Author: druginteractionchecker_lgaiz4

Theophylline 400 MG Extended Release Oral Tablet

Generic Name: THEOPHYLLINE
Brand Name: Theophylline (Anhydrous)
  • Substance Name(s):
  • THEOPHYLLINE ANHYDROUS

WARNINGS

Concurrent Illness Theophylline should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition: Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias) Conditions That Reduce Theophylline Clearance There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur . Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline concentrations in patients with the following risk factors: Age Neonates (term and premature) Children 60 years) Concurrent Diseases Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever; ≥102° for 24 hours or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants <3 months of age Sepsis with multi-organ failure Shock Cessation of Smoking Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See PRECAUTIONS, Drug Interactions , Table II ). When Signs or Symptoms of Theophylline Toxicity Are Present Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines , Table VI ). Dosage Increases Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the healthcare professional should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests ). As the rate of theophylline clearance may be dose-dependent (i.e., steady-state serum concentrations may increase disproportionately to the increase in dose), an increase in dose based upon a sub-therapeutic serum concentration measurement should be conservative. In general, limiting dose increases to about 25% of the previous total daily dose will reduce the risk of unintended excessive increases in serum theophylline concentration (see DOSAGE AND ADMINISTRATION , Table VI ).

DRUG INTERACTIONS

Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (See PRECAUTIONS, Drug Interactions , Table II ).

OVERDOSAGE

General The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose , i.e., ingestion of a single large excessive dose (>10 mg/kg), as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage , i.e., ingestion of repeated doses that are excessive for the patient’s rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or caregiver error in dosing, healthcare professional prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe. Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum theophylline concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL. Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient’s age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease. The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV. Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy. Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise. Overdose Management General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may continue to increase after presentation of the patient for medical care.) While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring. Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the healthcare professional should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain. Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL or chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient’s bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin , has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD 50 ). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD. Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia. Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in theophylline overdoses. Although ipecac induces emesis, it does not reduce the absorption of theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal. Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels. General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL. Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see , Extracorporeal Removal ). Specific Recommendations Acute Overdose Serum Concentration >2030100 mcg/mL Consider prophylactic anticonvulsant therapy. Administer multiple-dose oral activated charcoal and measures to control emesis. Consider extracorporeal removal, even if the patient has not experienced a seizure (see , Extracorporeal Removal ). Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Chronic Overdosage Serum Concentration >2030 mcg/mL in patients 30 mcg/mL in patients ≥ 60 years of age Consider prophylactic anticonvulsant therapy. Administer multiple-dose oral activated charcoal and measures to control emesis. Consider extracorporeal removal even if the patient has not experienced a seizure (see , Extracorporeal Removal). Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions. Extracorporeal Removal Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to sixfold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

DESCRIPTION

Theophylline (Anhydrous) Extended-Release Tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients. Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7- dihydro-1,3-dimethyl-, and is represented by the following structural formula: The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17. Each extended-release tablet for oral administration, contains 400 or 600 mg of anhydrous theophylline. Inactive ingredients: glyceryl behenate, silicified microcrystalline cellulose, silicon dioxide, and magnesium stearate. Theophylline Structural Formula

HOW SUPPLIED

Theophylline (Anhydrous) Extended-Release Tablets 400 mg are supplied as round, white, bisected, uncoated tablets, embossed with “N” “T4”, available in bottles of 100 tablets (NDC 29033-001-01) or 500 tablets (NDC 29033-001-05). Theophylline (Anhydrous) Extended-Release Tablets 600 mg are supplied as oblong, white, bisected,uncoated tablets, embossed with “NT6”, available in bottles of 100 tablets (NDC 29033-002-01). Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temerature]. Dispense in tight, light-resistant container. Manufactured by: Nostrum Laboratories, Inc. 1800 N. Topping Ave, Kansas City, MO 64120 Rev 02 January 2015

GERIATRIC USE

Geriatric Use Elderly patients are at a significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Theophylline clearance may be further reduced by concomitant diseases prevalent in the elderly, which further impair clearance of this drug and have the potential to increase serum levels and potential toxicity. These conditions include impaired renal function, chronic obstructive pulmonary disease, congestive heart failure, hepatic disease and an increased prevalence of use of certain medications (see PRECAUTIONS: Drug Interactions ) with the potential for pharmacokinetic and pharmacodynamic interaction. Protein binding may be decreased in the elderly resulting in an increased proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of theophylline after chronic overdosage than younger patients. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see PRECAUTIONS, Monitoring Serum Theophylline Concentrations , and DOSAGE AND ADMINISTRATION ). The maximum daily dose of theophylline in patients greater than 60 years of age ordinarily should not exceed 400 mg/day unless the patient continues to be symptomatic and the peak steady-state serum theophylline concentration is <10 mcg/mL (see DOSAGE AND ADMINISTRATION ). Theophylline doses greater than 400 mg/d should be prescribed with caution in elderly patients. Theophylline should be prescribed with caution in elderly male patients with pre-existing partial outflow obstruction, such as prostatic enlargement, due to the risk of urinary retention.

MECHANISM OF ACTION

Mechanism of Action: Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

INDICATIONS AND USAGE

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

PEDIATRIC USE

Pediatric Use Theophylline is safe and effective for the approved indications in pediatric patients. The maintenance dose of theophylline must be selected with caution in pediatric patients since the rate of theophylline clearance is highly variable across the pediatric age range (see CLINICAL PHARMACOLOGY , Table I , WARNINGS , AND DOSAGE AND ADMINISTRATION , Table V ).

PREGNANCY

Pregnancy: Teratogenic Effects: Category C In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects. In studies with mice, a single intraperitoneal dose at and above 100 mg/kg (approximately equal to the maximum recommended oral dose for adults on a mg/m 2 basis) during organogenesis produced cleft palate and digital abnormalities. Micromelia, micrognathia, clubfoot, subcutaneous hematoma, open eyelids, and embryolethality were observed at doses that are approximately 2 times the maximum recommended oral dose for adults on a mg/m 2 basis. In a study with rats dosed from conception through organogenesis, an oral dose of 150 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m 2 basis) produced digital abnormalities. Embryolethality was observed with a subcutaneous dose of 200 mg/kg/day (approximately 4 times the maximum recommended oral dose for adults on a mg/m 2 basis). In a study in which pregnant rabbits were dosed throughout organogenesis, an intravenous dose of 60 mg/kg/day (approximately 2 times the maximum recommended oral dose for adults on a mg/m 2 basis), which caused the death of one doe and clinical signs in others, produced cleft palate and was embryolethal. Doses at and above 15 mg/kg/day (less than the maximum recommended oral dose for adults on a mg/m 2 basis) increased the incidence of skeletal variations. There are no adequate and well-controlled studies in pregnant women. Theophylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of theophylline in breast milk is about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10-20 mcg/mL of theophylline per day is likely to receive 10-20 mg of theophylline per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum theophylline concentrations.

