Apomorphine Hydrochloride may be available in the countries listed below.
Apomorphine Hydrochloride (BANM) is known as Apomorphine in the US.
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
Treating acne.
Benzoyl Peroxide Bar is a keratolytic agent with antibacterial actions. The effectiveness of benzoyl peroxide appears to be due to its antibacterial, peeling (keratolytic), and drying actions.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Benzoyl Peroxide Bar. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Benzoyl Peroxide Bar. Because little, if any, of Benzoyl Peroxide Bar is absorbed into the blood, the risk of it interacting with another medicine is low.
Ask your health care provider if Benzoyl Peroxide Bar may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Benzoyl Peroxide Bar as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Benzoyl Peroxide Bar.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Dryness; feeling of warmth; irritation; itching; mild peeling, redness, or swelling of the skin.
Severe allergic reactions (rash; hives; itching; dizziness; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); excessive burning, itching, redness, swelling, or tenderness of your skin; extreme dryness.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Benzoyl Peroxide side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include excessive scaling, flushing, redness, or swelling.
Store at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly closed container. Store away from heat and light. Keep Benzoyl Peroxide Bar out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Benzoyl Peroxide Bar. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Piperacilin comp. Sandoz may be available in the countries listed below.
Piperacillin sodium salt (a derivative of Piperacillin) is reported as an ingredient of Piperacilin comp. Sandoz in the following countries:
Tazobactam sodium salt (a derivative of Tazobactam) is reported as an ingredient of Piperacilin comp. Sandoz in the following countries:
International Drug Name Search
Adalat 2-Phasen may be available in the countries listed below.
Nifedipine is reported as an ingredient of Adalat 2-Phasen in the following countries:
International Drug Name Search
*Potency expressed as levalbuterol
PRESCRIBING INFORMATION
Xopenex (levalbuterol HCl) Inhalation Solution is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol. Levalbuterol HCl is a relatively selective beta2-adrenergic receptor agonist (see CLINICAL PHARMACOLOGY). The chemical name for levalbuterol HCl is (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows:
The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is C13H21NO3•HCl. It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.
Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.
Xopenex (levalbuterol HCl) Inhalation Solution is supplied in unit-dose vials and requires no dilution before administration by nebulization. Each 3 mL unit-dose vial contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) or 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) or 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and sulfuric acid to adjust the pH to 4.0 (3.3 to 4.5).
Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3´, 5´-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.
While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart that comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established (see WARNINGS). However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.
Results from an in vitro study of binding to human beta-adrenergic receptors demonstrated that levalbuterol has approximately 2-fold greater binding affinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol. In guinea pig airways, levalbuterol HCl and racemic albuterol decreased the response to spasmogens (e.g., acetylcholine and histamine), whereas (S)-albuterol was ineffective. These results suggest that the bronchodilatory effects of racemic albuterol are attributable to the (R)-enantiomer.
Intravenous studies in rats with racemic albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.
The inhalation pharmacokinetics of Xopenex Inhalation Solution were investigated in a randomized cross-over study in 30 healthy adults following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of Xopenex Inhalation Solution and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization using a PARI LC Jet™ nebulizer with a Dura-Neb® 2000 compressor.
Following administration of a single 1.25 mg dose of Xopenex Inhalation Solution, exposure to (R)-albuterol (AUC of 3.3 ng•hr/mL) was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic albuterol inhalation solution (AUC of 1.7 ng•hr/mL) (see Table 1). Following administration of a cumulative 5 mg dose of Xopenex Inhalation Solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol were comparable (see Table 1).
γ Median (Min, Max) reported for Tmax. | ||||||
| Single Dose | Cumulative Dose | |||||
| Xopenex 1.25 mg | Racemic albuterol sulfate 2.5 mg | Xopenex 5 mg | Racemic albuterol sulfate 10 mg | |||
| Cmax (ng/mL) | ||||||
| (R)-albuterol | 1.1 (0.45) | 0.8 (0.41)** | 4.5 (2.20) | 4.2 (1.51)** | ||
| Tmax (h)γ | ||||||
| (R)-albuterol | 0.2 (0.17, 0.37) | 0.2 (0.17, 1.50) | 0.2 (–0.18*, 1.25) | 0.2 (–0.28*, 1.00) | ||
| AUC (ng.h/mL) | ||||||
| (R)-albuterol | 3.3 (1.58) | 1.7 (0.99)** | 17.4 (8.56) | 16.0 (7.12)** | ||
| T½ (h) | ||||||
| (R)-albuterol | 3.3 (2.48) | 1.5 (0.61) | 4.0 (1.05) | 4.1 (0.97) | ||
The pharmacokinetic parameters of (R)- and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data are presented in Table 2. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 2.
