocriptine use in pediatric patients under the age of 8 years. A single 8-year old patient treated with bromocriptine for a prolactin-secreting pituitary macroadenoma has been reported without therapeutic response.

      The use of bromocriptine for the treatment of prolactin-secreting adenomas in pediatric patients in the age group 11 to under 16 years is supported by evidence from well-controlled trials in adults, with additional data in a limited number (n=14) of children and adolescents 11 to 15 years of age with prolactin-secreting pituitary macro- and microadenomas who have been treated with bromocriptine. Of the 14 reported patients, 9 had successful outcomes, 3 partial responses, and 2 failed to respond to bromocriptine treatment. Chronic hypopituitarism complicated macroadenoma treatment in 5 of the responders, both in patients receiving bromocriptine alone and in those who received bromocriptine in combination with surgical treatment and/or pituitary irradiation.

      Safety and effectiveness of bromocriptine in pediatric patients have not been established for any other indication listed in the INDICATIONS AND USAGE section.

Geriatric Use

Clinical studies for bromocriptine did not include sufficient numbers of subjects aged 65 and over to determine whether the elderly respond differently from younger subjects. However, other reported clinical experiences, including postmarketing reporting of adverse events, have not identified differences in response or tolerability between elderly and younger patients. Even though no variation in efficacy or adverse reaction profile in geriatric patients taking bromocriptine has been observed, greater sensitivity of some elderly individuals cannot be categorically ruled out. In general, dose selection for an elderly patient should be cautious, starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy in this population.

ADVERSE REACTIONS

Adverse Reactions from Clinical Trials

Hyperprolactinemic Indications

The incidence of adverse effects is quite high (69%) but these are generally mild to moderate in degree. Therapy was discontinued in approximately 5% of patients because of adverse effects. These in decreasing order of frequency are: nausea (49%), headache (19%), dizziness (17%), fatigue (7%), lightheadedness (5%), vomiting (5%), abdominal cramps (4%), nasal congestion (3%), constipation (3%), diarrhea (3%) and drowsiness (3%).

      A slight hypotensive effect may accompany bromocriptine mesylate treatment. The occurrence of adverse reactions may be lessened by temporarily reducing dosage to ½ of a scored tablet 2 or 3 times daily. A few cases of cerebrospinal fluid rhinorrhea have been reported in patients receiving bromocriptine for treatment of large prolactinomas. This has occurred rarely, usually only in patients who have received previous transsphenoidal surgery, pituitary radiation, or both, and who were receiving bromocriptine for tumor recurrence. It may also occur in previously untreated patients whose tumor extends into the sphenoid sinus.

Acromegaly

The most frequent adverse reactions encountered in acromegalic patients treated with bromocriptine were: nausea (18%), constipation (14%), postural/orthostatic hypotension (6%), anorexia (4%), dry mouth/nasal stuffiness (4%), indigestion/dyspepsia (4%), digital vasospasm (3%), drowsiness/tiredness (3%) and vomiting (2%).

      Less frequent adverse reactions (less than 2%) were: gastrointestinal bleeding, dizziness, exacerbation of Raynaud’s syndrome, headache and syncope. Rarely (less than 1%) hair loss, alcohol potentiation, faintness, lightheadedness, arrhythmia, ventricular tachycardia, decreased sleep requirement, visual hallucinations, lassitude, shortness of breath, bradycardia, vertigo, paresthesia, sluggishness, vasovagal attack, delusional psychosis, paranoia, insomnia, heavy headedness, reduced tolerance to cold, tingling of ears, facial pallor and muscle cramps have been reported.

Parkinson’s Disease

In clinical trials in which bromocriptine was administered with concomitant reduction in the dose of levodopa/carbidopa, the most common newly appearing adverse reactions were: nausea, abnormal involuntary movements, hallucinations, confusion, “on-off’’ phenomenon, dizziness, drowsiness, faintness/fainting, vomiting, asthenia, abdominal discomfort, visual disturbance, ataxia, insomnia, depression, hypotension, shortness of breath, constipation, and vertigo.