INFORMATION FOR PATIENTS

Information for Patients The patient (or parent/caregiver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heartbeat occurs during treatment with theophylline, even if another cause is suspected. The patient should be instructed to contact their healthcare professional if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another healthcare professional adds a new medication or discontinues a previously prescribed medication. Patients should be informed that theophylline interacts with a wide variety of drugs (see Table II ). The dietary supplement St. John’s Wort (Hypericum perforatum) should not be taken at the same time as theophylline, since it may result in decreased theophylline levels. If patients are already taking St. John’s Wort and theophylline together, they should consult their healthcare professional before stopping the St. John’s Wort, since their theophylline concentrations may rise when this is done, resulting in toxicity. Patients should be instructed to inform all healthcare professionals involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their healthcare professional. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose. Theophylline (Anhydrous) Extended-Release Tablets can be taken once a day in the morning or evening. It is recommended that Theophylline (Anhydrous) Extended-Release Tablets be taken with meals. Patients should be advised that if they choose to take Theophylline (Anhydrous) Extended-Release Tablets with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food. Theophylline (Anhydrous) Extended-Release Tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity. The scored tablet may be split. Patients receiving Theophylline (Anhydrous) Extended-Release Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline.

DOSAGE AND ADMINISTRATION

Theophylline (Anhydrous) Extended-Release Tablets 400 or 600 mg Tablets can be taken once a day in the morning or evening. It is recommended that Theophylline (Anhydrous) Extended-Release Tablets be taken with meals. Patients should be advised that if they choose to take Theophylline (Anhydrous) Extended-Release Tablets with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food. Theophylline (Anhydrous) Extended-Release Tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving Theophylline (Anhydrous) Extended-Release 400 or 600 mg Tablets may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline. Stabilized patients, 12 years of age or older, who are taking an immediate-release or controlled-release theophylline product may be transferred to once-daily administration of 400 mg or 600 mg Theophylline (Anhydrous) Extended-Release Tablets on a mg-for-mg basis. It must be recognized that the peak and trough serum theophylline levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen. General Considerations The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400-1600 mg/day in adults <60 years old and 10-36 mg/kg/day in children 1-9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults <60 years or 22 mg/kg/d in children 1-9 years, the steady-state peak serum theophylline concentration will be <10 mcg/mL in about 30% of patients, 10-20 mcg/mL in about 50% and 20-30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (See Table V ). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady-state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and , Table VI ). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ). If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Table V. Dosing initiation and titration (as anhydrous theophylline). * A. Children (12-15 years) and adults (16-60 years) without risk factors for impaired clearance. Titration Step Children 45 kg and adults 1 If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS ). 1. Starting Dosage 12-14 mg/kg/day up to a maximum of 300 mg/day admin. QD* 300-400 mg/day1 admin. QD* 2. After 3 days, if tolerated , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day admin. QD* 400-600 mg/day 1 admin. QD* 3. After 3 more days, if tolerated , and if needed increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day admin. QD* As with all theophylline products, doses greater than 600 mg should be titrated according to blood level (see Table VI) B. Patients With Risk Factors For Impaired Clearance, The Elderly (>60 Years), And Those In Whom It Is Not Feasible To Monitor Serum Theophylline Concentrations: In children 12-15 years of age, the theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ≥16 years and adults, including the elderly, the theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. *Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. TABLE VI. Dosage adjustment guided by serum theophylline concentration. ¶Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce theophylline clearance occur (e.g. sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS ). Peak Serum Concentration Dosage Adjustment 30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

Plavix 75 MG (clopidogrel bisulfate 97.875 MG) Oral Tablet

WARNINGS

Thrombotic thrombocytopenic purpura (TTP) TTP has been reported rarely following use of PLAVIX, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. (See ADVERSE REACTIONS .)

DRUG INTERACTIONS

Drug Interactions Since clopidogrel is metabolized to its active metabolite by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 (e.g., omeprazole) should be discouraged. Study of specific drug interactions yielded the following results: Aspirin Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by PLAVIX. PLAVIX potentiated the effect of aspirin on collagen-induced platelet aggregation. PLAVIX and aspirin have been administered together for up to one year. Heparin In a study in healthy volunteers, PLAVIX did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by PLAVIX. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) In healthy volunteers receiving naproxen, concomitant administration of PLAVIX was associated with increased occult gastrointestinal blood loss. NSAIDs and PLAVIX should be coadministered with caution. Warfarin Because of the increased risk of bleeding, the concomitant administration of warfarin with PLAVIX should be undertaken with caution. (See PRECAUTIONS: General .) Other Concomitant Therapy No clinically significant pharmacodynamic interactions were observed when PLAVIX was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of PLAVIX was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of PLAVIX (clopidogrel bisulfate). At high concentrations in vitro, clopidogrel inhibits P450 (2C9). Accordingly, PLAVIX may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with PLAVIX. In addition to the above specific interaction studies, patients entered into clinical trials with PLAVIX received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), thrombolytics, heparins (unfractionated and LMWH), GPIIb/IIIa antagonists, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions. There are no data on the concomitant use of oral anticoagulants, non study oral anti-platelet drugs and chronic NSAIDs with clopidogrel.

OVERDOSAGE

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species. Recommendations About Specific Treatment Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of PLAVIX if quick reversal is required.