In children, AUC and Cmax of (R)-albuterol following administration of 0.63 mg Xopenex Inhalation Solution were comparable to those following administration of 1.25 mg racemic albuterol sulfate inhalation solution.
When the same dose of 0.63 mg of Xopenex was given to children and adults, the predicted Cmax of (R)–albuterol in children was similar to that in adults (0.52 vs. 0.56 ng/mL), while predicted AUC in children (2.55 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL). These data support lower doses for children 6-11 years old compared with the adult doses (see DOSAGE AND ADMINISTRATION).
a The values are predicted by assuming linear pharmacokinetics | |||||||
| Children 6-11 years | Adults ≥12 years | ||||||
| Treatment | Xopenex 0.31 mg | Xopenex 0.63 mg | Racemic albuterol 1.25mg | Racemic albuterol 2.5 mg | Xopenex 0.63 mg | Xopenex 1.25 mg | |
| AUC0-∞ (ng•hr/mL) c | 1.36 | 2.55 | 2.65 | 5.02 | 1.65 a | 3.3 b | |
| Cmax (ng/mL) d | 0.303 | 0.521 | 0.553 | 1.08 | 0.56 a | 1.1 b | |
Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.
The primary route of elimination of albuterol enantiomers is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Xopenex Inhalation Solution has not been evaluated.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in racemic albuterol clearance. Caution should be used when administering high doses of Xopenex Inhalation Solution to patients with renal impairment.
In a randomized, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate asthma received single doses of Xopenex Inhalation Solution (0.31, 0.63, and 1.25 mg) and racemic albuterol sulfate inhalation solution (2.5 mg). All doses of active treatment produced a significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean FEV1) than placebo, and there were no significant differences between any of the active treatment arms. The bronchodilator responses to 1.25 mg of Xopenex Inhalation Solution and 2.5 mg of racemic albuterol sulfate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action (>15% increase in FEV1 from baseline) after administration of 1.25 mg of Xopenex Inhalation Solution. Systemic beta-adrenergic adverse effects were observed with all active doses and were generally dose-related for (R)-albuterol. Xopenex Inhalation Solution at a dose of 1.25 mg produced a slightly higher rate of systemic beta-adrenergic adverse effects than the 2.5 mg dose of racemic albuterol sulfate inhalation solution.
In a randomized, double-blind, placebo-controlled, cross-over study, 12 adults with mild-to-moderate asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following administration of a single dose of 2.5 mg of racemic albuterol sulfate, 1.25 mg of Xopenex, 1.25 mg of (S)-albuterol, or placebo using a PARI LC Jet™ nebulizer. Racemic albuterol sulfate, Xopenex, and (S)-albuterol had a protective effect against methacholine-induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of Xopenex was comparable to that of 2.5 mg of racemic albuterol sulfate. At 180 minutes after administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.
In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change from baseline FEV1) and safety (as measured by heart rate, blood pressure, ECG, serum potassium, and tremor) were demonstrated after a cumulative dose of 5 mg of Xopenex Inhalation Solution (four consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulfate inhalation solution (four consecutive doses of 2.5 mg administered every 30 minutes).
The safety and efficacy of Xopenex Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV1 60% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive Xopenex 0.63 mg, Xopenex 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered dose inhaler (MDI) was used on an as-needed basis as the rescue medication.
Efficacy, as measured by the mean percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29. On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of Xopenex demonstrated the largest mean percent change from baseline FEV1 compared with the other active treatments. A dose of 0.63 mg of Xopenex and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV1 on both day 1 and day 29.
Figure 1: Mean Percent Change from Baseline FEV1 on Day 1, Adults and Adolescents ≥12 years old
Figure 2: Mean Percent Change from Baseline FEV1 on Day 29, Adults and Adolescents ≥12 years old
The mean time to onset of a 15% increase in FEV1 over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration of effect, as measured by a >15% increase from baseline FEV1, was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.
A multi-center, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV1 73% of predicted) (n=316). Following a 1-week placebo run-in, subjects were randomized to Xopenex (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.
Efficacy, as measured by mean peak percent change from baseline FEV1, was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21. Time profile FEV1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15% increase in FEV1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.
Figure 3: Mean Percent Change from Baseline FEV1 on Day 1, Children 6-11 Years of Age
Figure 4: Mean Percent Change from Baseline FEV1 on Day 21, Children 6-11 Years of Age
Xopenex (levalbuterol HCl) Inhalation Solution is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.