      Less common adverse reactions which may be encountered include: anorexia, anxiety, blepharospasm, dry mouth, dysphagia, edema of the feet and ankles, erythromelalgia, epileptiform seizure, fatigue, headache, lethargy, mottling of skin, nasal stuffiness, nervousness, nightmares, paresthesia, skin rash, urinary frequency, urinary incontinence, urinary retention, and rarely, signs and symptoms of ergotism such as tingling of fingers, cold feet, numbness, muscle cramps of feet and legs or exacerbation of Raynaud’s syndrome.

      Abnormalities in laboratory tests may include elevations in blood urea nitrogen, SGOT, SGPT, GGPT, CPK, alkaline phosphatase and uric acid, which are usually transient and not of clinical significance.

Adverse Reactions from Postmarketing Experience

Pleural and pericardial effusions, pleural, and pulmonary fibrosis or retroperitoneal fibrosis and constrictive pericarditis have been reported rarely in patients treated with bromocriptine.

      Very rarely, a syndrome resembling Neuroleptic Malignant Syndrome has been reported on abrupt withdrawal of bromocriptine.

      Blurred vision, dyskinesia, and psychomotor agitation/excitation have also occurred in postmarketing experiences.

Adverse Events Observed in Other Conditions

Postpartum Patients

In postpartum studies with bromocriptine 23 percent of postpartum patients treated had at least 1 side effect, but they were generally mild to moderate in degree. Therapy was discontinued in approximately 3% of patients. The most frequently occurring adverse reactions were: headache (10%), dizziness (8%), nausea (7%), vomiting (3%), fatigue (1.0%), syncope (0.7%), diarrhea (0.4%) and cramps (0.4%). Decreases in blood pressure (≥ 20 mm Hg systolic and ≥ 10 mm Hg diastolic) occurred in 28% of patients at least once during the first 3 postpartum days; these were usually of a transient nature. Reports of fainting in the puerperium may possibly be related to this effect. In postmarketing experience in the U.S. serious adverse reactions reported include 72 cases of seizures (including 4 cases of status epilepticus), 30 cases of stroke, and 9 cases of myocardial infarction among postpartum patients. Seizure cases were not necessarily accompanied by the development of hypertension. An unremitting and often progressively severe headache, sometimes accompanied by visual disturbance, often preceded by hours to days many cases of seizure and/or stroke. Most patients had shown no evidence of any of the hypertensive disorders of pregnancy including eclampsia, preeclampsia or pregnancy induced hypertension. One stroke case was associated with sagittal sinus thrombosis, and another was associated with cerebral and cerebellar vasculitis. One case of myocardial infarction was associated with unexplained disseminated intravascular coagulation and a second occurred in conjunction with use of another ergot alkaloid. The relationship of these adverse reactions to bromocriptine administration has not been established.

OVERDOSAGE

The most commonly reported signs and symptoms associated with acute bromocriptine mesylate overdose are: nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established and the drug has a very wide margin of safety. However, one death occurred in a patient who committed suicide with an unknown quantity of bromocriptine and chloroquine.

      Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering I.V. fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.

DOSAGE AND ADMINISTRATION

General

It is recommended that bromocriptine mesylate be taken with food. Patients should be evaluated frequently during dose escalation to determine the lowest dosage that produces a therapeutic response.

Hyperprolactinemic Indications

The initial dosage of bromocriptine in adults is ½ to one 2½ mg scored tablet daily. An additional 2½ mg tablet may be added to the treatment regimen as tolerated every 2-7 days until an optimal therapeutic response is achieved. The therapeutic dosage ranged from 2.5-15 mg daily in adults studied clinically.

      Based on limited data in children of age 11 to 15, (see Pediatric Use) the initial dose is ½ to one 2½ mg scored tablet daily. Dosing may need to be increased as tolerated until a therapeutic response is achieved. The therapeutic dosage ranged from 2.5-10 mg daily in children with prolactin-secreting pituitary adenomas.

      In order to reduce the likelihood of prolonged exposure to bromocriptine should an unsuspected pregnancy occur, a mechanical contraceptive should be used in conjunction with bromocriptine therapy until normal ovulatory menstrual cycles have been restored. Contraception may then be discontinued in patients desiring pregnancy.

      Thereafter, if menstruation does not occur within 3 days of the expected date, bromocriptine therapy should be discontinued and a pregnancy test performed.