DESCRIPTION

PLAVIX (clopidogrel bisulfate) is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and its molecular weight is 419.9. The structural formula is as follows: Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°. PLAVIX for oral administration is provided as either pink, round, biconvex, debossed, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base or pink, oblong, debossed film-coated tablets containing 391.5 mg of clopidogrel bisulfate which is the molar equivalent of 300 mg of clopidogrel base. Each tablet contains hydrogenated castor oil, hydroxypropylcellulose, mannitol, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredients. The pink film coating contains ferric oxide, hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin. The tablets are polished with Carnauba wax. Chemical Structure

CLINICAL STUDIES

The clinical evidence for the efficacy of PLAVIX is derived from four double-blind trials involving 81,090 patients: the CAPRIE study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events), a comparison of PLAVIX to aspirin, and the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events), the COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study) studies comparing PLAVIX to placebo, both given in combination with aspirin and other standard therapy and CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction). Recent Myocardial Infarction (MI), Recent Stroke or Established Peripheral Arterial Disease The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing PLAVIX (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) objectively established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years). The trial’s primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular. Table 2: Outcome Events in the CAPRIE Primary Analysis Patients PLAVIX 9599 aspirin 9586 IS (fatal or not) 438 (4.6%) 461 (4.8%) MI (fatal or not) 275 (2.9%) 333 (3.5%) Other vascular death 226 (2.4%) 226 (2.4%) Total 939 (9.8%) 1020 (10.6%) As shown in the table, PLAVIX (clopidogrel bisulfate) was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.8% vs. 10.6%) was 8.7%, P=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the PLAVIX group. The curves showing the overall event rate are shown in Figure 1. The event curves separated early and continued to diverge over the 3-year follow-up period. Figure 1: Fatal or Non-Fatal Vascular Events in the CAPRIE Study Although the statistical significance favoring PLAVIX over aspirin was marginal (P=0.045), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs. placebo) in reducing cardiovascular events in patients with recent myocardial infarction or stroke. Thus, the difference between PLAVIX and placebo, although not measured directly, is substantial. The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of PLAVIX relative to aspirin was heterogeneous across these randomized subgroups (P=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of PLAVIX over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, PLAVIX was not numerically superior to aspirin. In the meta-analyses of studies of aspirin vs. placebo in patients similar to those in CAPRIE, aspirin was associated with a reduced incidence of thrombotic events. There was a suggestion of heterogeneity in these studies too, with the effect strongest in patients with a history of myocardial infarction, weaker in patients with a history of stroke, and not discernible in patients with a history of peripheral vascular disease. With respect to the inferred comparison of PLAVIX to placebo, there is no indication of heterogeneity. Figure Acute Coronary Syndrome The CURE study included 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST segment elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age. Patients were randomized to receive PLAVIX (300 mg loading dose followed by 75 mg/day) or placebo, and were treated for up to one year. Patients also received aspirin (75–325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization. The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.30%) in the PLAVIX-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%–28%; p=0.00009) for the PLAVIX-treated group (see Table 3). At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the PLAVIX-treated group and 1187 (18.83%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%–21%, p=0.0005) for the PLAVIX-treated group (see Table 3). In the PLAVIX-treated group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo-treated group. Table 3: Outcome Events in the CURE Primary Analysis Outcome PLAVIX (+ aspirin)Other standard therapies were used as appropriate. Placebo (+ aspirin) Relative Risk Reduction (%) (95% CI) (n=6259) (n=6303) Primary outcome 582 (9.3%) 719 (11.4%) 20% (Cardiovascular death, MI, Stroke) (10.3, 27.9) P=0.00009 Co-primary outcome 1035 (16.5%) 1187 (18.8%) 14% (Cardiovascular death, MI, Stroke, Refractory Ischemia) (6.2, 20.6) P=0.00052 All Individual Outcome Events: CV death 318 (5.1%) 345 (5.5%) 7% (-7.7, 20.6) MI 324 (5.2%) 419 (6.6%) 23% (11.0, 33.4) Stroke 75 (1.2%) 87 (1.4%) 14% (-17.7, 36.6) Refractory ischemia 544 (8.7%) 587 (9.3%) 7% (-4.0, 18.0) The benefits of PLAVIX (clopidogrel bisulfate) were maintained throughout the course of the trial (up to 12 months). Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study In CURE, the use of PLAVIX was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with PLAVIX were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH (low molecular weight heparin), IV glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of PLAVIX was observed independently of the dose of aspirin (75–325 mg once daily). The use of oral anticoagulants, non-study anti-platelet drugs and chronic NSAIDs was not allowed in CURE. Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study The use of PLAVIX in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the PLAVIX group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%, P=0.0001), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the PLAVIX group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%, P=0.003). The use of PLAVIX in CURE did not impact the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the PLAVIX group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%, P=0.1658). In patients with ST-segment elevation acute myocardial infarction, safety and efficacy of clopidogrel have been evaluated in two randomized, placebo-controlled, double-blind studies, COMMIT- a large outcome study conducted in China – and CLARITY- a supportive study of a surrogate endpoint conducted internationally. The randomized, double-blind, placebo-controlled, 2×2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected myocardial infarction with supporting ECG abnormalities (i.e., ST elevation, ST depression or left bundle-branch block). Patients were randomized to receive PLAVIX (75 mg/day) or placebo, in combination with aspirin (162 mg/day), for 28 days or until hospital discharge whichever came first. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The patient population included 28% women, 58% patients ≥60 years (26% patients ≥70 years) and 55% patients who received thrombolytics, 68% received ace-inhibitors, and only 3% had percutaneous coronary intervention (PCI). As shown in Table 4 and Figures 4 and 5 below, PLAVIX significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002). Table 4: Outcome Events in the COMMIT Analysis Event PLAVIX (+ aspirin) (N=22961) Placebo (+ aspirin) (N=22891) Odds ratio (95% CI) p-value Composite endpoint: Death, MI, or Stroke 2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0.002 Death 1726 (7.5%) 1845 (8.1%) 0.93 (0.87, 0.99) 0.029 Non-fatal MINon-fatal MI and non-fatal stroke exclude patients who died (of any cause). 270 (1.2%) 330 (1.4%) 0.81 (0.69, 0.95) 0.011 Non-fatal Stroke 127 (0.6%) 142 (0.6%) 0.89 (0.70, 1.13) 0.33 Figure 4: Cumulative Event Rates for Death in the COMMIT Study Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study The effect of PLAVIX did not differ significantly in various pre-specified subgroups as shown in Figure 6. Additionally, the effect was similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history (see Figure 7). Such subgroup analyses should be interpreted very cautiously. Figure 6: Effects of Adding PLAVIX to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study Figure 7: Effects of Adding PLAVIX to Aspirin in the Non-Prespecified Subgroups in the COMMIT Study The randomized, double-blind, placebo-controlled CLARITY trial included 3,491 patients, 5% U.S., presenting within 12 hours of the onset of a ST elevation myocardial infarction and planned for thrombolytic therapy. Patients were randomized to receive PLAVIX (300-mg loading dose, followed by 75 mg/day) or placebo until angiography, discharge, or Day 8. Patients also received aspirin (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin for 48 hours. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery (defined as TIMI Flow Grade 0 or 1) on the predischarge angiogram, or death or recurrent myocardial infarction by the time of the start of coronary angiography. The patient population was mostly Caucasian (89.5%) and included 19.7% women and 29.2% patients ≥65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors and 63% statins. The number of patients who reached the primary endpoint was 262 (15.0%) in the PLAVIX-treated group and 377 (21.7%) in the placebo group, but most of the events related to the surrogate endpoint of vessel patency. Table 5: Event Rates for the Primary Composite Endpoint in the CLARITY Study Clopidogrel 1752 Placebo 1739 OR 95% CI *The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event. Number (%) of patients reporting the composite endpoint 262 (15.0%) 377 (21.7%) 0.64 0.53, 0.76 Occluded IRA N (subjects undergoing angiography) 1640 1634 n (%) patients reporting endpoint 192 (11.7%) 301 (18.4%) 0.59 0.48, 0.72 Death n (%) patients reporting endpoint 45 (2.6%) 38 (2.2%) 1.18 0.76, 1.83 Recurrent MI n (%) patients reporting endpoint 44 (2.5%) 62 (3.6%) 0.69 0.47, 1.02 Figure Figure Figure Figure Figure Figure