Xopenex (levalbuterol HCl) Inhalation Solution is contraindicated in patients with a history of hypersensitivity to levalbuterol HCl or racemic albuterol.
Levalbuterol HCl, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.
Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-adrenergic agonist medications, levalbuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.
See illustrated Patient's Instructions for Use.
The action of Xopenex (levalbuterol HCl) Inhalation Solution may last up to 8 hours. Xopenex Inhalation Solution should not be used more frequently than recommended. Do not increase the dose or frequency of dosing of Xopenex Inhalation Solution without consulting your physician. If you find that treatment with Xopenex Inhalation Solution becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are taking Xopenex Inhalation Solution, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, headache, dizziness, and tremor or nervousness. If you are pregnant or nursing, contact your physician about the use of Xopenex Inhalation Solution.
Effective and safe use of Xopenex Inhalation Solution requires consideration of the following information in addition to that provided under Patient's Instructions for Use:
Xopenex Inhalation Solution single-use low-density polyethylene (LDPE) vials should be protected from light and excessive heat. Store in the protective foil pouch between 20°C and 25°C (68°F and 77°F) [see USP Controlled Room Temperature]. Do not use after the expiration date stamped on the container. Unused vials should be stored in the protective foil pouch. Once the foil pouch is opened, the vials should be used within 2 weeks. Vials removed from the pouch, if not used immediately, should be protected from light and used within 1 week. Discard any vial if the solution is not colorless.
The drug compatibility (physical and chemical), efficacy, and safety of Xopenex Inhalation Solution when mixed with other drugs in a nebulizer have not been established.
Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should be used with caution with levalbuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.
No carcinogenesis or impairment of fertility studies have been carried out with levalbuterol HCl alone. However, racemic albuterol sulfate has been evaluated for its carcinogenic potential and ability to impair fertility.
In a 2-year study in Sprague-Dawley rats, racemic albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 2 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m2 basis). In another study, this effect was blocked by the coadministration of propranolol, a nonselective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 260 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m2 basis). In a 22-month study in the Golden hamster, racemic albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 35 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults and children on a mg/m2 basis).
Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Although levalbuterol HCl has not been tested for clastogenicity, racemic albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 55 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis).
A reproduction study in New Zealand White rabbits demonstrated that levalbuterol HCl was not teratogenic when administered orally at doses up to 25 mg/kg (approximately 110 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis). However, racemic albuterol sulfate has been shown to be teratogenic in mice and rabbits. A study in CD-1 mice given racemic albuterol sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg of isoproterenol (positive control).
A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when racemic albuterol sulfate was administered orally at a dose of 50 mg/kg (approximately 110 times the maximum recommended daily inhalation dose of levalbuterol HCl for adults on a mg/m2 basis).
A study in which pregnant rats were dosed with radiolabeled racemic albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus.
There are no adequate and well-controlled studies of Xopenex Inhalation Solution in pregnant women. Because animal reproduction studies are not always predictive of human response, Xopenex Inhalation Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
During marketing experience of racemic albuterol, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with racemic albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between racemic albuterol use and congenital anomalies has not been established.
Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of Xopenex Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.
Levalbuterol HCl has not been approved for the management of preterm labor. The benefit:risk ratio when levalbuterol HCl is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including racemic albuterol.
Plasma levels of levalbuterol after inhalation of therapeutic doses are very low in humans, but it is not known whether levalbuterol is excreted in human milk.
Because of the potential for tumorigenicity shown for racemic albuterol in animal studies and the lack of experience with the use of Xopenex Inhalation Solution by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Caution should be exercised when Xopenex Inhalation Solution is administered to a nursing woman.
The safety and efficacy of Xopenex (levalbuterol HCl) Inhalation Solution have been established in pediatric patients 6 years of age and older in one adequate and well-controlled clinical trial (see CLINICAL PHARMACOLOGY; Pharmacokinetics and Clinical Trials). Use of Xopenex in children is also supported by evidence from adequate and well-controlled studies of Xopenex in adults, considering that the pathophysiology and the drug's exposure level and effects in pediatric and adult patients are substantially similar. Safety and effectiveness of Xopenex in pediatric patients below the age of 6 years have not been established.
Data on the use of Xopenex in patients 65 years of age and older are very limited. A very small number of patients 65 years of age and older were treated with Xopenex Inhalation Solution in a 4-week clinical study (see CLINICAL PHARMACOLOGY; Clinical Trials) (n=2 for 0.63 mg and n=3 for 1.25 mg). In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment. There are insufficient data to determine if the safety and efficacy of Xopenex Inhalation Solution are different in patients < 65 years of age and patients 65 years of age and older. In general, patients 65 years of age and older should be started at a dose of 0.63 mg of Xopenex Inhalation Solution. If clinically warranted due to insufficient bronchodilator response, the dose of Xopenex Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose (see DOSAGE AND ADMINISTRATION).