Acromegaly

Virtually all acromegalic patients receiving therapeutic benefit from bromocriptine also have reductions in circulating levels of growth hormone. Therefore, periodic assessment of circulating levels of growth hormone will, in most cases, serve as a guide in determining the therapeutic potential of bromocriptine. If, after a brief trial with bromocriptine therapy, no significant reduction in growth hormone levels has taken place, careful assessment of the clinical features of the disease should be made, and if no change has occurred, dosage adjustment or discontinuation of therapy should be considered.

      The initial recommended dosage of bromocriptine is ½ to one 2½ mg scored tablet on retiring (with food) for 3 days. An additional ½ to 1 tablet should be added to the treatment regimen as tolerated every 3-7 days until the patient obtains optimal therapeutic benefit. Patients should be reevaluated monthly and the dosage adjusted based on reductions of growth hormone or clinical response. The usual optimal therapeutic dosage range of bromocriptine varies from 20-30 mg/day in most patients. The maximal dosage should not exceed 100 mg/day.

      Patients treated with pituitary irradiation should be withdrawn from bromocriptine therapy on a yearly basis to assess both the clinical effects of radiation on the disease process as well as the effects of bromocriptine therapy. Usually a 4-8 week withdrawal period is adequate for this purpose. Recurrence of the signs/symptoms or increases in growth hormone indicate the disease process is still active and further courses of bromocriptine should be considered.

Parkinson’s Disease

The basic principle of bromocriptine therapy is to initiate treatment at a low dosage and, on an individual basis, increase the daily dosage slowly until a maximum therapeutic response is achieved. The dosage of levodopa during this introductory period should be maintained, if possible. The initial dose of bromocriptine is ½ of a 2½ mg scored tablet twice daily with meals. Assessments are advised at 2-week intervals during dosage titration to ensure that the lowest dosage producing an optimal therapeutic response is not exceeded. If necessary, the dosage may be increased every 14-28 days by 2½ mg/day with meals. Should it be advisable to reduce the dosage of levodopa because of adverse reactions, the daily dosage of bromocriptine, if increased, should be accomplished gradually in small (2½ mg) increments.

      The safety of bromocriptine has not been demonstrated in dosages exceeding 100 mg/day.

HOW SUPPLIED

Bromocriptine Mesylate Capsules, USP

5 mg

Yellow and white capsules, each containing 5 mg bromocriptine (as the mesylate). Imprinted in red ink “GG” on one half and “537” on other half.

      Packages of 30……………………………………………………..NDC 0781-2119-31

      Packages of 100……………………………………………………NDC 0781-2119-01

Store and Dispense

Below 25ºC (77ºF); tight, light-resistant container.

REV: NOVEMBER 2009                                  T2009-116                                                            

Manufactured by:

Novartis Pharmaceuticals Corporation

Suffern, NY 10901 for

Sandoz Inc.

Princeton, NJ 08540

PRINCIPAL DISPLAY PANEL

Package Label – 5 mg

Rx Only             NDC 0781-2119-01

Bromocriptine Mesylate Capsules, USP

Each capsule contains:

bromocriptine (as the mesylate)

100 capsules

BROMOCRIPTINE MESYLATE  bromocriptine mesylate  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0781-2119 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BROMOCRIPTINE (BROMOCRIPTINE) BROMOCRIPTINE 5 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   GELATIN   LACTOSE   MAGNESIUM STEARATE   FERRIC OXIDE RED   SILICON DIOXIDE   SODIUM LAURYL SULFATE   STARCH, CORN   TITANIUM DIOXIDE   FERRIC OXIDE YELLOW

Product Characteristics Color YELLOW (yellow and white) Score no score Shape CAPSULE Size 16mm Flavor Imprint Code GG;537 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0781-2119-01 100 CAPSULE In 1 PACKAGE None 2 0781-2119-31 30 CAPSULE In 1 PACKAGE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA AUTHORIZED GENERIC	NDA017962	06/28/1978

Labeler - Sandoz Inc (110342024)

Revised: 04/2010

Bupropion Tablets

Dosage Form: tablet, film coated, extended release
Bupropion Hydrochloride Extended-Release Tablets USP (XL)

“Medication Guide” enclosed.