HOW SUPPLIED

PLAVIX (clopidogrel bisulfate) 75-mg tablets are available as pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other. Tablets are provided as follows: NDC 67046-099-30 blister of 30 Storage Store at 25° C (77° F); excursions permitted to 15°–30° C (59°–86° F) [See USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use Of the total number of subjects in the CAPRIE, CURE and CLARITY controlled clinical studies, approximately 50% of patients treated with PLAVIX were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with PLAVIX were 60 years and older, 26% of whom were 70 years and older. The observed risk of thrombotic events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Figures 3 and 6 for the CURE and COMMIT trials, respectively (see CLINICAL STUDIES ). The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Tables 6 and 7 for the CURE and COMMIT trials, respectively (see ADVERSE REACTIONS ).

MECHANISM OF ACTION

Mechanism of Action and Pharmacodynamic Properties Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting platelet function can reduce the event rate. Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition. Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of PLAVIX. Repeated doses of 75 mg PLAVIX per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg PLAVIX per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

INDICATIONS AND USAGE

PLAVIX (clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events as follows: Recent MI, Recent Stroke or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, PLAVIX has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death. Acute Coronary Syndrome -For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, PLAVIX has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. -For patients with ST-segment elevation acute myocardial infarction, PLAVIX has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in the pediatric population have not been established.

PREGNANCY

Pregnancy Pregnancy Category B Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, PLAVIX should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.

INFORMATION FOR PATIENTS

Information for Patients Patients should be told that it may take them longer than usual to stop bleeding, that they may bruise and/or bleed more easily when they take PLAVIX or PLAVIX combined with aspirin, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking PLAVIX and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.

DOSAGE AND ADMINISTRATION

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease The recommended daily dose of PLAVIX is 75 mg once daily. Acute Coronary Syndrome For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), PLAVIX should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Aspirin (75 mg–325 mg once daily) should be initiated and continued in combination with PLAVIX. In CURE, most patients with Acute Coronary Syndrome also received heparin acutely (see CLINICAL STUDIES ). For patients with ST-segment elevation acute myocardial infarction, the recommended dose of PLAVIX is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. PLAVIX may be initiated with or without a loading dose (300 mg was used in CLARITY; see CLINICAL STUDIES ). Pharmacogenetics CYP2C19 poor metabolizer status is associated with diminished response to clopidogrel. The optimal dose regimen for poor metabolizers has yet to be determined. (See CLINICAL PHARMACOLOGY: Pharmacogenetics .) No dosage adjustment is necessary for elderly patients or patients with renal disease. (See CLINICAL PHARMACOLOGY: Special Populations.)

Mefenamic Acid 250 MG Oral Capsule

Generic Name: MEFENAMIC ACID
Brand Name: Mefenamic Acid
  • Substance Name(s):
  • MEFENAMIC ACID

WARNINGS

Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that the concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as mefenamic acid, increases the risk of serious gastrointestinal (GI) events (see ; Gastrointestinal Bleeding, Ulceration, and Perforation ). Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 persons years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of mefenamic acid in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If mefenamic acid is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including mefenamic acid, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other risk factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitate patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated Patients Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert to signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue mefenamic acid until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding (see PRECAUTIONS; Drug Interactions ). Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including mefenamic acid. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue mefenamic acid immediately, and perform a clinical evaluation of the patient. Hypertension NSAIDs, including mefenamic acid, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see PRECAUTIONS; Drug Interactions ). Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and tradional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of Patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of mefenamic acid may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) (see PRECAUTIONS; Drug Interactions ). Avoid the use of mefenamic acid in patients with severe heart failure unless the benefits are expected to outweigh the risks of worsening heart failure. If mefenamic acid is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of mefenamic acid in patients with advanced renal disease. The renal effects of mefenamic acid may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating mefenamic acid. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of mefenamic acid (see ​ PRECAUTIONS; Drug Interactions ). Avoid the use of mefenamic acid in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If mefenamic acid is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions Mefenamic acid has been associated with anaphylactic reactions in patients with and without known hypersensitivity to mefenamic acid and in patients with aspirin-sensitive asthma (see CONTRAINDICATIONS , ; Exacerbation of Asthma Related to Aspirin Sensitivity ). Seek emergency help if anaphylactic reaction occurs. Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, mefenamic acid is contraindicated in patients with this form of aspirin sensitivity (see CONTRAINDICATIONS ). When mefenamic acid is used in patients with pre-existing asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions NSAIDs, including mefenamic acid, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of mefenamic acid at the first appearance of skin rash or any other sign of hypersensitivity. Mefenamic acid is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS ). Premature Closure of Fetal Ducts Arteriosus Mefenamic acid may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including mefenamic acid, in pregnant women starting at 30 weeks of gestation (third trimester) (see PRECAUTIONS; Pregnancy ). Hematological Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with mefenamic acid has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including mefenamic acid, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding (see PRECAUTIONS; Drug Interactions ).

DRUG INTERACTIONS

Drug Interactions See Table 2 for clinically significant drug interactions with mefenamic acid. Table 2: Clinically Significant Drug Interactions with mefenamic acid Drugs That Interfere with Hemostasis Clinical Impact: Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ). Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ). Intervention: Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity ). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia ). Digoxin Clinical Impact: The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ). Intervention: The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Antacid Clinical Impact: In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. Intervention: Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.

OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare (see WARNINGS; Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation, Hypertension, Renal Toxicity and Hyperkalemia ). Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdose (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment, contact a poison control center (1-800-222-1222).