Adverse events reported in ≥2% of patients receiving Xopenex Inhalation Solution or racemic albuterol and more frequently than in patients receiving placebo in a 4-week, controlled clinical trial are listed in Table 3.
| Percent of Patients | ||||
| Body System Preferred Term | Placebo (n=75) | Xopenex 1.25 mg (n=73) | Xopenex 0.63 mg (n=72) | Racemic albuterol 2.5 mg (n=74) |
| Body as a Whole | ||||
| Allergic reaction | 1.3 | 0 | 0 | 2.7 |
| Flu syndrome | 0 | 1.4 | 4.2 | 2.7 |
| Accidental injury | 0 | 2.7 | 0 | 0 |
| Pain | 1.3 | 1.4 | 2.8 | 2.7 |
| Back pain | 0 | 0 | 0 | 2.7 |
| Cardiovascular System | ||||
| Tachycardia | 0 | 2.7 | 2.8 | 2.7 |
| Migraine | 0 | 2.7 | 0 | 0 |
| Digestive System | ||||
| Dyspepsia | 1.3 | 2.7 | 1.4 | 1.4 |
| Musculoskeletal System | ||||
| Leg cramps | 1.3 | 2.7 | 0 | 1.4 |
| Central Nervous System | ||||
| Dizziness | 1.3 | 2.7 | 1.4 | 0 |
| Hypertonia | 0 | 0 | 0 | 2.7 |
| Nervousness | 0 | 9.6 | 2.8 | 8.1 |
| Tremor | 0 | 6.8 | 0 | 2.7 |
| Anxiety | 0 | 2.7 | 0 | 0 |
| Respiratory System | ||||
Haenal-Polidocanol may be available in the countries listed below.
Lauromacrogol 400 is reported as an ingredient of Haenal-Polidocanol in the following countries:
International Drug Name Search
Biotrefon-L may be available in the countries listed below.
Cobamamide is reported as an ingredient of Biotrefon-L in the following countries:
International Drug Name Search
Quazépam may be available in the countries listed below.
Quazépam (DCF) is known as Quazepam in the US.
International Drug Name Search
Glossary
| DCF | Dénomination Commune Française |
May Clindamycin may be available in the countries listed below.
Clindamycin dihydrogen phosphate (a derivative of Clindamycin) is reported as an ingredient of May Clindamycin in the following countries:
Clindamycin hydrochloride (a derivative of Clindamycin) is reported as an ingredient of May Clindamycin in the following countries:
International Drug Name Search
Actiferrina may be available in the countries listed below.
Ferrous Sulfate is reported as an ingredient of Actiferrina in the following countries:
International Drug Name Search
Propranolol Actavis may be available in the countries listed below.
Propranolol is reported as an ingredient of Propranolol Actavis in the following countries:
International Drug Name Search
0023167-96-6
C7-H13-K-O8
264
Pharmaceutic aid
Treatment of potassium deficiency
D-glycero-D-gulo-Heptonic acid, monopotassium salt
International Drug Name Search
Glossary
| IS | Inofficial Synonym |
Prescribing Information
Rx only
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 (SR) 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 (SR) 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.)
WELLBUTRIN®, bupropion hydrochloride extended-release tablets (SR) and WELLBUTRIN 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 being 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 postmarketing 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 premarketing 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 postmarketing cases, resolution of symptoms after discontinuation of ZYBAN® was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. ZYBAN® has been demonstrated to increase the likelihood of abstinence from smoking for as long as 6 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.)
Bupropion hydrochloride extended-release tablets (SR), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is 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 (SR) are supplied for oral administration as 100-mg and 150-mg, film-coated, extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, magnesium stearate, and microcrystalline cellulose. The 100-mg tablet also contains FD&C Red No. 40, FD&C Yellow No. 5, hypromellose, iron oxide yellow, macrogol, polydextrose, titanium dioxide and triacetin. The 150-mg tablet also contains hypromellose, iron oxide yellow, macrogol, polydextrose, titanium dioxide and triacetin.
This product meets USP Drug Release Test #3.
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.
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 chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, peak plasma concentrations of bupropion at steady state for bupropion hydrochloride extended-release tablets (SR) was approximately 85% of those achieved with the immediate-release formulation. There was equivalence for bupropion AUCs, as well as equivalence for both peak plasma concentration and AUCs for all 3 of the detectable bupropion metabolites. Thus, at steady state, bupropion hydrochloride extended-release tablets (SR), given twice daily, and the immediate-release formulation of bupropion, given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.