WARNING

Suicidality and Antidepressant Drugs

Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of bupropion hydrochloride extended-release tablets (XL) or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Bupropion hydrochloride extended-release tablets (XL) are not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)

Use in Smoking Cessation Treatment: WELLBUTRIN® (bupropion hydrochloride tablets), WELLBUTRIN SR® (bupropion hydrochloride extended-release tablets (SR)), and bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment, but bupropion under the name ZYBAN® is approved for this use. Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking bupropion for smoking cessation. Some 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.

All patients treated with Bupropion for smoking cessation treatment should be observed for neuropsychiatric symptoms including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking ZYBAN® in the post-marketing experience. When symptoms were reported, most were during treatment with ZYBAN®, but some were following discontinuation of treatment with ZYBAN®. These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses.

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, hostility, depressed mood, or changes in thinking or behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing 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. (See WARNINGS: Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients.)

DESCRIPTION

Bupropion hydrochloride extended-release tablets (XL), an antidepressant of the aminoketone class, are 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 C13H18ClNO•HCl. 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. The structural formula is:

Bupropion hydrochloride extended-release tablets (XL) are supplied for oral administration as 150-mg and 300-mg, round white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: dehydrated alcohol, ethylcellulose, hydrochloric acid, hydroxypropylcellulose, methacrylic acid copolymer, povidone, silicon dioxide, hydrogenated vegetable oil and ethyl alcohol. The tablets are printed with edible black ink.

The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is eliminated in the feces. USP drug release testing is pending.

CLINICAL PHARMACOLOGY

Pharmacodynamics:

Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of serotonin. While the mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.

Pharmacokinetics:

Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.

In a study comparing 14-day dosing with a bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the 3 metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with a bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the 3 metabolites.

Absorption: Following oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, time to peak plasma concentrations for bupropion was approximately 5 hours and food did not affect the Cmax or AUC of bupropion.

Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been shown to be 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 cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 isoenzymes 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.

Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by or which inhibit /induce the cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir or efavirenz. In a healthy volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38% and the erythrohydrobupropion decreased by 48%.

In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50% and the erythrohydrobupropion decreased by 68%.

In another healthy volunteer study, KALETRA® * (lopinavir 400 mg/ritonavir 100 mg twice daily) decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were decreased by 50% and 31%, respectively, (see PRECAUTIONS: Drug Interactions).

In a study in healthy volunteers, efzvirenz 600mg once daily for 2 weeks reduces the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.

Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is coadministered with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).

In humans, peak plasma concentrations of hydroxybupropion occur approximately 7 hours after administration of bupropion hydrochloride extended-release tablets (XL). Following administration of bupropion hydrochloride extended-release tablets (XL), peak plasma concentrations of hydroxybupropion are approximately 7 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, approximately 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.4 and 7 times that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.

Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.

Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. 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.

Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in patients with mild to severe cirrhosis. The first study showed that the half-life of hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in 8 healthy volunteers (32±14 hours versus 21±5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 patient groups were minimal.

The second study showed no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Renal: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A second study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150 mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced by impaired renal function (see PRECAUTIONS: Renal Impairment).

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), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy volunteers.

Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use).

Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.

Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

CLINICAL TRIALS

Major Depressive Disorder: The efficacy of bupropion as a treatment for major depressive disorder was established with the immediate-release formulation of bupropion in two 4-week, placebo-controlled trials in adult inpatients and in one 6-week, placebo-controlled trial in adult outpatients. In the first study, patients were titrated in a bupropion dose range of 300 to 600 mg/day of the immediate-release formulation on a 3 times daily schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated the effectiveness of bupropion on the Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A second study included 2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial demonstrated the effectiveness of bupropion, but only at the 450-mg/day dose of the immediate-release formulation; the results were positive for the HDRS total score and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received 300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the effectiveness of bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI improvement score.

In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on bupropion (150 mg twice daily of the sustained-release formulation) were randomized to continuation of their same dose of bupropion or placebo, for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued bupropion treatment experienced significantly lower relapse rates over the subsequent 44 weeks compared to those receiving placebo.