DESCRIPTION

Mefenamic Acid Capsules, USP are a member of the fenamate group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each blue-banded, ivory capsule contains 250 mg of mefenamic acid for oral administration. Mefenamic acid is a white to greyish-white, odorless, microcrystalline powder with a melting point of 230°-231°C and water solubility of 0.004% at pH 7.1. The chemical name is N-2,3-xylylanthranilic acid. The molecular weight is 241.29. Its molecular formula is C15H15NO2 and the structural formula of mefenamic acid is: Each capsule also contains lactose, NF. The capsule shell and/or band contains citric acid, USP; D&C yellow No. 10; FD&C blue No. 1; FD&C red No. 3; FD&C yellow No. 6; gelatin, NF; glycerol monooleate; silicon dioxide, NF; sodium benzoate, NF; sodium lauryl sulfate, NF; titanium dioxide, USP. The structrual formula from mefenamic acid.

HOW SUPPLIED

Mefenamic acid is available as 250 mg blue-banded, ivory capsules, imprinted with “ FHPC 400″ and “PONSTEL®”. Bottles of 30 NDC 66993-070-30 Dispense in a tight container as defined in the USP. Image of capsule imprint Storage Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Distributed by: Prasco Laboratories Mason, OH 45040 USA Manufactured by: Halo Pharmaceutical Inc Whippany, NJ 07981 Revised 06/2016 For inquiries call 1-800-849-9707

GERIATRIC USE

Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS; Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation, Hepatotoxicity, Renal Toxicity and Hyperkalemia, PRECAUTIONS; Laboratory Monitoring ). Clinical studies of mefenamic acid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY , A DVERSE REACTIONS ).

MECHANISM OF ACTION

Mechanism of Action Mefenamic acid has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Mefenamic acid, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Mefenamic acid is a potent inhibitor of prostaglandin synthesis in vitro. Mefenamic acid concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because mefenamic acid is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ; G astrointestinal Bleeding, Ulceration, and Perforation ). Mefenamic acid is indicated: For relief of mild to moderate pain in patients ≥ 14 years of age, when therapy will not exceed one week (7 days). For treatment of primary dysmenorrhea.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients below the age of 14 have not been established.

PREGNANCY

Pregnancy Risk Summary Use of NSAIDs, including mefenamic acid, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arterious. Avoid use of NSAIDs, including mefenamic acid, in pregnant women starting at 30 weeks of gestation (third trimester) (see WARNINGS ; Premature Closure of Fetal Ductus Arteriosus ). There are no adequate and well-controlled studies of mefenamic acid in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats and rabbits when dosed throughout gestation, there were no evidence of developmental effects at a dose of mefenamic acid 1.6-times and 0.6-times the maximum recommended human dose (MRHD), respectively. Dietary administration of mefenamic acid at a dose 1.2 -times the MRHD from gestation day (GD) 15 to weaning or at a dose equivalent to the MRHD from 15 days prior to mating through to weaning resulted in greater incidences of perinatal death [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as mefenamic acid, resulted in increased pre- and post-implantation loss. Data Animal data Pregnant rats administered 249 mg/kg of mefenamic acid (1.6-times the MRHD of 1500 mg/day on a mg/m2 basis) from GD 6 to GD 15 did not result in any clear adverse developmental effects. Pregnant rabbits given 50 mg/kg of mefenamic acid (0.6-times the MRHD on a mg/m2 basis) from GD 6 to GD 18 did not result in any clear treatment-related adverse developmental effects. However, incidences of resorption were greater in treated compared to control animals. This dose was associated with some evidence of maternal toxicity with 4 of 18 rabbits exhibiting diarrhea and weight loss. Dietary administration of mefenamic acid at a dose of 181 mg/kg (1.2-times the MRHD on a mg/m2 basis) to pregnant rats from GD 15 to weaning resulted in an increased incidence of perinatal death. Treated dams were associated with decreased weight gain and delayed parturition. In another study, dietary administration of mefenamic acid at a dose of 155 mg/kg (equivalent to the MRHD of 1500 mg/day on a mg/m2 basis) to females 15 days prior to mating through to weaning resulted in smaller average litter sizes and higher incidence of perinatal death.

NUSRING MOTHERS

Nursing Mothers Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Because of the potential for serious adverse reactions in nursing infants from mefenamic acid, 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.

INFORMATION FOR PATIENTS

Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families and their caregivers of the following information before initiating therapy with mefenamic acid and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS; Cardiovascular Thrombotic Events ). Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation ). Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop mefenamic acid and seek immediate medical therapy (see WARNINGS; Hepatotoxicity ). Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS; Heart Failure and Edema ). Anaphylactic Reactions Inform patients of the signs of the anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see CONTRAINDICATIONS , WARNINGS; Anaphylactic Reactions ). Serious Skin Reactions Advise patients to stop mefenamic acid immediately if they develop any type of rash and contact their healthcare provider as soon as possible (see WARNINGS; Serious Skin Reactions ). Female Fertility Advise female or reproductive potential who desire pregnancy that NSAIDs, including mefenamic acid, maybe associated with reversible delay in ovulation. (see PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility ). Fetal Toxicity Inform pregnant women to avoid use of mefenamic acid and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closure of the fetal ductus arteriosus (see WARNINGS; Premature Closure of Fetal Ductus Arteriosus ). Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation , PRECAUTIONS; Drug Interactions ). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with mefenamic acid until they talk to their healthcare provider (see PRECAUTIONS; Drug Interactions ).

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of mefenamic acid and other treatment options before deciding to use mefenamic acid. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ; Gastrointestinal Bleeding, Ulceration, and Perforation) . After observing the response to initial therapy with mefenamic acid, the dose and frequency should be adjusted to suit an individual patient’s needs. For the relief of acute pain in adults and adolescents ≥14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week. For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, given orally, starting with the onset of bleeding and associated symptoms. Clinical studies indicate that effective treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days.

Metronidazole 500 MG Oral Tablet

Generic Name: METRONIDAZOLE
Brand Name: Metronidazole
  • Substance Name(s):
  • METRONIDAZOLE

WARNINGS

Central and Peripheral Nervous System Effects Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity. Convulsive seizures have been reported in patients treated with metronidazole. Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS ).