Following oral administration of bupropion hydrochloride extended-release tablets (SR) to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food increased Cmax and AUC of bupropion by 11% and 17%, respectively, indicating that there is no clinically significant food effect.
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.
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. 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).
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).
Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 6 hours after administration of bupropion hydrochloride extended-release tablets (SR). Peak plasma concentrations of hydroxybupropion are approximately 10 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 17 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, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.
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.
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.
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 (t1/2) 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 11/2-fold for hydroxybupropion and about 21/2-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).
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).
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.
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).
A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
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.
The efficacy of the immediate-release formulation of bupropion as a treatment for depression was established in two 4-week, placebo-controlled trials in adult inpatients with depression and in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study, patients were titrated in a bupropion dose range of 300 to 600 mg/day on a 3 times daily schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated the effectiveness of the immediate-release formulation 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 the immediate-release formulation of bupropion, but only at the 450-mg/day dose; 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 the immediate-release formulation 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.
Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the extended-release formulation of bupropion, studies have demonstrated the bioequivalence of the immediate-release and extended-release forms of bupropion under steady-state conditions, i.e., bupropion extended-release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.
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.
Bupropion hydrochloride extended-release tablets (SR) 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 depressed inpatients and in one 6-week controlled trial of depressed outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY).
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 PHARMACOLOGY). Nevertheless, the physician who elects to use bupropion hydrochloride extended-release tablets (SR) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder.
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients treated with ZYBAN® [bupropion hydrochloride extended-release tablets (SR)]; WELLBUTRIN® (bupropion hydrochloride tablets), the immediate-release formulation; WELLBUTRIN XL® [bupropion hydrochloride extended-release tablets (XL)], the extended-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent.
Bupropion hydrochloride extended-release tablets (SR) 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 (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).
The concurrent administration of bupropion hydrochloride extended-release tablets (SR) 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 (SR).
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride extended-release tablets (SR).
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 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
|---|---|
| Increases Compared to Placebo | |
| < 18 | 14 additional cases |
| 18 to 24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25 to 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 (SR) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
WELLBUTRIN®, bupropion hydrochloride extended-release tablets (SR), and WELLBUTRIN 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 stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of ZYBAN® was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. ZYBAN® has been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
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 (SR) are not approved for use in treating bipolar depression.
Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contains the same active ingredient found in ZYBAN®, used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN®, or any other medications that contain bupropion, such as WELLBUTRIN® (bupropion hydrochloride), the immediate-release formulation or WELLBUTRIN XL® (bupropion hydrochloride), the extended-release formulation.
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 (SR).
Bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment.
Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if
Bupropion hydrochloride extended-release tablets (SR) 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.
Bupropion hydrochloride extended-release tablets (SR) 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 100 mg every day or 150 mg every other day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
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.
Patients in placebo-controlled trials with bupropion hydrochloride extended-release tablets (SR) experienced agitation, anxiety, and insomnia as shown in Table 2.
| Adverse Event Term | Bupropion hydrochloride extended-release Tablets (SR) 300 mg/day (n=376) | Bupropion hydrochloride extended-release Tablets (SR) 400 mg/day (n=114) | Placebo (n=385) |
|---|---|---|---|
| Agitation | 3% | 9% | 2% |
| Anxiety | 5% | 6% | 3% |
| Insomnia | 11% | 16% | 6% |
In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.
Symptoms 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 hydrochloride extended-release tablets (SR) and 0.8% of patients treated with placebo.
Depressed patients treated with an immediate-release formulation of bupropion or with bupropion hydrochloride extended-release tablets (SR) 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.
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 (SR) are expected to pose similar risks.
In placebo-controlled studies, patients experienced weight gain or weight loss as shown in Table 3.
| Weight Change | Bupropion hydrochloride extended-release Tablets (SR) 300 mg/day (n=339) | Bupropion hydrochloride extended-release Tablets (SR) 400 mg/day (n=112) | Placebo (n=347) |
|---|---|---|---|
| Gained > 5 lbs | 3% | 2% | 4% |
| Lost > 5 lbs | 14% | 19% | 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 (SR) should be considered.
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 (SR) 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.
The 100 mg strength of this product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.
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 both patients with and without evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN® Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of ZYBAN® and NTS and 1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with ZYBAN® or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
There is no clinical experience establishing the safety of bupropion hydrochloride extended-release tablets (SR) in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.
Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required. Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in patients with mild-to-moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY, WARNINGS, and DOSAGE AND ADMINISTRATION).
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, w