Although there are no independent trials demonstrating the antidepressant effectiveness of bupropion hydrochloride extended-release tablets (XL), studies have demonstrated similar bioavailability of bupropion hydrochloride extended-release tablets (XL) to both the immediate-release formulation and to the sustained-release formulation of bupropion under steady-state conditions, i.e., bupropion hydrochloride extended-release tablets (XL) 300 mg once daily was shown to have bioavailability that was similar to that of 100 mg 3 times daily of the immediate-release formulation of bupropion and to that of 150 mg 2 times daily of the sustained-release formulation of bupropion, with regard to both peak plasma concentration and extent of absorption, for parent drug and metabolites.

Seasonal Affective Disorder: The efficacy of bupropion hydrochloride extended-release tablets (XL) for the prevention of seasonal major depressive episodes associated with seasonal affective disorder was established in 3 double-blind, placebo-controlled trials in adult outpatients with a history of major depressive disorder with an autumn-winter seasonal pattern (as defined by DSM-IV criteria). Treatment was initiated prior to the onset of symptoms in the autumn (September to November) and was discontinued following a 2 week taper that began 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. At the start of the study, patients were randomized to receive placebo or bupropion hydrochloride extended-release tablets (XL) 150 mg once daily for 1 week, followed by up-titration to 300 mg once daily. Patients who were deemed by the investigator to be unlikely or unable to tolerate 300 mg once daily were allowed to remain on, or had their dose reduced to, 150 mg once daily. The mean doses of bupropion hydrochloride extended-release tablets (XL) in the 3 studies ranged from 257 to 280 mg/day.

In these 3 trials, the percentage of patients who were depression-free at the end of treatment was significantly higher for bupropion hydrochloride extended-release tablets (XL) than for placebo: 81.4% vs 69.7%, 87.2% vs 78.7%, and 84.0% vs 69.0% for Study 1, 2 and 3, respectively; with a depression-free rate for the 3 studies combined of 84.3% vs 72.0%.

INDICATIONS AND USAGE

Major Depressive Disorder: Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder.

The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of inpatients and in one 6-week controlled trial of outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL TRIALS).

A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt, or suicidal ideation.

The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial with the sustained-release formulation of bupropion (see CLINICAL TRIALS). Nevertheless, the physician who elects to use bupropion hydrochloride extended-release tablets (XL) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Seasonal Affective Disorder: Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder.

The efficacy of bupropion hydrochloride extended-release tablets (XL) for the prevention of seasonal major depressive episodes was established in 3 controlled trials of adult outpatients with a history of major depressive disorder with an autumn-winter seasonal pattern as defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria (see CLINICAL TRIALS).

Seasonal affective disorder is characterized by recurrent major depressive episodes, most commonly occurring during the autumn and/or winter months. Episodes may last up to 6 months in duration, typically beginning in the autumn and remitting in the springtime. Although patients with seasonal affective disorder may have depressive episodes during other times of the year, the diagnosis of seasonal affective disorder requires that the number of seasonal episodes substantially outnumber the number of non-seasonal episodes during the individual's lifetime.

CONTRAINDICATIONS

Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a seizure disorder.

Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients treated with ZYBAN® (bupropion hydrochloride extended-release tablets (XL)); WELLBUTRIN® (bupropion hydrochloride tablets), the immediate-release formulation; WELLBUTRIN SR® (bupropion hydrochloride extended-release tablets (SR)), the sustained-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent.

Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia with the immediate-release formulation of bupropion.

Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).

The concurrent administration of bupropion hydrochloride extended-release tablets (XL) and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride extended-release tablets (XL).

Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride extended-release tablets (XL).

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.

Table 1.

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18	14 additional cases
18-24	5 additional cases
Decreases Compared to Placebo
25-64	1 fewer case
>65	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 extended-release tablets (XL) 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: WELLBUTRIN® (bupropion hydrochloride tables), WELLBUTRIN SR® (bupropion hydrochloride extended-release tablets), and Bupropion hydrochloride extended-release tablets (XL) are not approved for smoking cessation treatment, but bupropion under the name ZYBAN® 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 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 post-marketing 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 extended-release tablets (XL) are not approved for use in treating bipolar depression.

Bupropion-Containing Products: Patients should be made aware that bupropion hydrochloride extended-release tablets (XL) contain the same active ingredient found in ZYBAN®, used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (XL) should not be used in combination with ZYBAN®, or any other medications that contain bupropion, such as WELLBUTRIN SR® (bupropion hydrochloride extended-release tablets (SR)), the sustained-release formulation or WELLBUTRIN® (bupropion hydrochloride tablets), the immediate-release formulation.

Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride extended-release tablets (XL).

Bupropion hydrochloride extended-release tablets (XL) should be discontinued and not restarted in patients who experience a seizure while on treatment.

As bupropion hydrochloride extended-release tablets (XL) are bioequivalent to both the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion, the seizure incidence with bupropion hydrochloride extended-release tablets (XL), while not formally evaluated in clinical trials, may be similar to that presented below for the immediate-release and sustained-release formulations of bupropion.

• Dose: At doses up to 300 mg/day of the sustained-release formulation of bupropion, the incidence of seizure is approximately 0.1% (1/1,000).

Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300 to 450 mg/day. This seizure incidence (0.4%) may exceed that of some other marketed antidepressants.

Additional data accumulated for the immediate-release formulation of bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The 600 mg dose is twice the usual adult dose and one and one-third the maximum recommended daily dose (450 mg) of bupropion hydrochloride extended-release tablets (XL). This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.

• 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 suggests that the risk of seizure may be minimized if

• the total daily dose of bupropion hydrochloride extended-release tablets (XL) does not exceed 450 mg,


• the rate of incrementation of dose is gradual.

Bupropion hydrochloride extended-release tablets (XL) 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 extended-release tablets (XL) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency and/or dose 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 150 mg every other 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.

PRECAUTIONS

General:

Agitation and Insomnia: Increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment, have been associated with treatment with bupropion. In 3 placebo-controlled clinical trials of seasonal affective disorder with bupropion hydrochloride extended-release tablets (XL), the incidence of agitation, anxiety, and insomnia are shown in Table 2.

Table 2. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials of Bupropion Hydrochloride Extended-Release Tablets (XL) for Seasonal Affective Disorder

Adverse Event Term	Bupropion Hydrochloride Extended-Release Tablets (XL) 150 to 300 mg/day (n = 537)	Placebo (n = 511)
Agitation Anxiety Insomnia	2% 7% 20%	<1% 5% 13%

Patients in placebo-controlled trials of major depressive disorder with the sustained-release formulation of bupropion, experienced agitation, anxiety, and insomnia as shown in Table 3.

Table 3. Incidence of Agitation, Anxiety, and Insomnia in Placebo-Controlled Trials of Sustained-Release Formulation of Bupropion for Major Depressive Disorder

Adverse Event Term	Sustained- Release Formulation of Bupropion 300 mg/day (n = 376)	Sustained- Release Formulation of Bupropion 400 mg/day (n = 114)	Placebo (n = 385)
Agitation Anxiety Insomnia	3% 5% 11%	9% 6% 16%	2% 3% 6%

In clinical studies of major depressive disorder, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.

Symptoms in these studies were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion sustained-release tablets and 0.8% of patients treated with placebo.

Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed patients treated with bupropion have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Bupropion hydrochloride extended-release tablets (XL) are expected to pose similar risks.

Altered Appetite and Weight: In 3 placebo-controlled clinical trials of seasonal affective disorder with bupropion hydrochloride extended-release tablets (XL), the percentage of patients with weight gain or weight loss are shown in Table 4.

Table 4. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials of Bupropion Hydrochloride Extended-Release Tablets (XL) for Seasonal Affective Disorder

Weight Change	Bupropion Hydrochloride Extended-Release Tablets (XL) 150 to 300 mg/day (n = 537)	Placebo (n = 511)
Gained >5 lbs Lost >5 lbs	11% 23%	21% 11%

In placebo-controlled studies of major depressive disorder using the sustained-release formulation of bupropion, patients experienced weight gain or weight loss as shown in Table 5.

Table 5. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials of Sustained-Release Formulation of Bupropion for Major Depressive Disorder

Weight Change	Sustained- Release Formulation of Bupropion 300 mg/day (n = 339)	Sustained- Release Formulation of Bupropion 400 mg/day (n = 112)	Placebo (n = 347)
Gained >5 lbs Lost >5 lbs	3% 14%	2% 19%	4% 6%

In studies conducted with the immediate-release formulation of bupropion, 35% of patients receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride extended-release tablets (XL) should be considered.

Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking bupropion hydrochloride extended-release tablets (XL) and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in bot