DRUG INTERACTIONS

Drug Interactions Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks (see CONTRAINDICATIONS ). Alcoholic Beverages Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (see CONTRAINDICATIONS ). Warfarin and other Oral Anticoagulants Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When metronidazole tablets are prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored. L ithium In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication. Bu sulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. Drugs that Inhibit CYP450 Enzymes The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. Drugs that Induce CYP450 Enzymes The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

OVERDOSAGE

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day. Treatment of Overdosage: There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

DESCRIPTION

Metronidazole tablets, USP, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazole antimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula: Metronidazole 250 mg and 500 mg tablets, USP, for oral administration, contain the inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, lactose (anhydrous), microcrystalline cellulose, sodium starch glycolate, and stearic acid. Chemical Structure

HOW SUPPLIED

Metronidazole tablets, USP, 250 mg are available as white, round, convex tablets debossed with “3969” on one side and “WPI” on the other side and are packaged as follows: NDC 50268-538-15 (10 tablets per card, 5 cards per carton). Metronidazole tablets, USP, 500 mg are available as white, oblong tablets, debossed with “3970” on one side and “WPI” on the other side and are packaged as follows: NDC 50268-539-15 (10 tablets per card, 5 cards per carton). Dispensed in Unit Dose Package. For Institutional Use Only. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use In elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY , PRECAUTIONS ). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION ).

MECHANISM OF ACTION

Mechanism of Action Metronidazole, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear. Drug Resistance A potential for development of resistance exists against metronidazole. Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair. Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes. Activity In Vitro and in Clinical Infections Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. G r a m- p ositive anaerobes C lostridium species Eubacterium species e Peptococcus species Peptostreptococcus species G r a m- n e gative anaerobes Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B.vulgatus) Fusobacterium species P r o t ozoal parasites Entamoeba histolytica T richomonas vaginalis The following in vitro data are available, but their clinical significance is unknown: Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (greater than or equal to 90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials. G r a m- n e gative anaerobes Bacteroides fragilis group (B. caccae, B. uniformis) Prevotella species (P. bivia, P. buccae, P. disiens) Su sceptibility Tests: When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial or community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

INDICATIONS AND USAGE

Symptomatic Trichomoniasis Metronidazole tablets, USP are indicated for the treatment of T. vaginalis infection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). Asymptomatic Trichomoniasis Metronidazole tablets, USP are indicated in the treatment of asymptomatic T. vaginalis infection in females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Since there is evidence that presence of the trichomonad can interfere with accurate assessment of abnormal cytological smears, additional smears should be performed after eradication of the parasite. Treatment of Asymptomatic Sexual Partners T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent reinfection of the partner. The decision as to whether to treat an asymptomatic male partner who has a negative culture or one for whom no culture has been attempted is an individual one. In making this decision, it should be noted that there is evidence that a woman may become reinfected if her sexual partner is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures cannot be relied upon in this regard. In any event, the sexual partner should be treated with metronidazole tablets, USP in cases of reinfection. Amebiasis Metronidazole tablets, USP are indicated in the treatment of acute intestinal amebiasis (amebic dysentery) and amebic liver abscess. In amebic liver abscess, metronidazole tablet therapy does not obviate the need for aspiration or drainage of pus. Anaerobic Bacterial Infections Metronidazole tablets USP are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with metronidazole tablet therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of the aerobic infection should be used in addition to metronidazole tablets, USP. INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species, Eubacterium species, Peptococcus species, and Peptostreptococcus species. SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species, and Fusobacterium species. BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group and Clostridium species. BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused by Bacteroides species including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis group. To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole tablets, USP and other antibacterial drugs, metronidazole tablets, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis.

PREGNANCY

Pregnancy: Teratogenic Effects: Pregnancy Category B There are no adequate and well controlled studies of metronidazole in pregnant women. There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited. Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

NUSRING MOTHERS

Nursing Mothers Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, 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. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

BOXED WARNING

WARNING Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS ). Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the INDICATIONS AND USAGE section below.

DOSAGE AND ADMINISTRATION

Trichomoniasis In the Female One-day treatment − two grams of metronidazole tablets, given either as a single dose or in two divided doses of one gram each, given in the same day. Seven-day course of treatment − 250 mg three times daily for seven consecutive days. There is some indication from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. The dosage regimen should be individualized. Single-dose treatment can assure compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. Further, some patients may tolerate one treatment regimen better than the other. Pregnant patients should not be treated during the first trimester (see CONTRAINDICATIONS ). In pregnant patients for whom alternative treatment has been inadequate, the one-day course of therapy should not be used, as it results in higher serum levels which can reach the fetal circulation (see PRECAUTIONS, Pregnancy). When repeat courses of the drug are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment. In the Male Treatment should be individualized as it is for the female. Amebiasis Adults For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times daily for 5 to 10 days. For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days. Pediatric patients 35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days. Anaerobic Bacterial Infections In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70 kg adult). A maximum of 4 g should not be exceeded during a 24-hour period. The usual duration of therapy is 7 to 10 days; however, infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. Dosage Adjustments P atients with Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), the dose of metronidazole should be reduced by 50% (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). P atients Undergoing Hemodialysis: Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from the hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient’s clinical situation (see CLINICAL PHARMACOLOGY ).

Augmentin XR 12 HR 1000 MG Extended Release Oral Tablet

Generic Name: AMOXICILLIN AND CLAVULANATE POTASSIUM
Brand Name: AugmentinXR
  • Substance Name(s):
  • CLAVULANATE POTASSIUM
  • AMOXICILLIN

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH AUGMENTIN XR, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AUGMENTIN XR SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AUGMENTIN XR, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. AUGMENTIN XR should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin/clavulanate potassium is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications (see CONTRAINDICATIONS and ADVERSE REACTIONS—Liver).

OVERDOSAGE

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients. In the case of overdosage, discontinue AUGMENTIN XR, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.5 Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis (see DOSAGE AND ADMINISTRATION).

DESCRIPTION

AUGMENTIN XR is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin (present as amoxicillin trihydrate and amoxicillin sodium) and the β-lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus 6-aminopenicillanic acid. The amoxicillin trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45. Chemically, amoxicillin trihydrate is (2S,5R ,6R)-6-[(R )-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as: The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is 387.39. Chemically, amoxicillin sodium is [2S-[2α,5α,6β(S *)]]-6-[[Amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monosodium salt and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)-(2R ,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as: Inactive IngredientsCitric acid, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and xanthan gum. Each tablet of AUGMENTIN XR contains 12.6 mg (0.32 mEq) of potassium and 29.3 mg (1.27 mEq) of sodium. image of chemical structure 1 image of chemical structure 2 image of chemical structure 3

CLINICAL STUDIES

Acute Bacterial SinusitisAdults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies. In one study, 363 patients were randomized to receive either AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind, multicenter, prospective trial. These patients were clinically and radiologically evaluated at the test of cure (day 17-28) visit. The combined clinical and radiological responses were 83.7% for AUGMENTIN XR and 84.3% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference = -9.4, 8.3). The clinical response rates at the test of cure were 87.0% and 88.6%, respectively. The other 2 trials were non-comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of AUGMENTIN XR (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2288 patients with ABS. Evaluation timepoints were the same as in the prior study. Patients underwent maxillary sinus puncture for culture prior to receiving study medication. At test of cure, the clinical success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1% (per protocol populations). Patients with acute bacterial sinusitis due to S. pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open-label non-comparative clinical trials. Microbiologic eradication rates for key pathogens in these studies are shown in the following table: Clinical Outcome for ABS Penicillin MICs of S. pneumoniae Isolates Intent-To-Treat Clinically Evaluable n/Na % 95% CIb n/Na % 95% CIb All S. pneumoniae 344/370 93.0 — 318/326 97.5 — MIC ≥ 2.0 mcg/mLc 35/36 97.2 85.5, 99.9 30/31 95.8 83.3, 99.9 MIC = 2.0 mcg/mL 23/24 95.8 78.9, 99.9 19/20 95.0 75.1, 99.9 MIC ≥ 4.0 mcg/mLd 12/12 100 73.5, 100 11/11 100 71.5, 100 H. influenzae 265/305 86.9 — 242/259 93.4 — M. catarrhalis 94/105 89.5 — 86/90 95.6 — a n/N = patients with pathogen eradicated or presumed eradicated/total number of patients. b Confidence limits calculated using exact probabilities. c S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin. d Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL. Community-Acquired PneumoniaFour randomized, controlled, double-blind clinical studies and one non-comparative study were conducted in adults with community-acquired pneumonia (CAP). In comparative studies, 904 patients received AUGMENTIN XR at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days. In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours for 7 days. In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86.3% to 94.7% in clinically evaluable patients who received AUGMENTIN XR; in the non-comparative study, the clinical success rate was 85.6%. Data on the efficacy of AUGMENTIN XR in the treatment of community-acquired pneumonia due to S. pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled clinical studies and the 1 non-comparative study. The majority of these cases were accrued from the non-comparative study. Clinical Outcome for CAP due to S. pneumoniae Penicillin MICs of S. pneumoniae Isolates Intent-To-Treat Clinically Evaluable n/Na % 95% CIb n/N a % 95% CIb All S. pneumoniae 318/367 86.6 — 275/297 92.6 — MIC ≥ 2.0 mcg/mLc 30/35 85.7 69.7, 95.2 24/25 96.0 79.6, 99.9 MIC = 2.0 mcg/mL 22/24 91.7 73.0, 99.0 18/18 100 81.5, 100 MIC ≥ 4.0 mcg/mLd 8/11 72.7 39.0, 94.0 6/7 85.7 42.1, 99.6 a n/N = patients with pathogen eradicated or presumed eradicated/total number of patients. b Confidence limits calculated using exact probabilities. c S. pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin. d Includes one patient each with S. pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent-To-Treat group only. SafetyIn 2 randomized, double-blind, multicenter studies, AUGMENTIN XR (2,000 mg/125 mg orally every 12 hours, n = 577) was compared to AUGMENTIN (875 mg/125 mg orally every 12 hours, n = 570), administered for 7 days for the treatment of community-acquired pneumonia. Adverse events, regardless of relationship to test drug, were reported by 44.4% of patients who received AUGMENTIN XR (versus 46.3% in comparator group). Treatment-related adverse events were reported in 21.7% of patients who received AUGMENTIN XR (versus 21.2% in comparator group); most were mild and transient in nature. Adverse events which led to withdrawal were reported by 2.8% of patients who received AUGMENTIN XR (versus 5.3% in comparator group). In each group, the most frequently reported adverse events were diarrhea (14.4% versus 13.0%, p = 0.47), nausea (3.5 % versus 4.4%), and headache (3.5% versus 3.2%). Only 2 patients (0.3%) who received AUGMENTIN XR and 3 patients (0.5%) in the comparator group withdrew due to diarrhea. Serious adverse events considered suspected or probably related to test drug were reported in 0.3% of patients (versus 0.5% in comparator).

HOW SUPPLIED

AUGMENTIN XR Extended Release TabletsEach white, oval film-coated bilayer scored tablet, debossed with AUGMENTIN XR, contains amoxicillin trihydrate and amoxicillin sodium equivalent to a total of 1,000 mg of amoxicillin and clavulanate potassium equivalent to 62.5 mg of clavulanic acid. NDC 54868-4735-0 Bottles of 20 NDC 54868-4735-2 Bottles of 28 (7 day XR pack) NDC 54868-4735-1 Bottles of 40 (10 day XR pack)

INDICATIONS AND USAGE

AUGMENTIN XR Extended Release Tablets are indicated for the treatment of patients with community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase−producing pathogens (i.e., H. influenzae, M. catarrhalis, H. parainfluenzae, K. pneumoniae, or methicillin-susceptible S. aureus) and S. pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs = 2 mcg/mL). AUGMENTIN XR is not indicated for the treatment of infections due to S. pneumoniae with penicillin MICs ≥ 4 mcg/mL. Data are limited with regard to infections due to S. pneumoniaewith penicillin MICs ≥ 4 mcg/mL (see CLINICAL STUDIES). Of the common epidemiological risk factors for patients with resistant pneumococcal infections, only age > 65 years was studied. Patients with other common risk factors for resistant pneumococcal infections (e.g., alcoholism, immune-suppressive illness, and presence of multiple co-morbid conditions) were not studied. In patients with community-acquired pneumonia in whom penicillin-resistant S. pneumoniae is suspected, bacteriological studies should be performed to determine the causative organisms and their susceptibility when AUGMENTIN XR is prescribed. Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain of S. pneumoniae plus a β-lactamase−producing pathogen can be treated with another AUGMENTIN® (amoxicillin/clavulanate potassium) product containing lower daily doses of amoxicillin (i.e., 500 mg every 8 hours or 875 mg every 12 hours). Acute bacterial sinusitis or community-acquired pneumonia due to S. pneumoniae alone can be treated with amoxicillin. To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN XR and other antibacterial drugs, AUGMENTIN XR should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION

AUGMENTIN XR should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Absorption of the amoxicillin component is decreased when AUGMENTIN XR is taken on an empty stomach (see CLINICAL PHARMACOLOGY). The recommended dose of AUGMENTIN XR is 4,000 mg/250 mg daily according to the following table: Indication Dose Duration Acute bacterial sinusitis 2 tablets q12h 10 days Community-acquired pneumonia 2 tablets q12h 7-10 days Tablets of AUGMENTIN (250 mg or 500 mg) CANNOT be used to provide the same dosages as AUGMENTIN XR Extended Release Tablets. This is because AUGMENTIN XR contains 62.5 mg of clavulanic acid, while the AUGMENTIN 250-mg and 500-mg tablets each contain 125 mg of clavulanic acid. In addition, the Extended Release Tablet provides an extended time course of plasma amoxicillin concentrations compared to immediate-release Tablets. Thus, two AUGMENTIN 500-mg tablets are not equivalent to one AUGMENTIN XR tablet. Scored AUGMENTIN XR Extended Release Tablets are available for greater convenience for adult patients who have difficulty swallowing. The scored tablet is not intended to reduce the dosage of medication taken; as stated in the table above, the recommended dose of AUGMENTIN XR is two tablets twice a day (every 12 hours). Renally Impaired PatientsThe pharmacokinetics of AUGMENTIN XR have not been studied in patients with renal impairment. AUGMENTIN XR is contraindicated in patients with a creatinine clearance of < 30 mL/min. and in hemodialysis patients (see CONTRAINDICATIONS). Hepatically Impaired PatientsHepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals (see WARNINGS). Pediatric UsePediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose. Geriatric UseNo dosage adjustment is required for the elderly (see PRECAUTIONS, Geriatric Use).

Potassium Chloride 8 MEQ Extended Release Oral Capsule

Generic Name: POTASSIUM CHLORIDE
Brand Name: Potassium Chloride
  • Substance Name(s):
  • POTASSIUM CHLORIDE

WARNINGS

: (see ) Hyperkalemia OVERDOSAGE In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustments. Interaction with Potassium-Sparing Diuretics Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (e.g., spironolactone, triamterene, or amiloride), since the simultaneous administration of these agents can produce severe hyperkalemia. Interaction with Angiotensin Converting Enzyme Inhibitors Angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) will produce some potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring. Gastrointestinal Lesions Solid oral dosage forms of potassium chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric coated preparations of potassium chloride are associated with an increased frequency of small bowel lesions (40 – 50 per 100,000 patient years) compared to sustained-release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric coated products is not available. Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq are microencapsulated capsules formulated to provide a controlled rate of release of microencapsulated potassium chloride and thus to minimize the possibility of high local concentration of potassium near the gastrointestinal wall. Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after one week of solid oral potassium chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (i.e., 96 mEq per day in divided doses of potassium chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (hemoccult testing). The relevance of these findings to the usual conditions (i.e., non-fasting, no anticholinergic agent, smaller doses) under which controlled-release potassium chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq should be discontinued immediately and the possibility of ulceration, obstruction or perforation considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occur. Metabolic Acidosis Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

DRUG INTERACTIONS

Potassium-sparing diuretics, angiotensin converting enzyme inhibitors (see ). Drug Interactions WARNINGS

OVERDOSAGE

: The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see and ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of ST segment, and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L). CONTRAINDICATIONS WARNINGS Treatment measures for hyperkalemia include the following: (1) elimination of foods and medications containing potassium and of any agents with potassium-sparing properties; (2) intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10 to 20 units of crystalline insulin per 1,000 mL; (3) correction of acidosis, if present, with intravenous sodium bicarbonate; (4) use of exchange resins, hemodialysis, or peritoneal dialysis. In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity. The extended release feature means that absorption and toxic effects may be delayed for hours. Consider standard measures to remove any unabsorbed drug.

DESCRIPTION

: Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq are oral dosage forms of microencapsulated potassium chloride containing 600 and 750 mg, respectively, of potassium chloride USP equivalent to 8 and 10 mEq of potassium. Dispersibility of potassium chloride (KCI) is accomplished by microencapsulation and a dispersing agent. The resultant flow characteristics of the KCI microcapsules and the controlled release of K+ ions by the microcapsular membrane are intended to avoid the possibility that excessive amounts of KCI can be localized at any point on the mucosa of the gastrointestinal tract. Each crystal of KCI is microencapsulated by a process with an insoluble polymeric coating which functions as a semi-permeable membrane; it allows for the controlled release of potassium and chloride ions over an eight-to-ten-hour period. Fluids pass through the membrane and gradually dissolve the potassium chloride within the micro-capsules. The resulting potassium chloride solution slowly diffuses outward through the membrane. Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq are electrolyte replenishers. The chemical name of the active ingredient is potassium chloride and the structural formula is KCI. Potassium chloride USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol. The inactive ingredients are, ethylcellulose, FD&C blue #1, FD&C red # 40, gelatin, sodium lauryl sulfate, titanium oxide and triacetin.

HOW SUPPLIED

: NDC:68151-0609-0 in a PACKAGE of 1 CAPSULE, EXTENDED RELEASES

GERIATRIC USE

Clinical studies of Potassium Chloride Extended-release Capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Geriatric Use This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

INDICATIONS AND USAGE

: BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE POTASSIUM CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxications, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop e.g., digitalized patients or patients with significant cardiac arrhythmias, hepatic cirrhosis with ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, and certain diarrheal states. The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

PEDIATRIC USE

Safety and effectiveness in pediatric patients have not been established. Pediatric Use

PREGNANCY

Animal reproduction studies have not been conducted with Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity. Pregnancy: Teratogenic Effects: Category C

NUSRING MOTHERS

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of potassium chloride supplementation should have little or no effect on the level in human milk. Nursing Mothers

INFORMATION FOR PATIENTS

Information For Patients Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other suitable liquid. To take each dose without crushing, chewing, or sucking the capsules. To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations. To check with the physician if there is trouble swallowing capsules or if the capsules seem to stick in the throat. To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

DOSAGE AND ADMINISTRATION

: The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store. Dosage must be adjusted to the individual needs of each patients. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40 to 100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose. Because of the potential for gastric irritation (see ), Potassium Chloride Extended-release Capsules, USP, 8 mEq and 10 mEq should be taken with meals and with a full glass of water or other liquid. WARNINGS Patients who have difficulty swallowing capsules may sprinkle the contents of the capsule onto a spoonful of soft food. The soft food, such as applesauce or pudding, should be swallowed immediately without chewing and followed with a glass of cool water or juice to ensure complete swallowing of the microcapsules. The food used should not be hot and should be soft enough to be swallowed without chewing. Any microcapsule/food mixture should be used immediately and not stored for future use.

Dextromethorphan Hydrobromide 1 MG/ML / Guaifenesin 20 MG/ML / Phenylephrine Hydrochloride 0.5 MG/ML Oral Solution

Generic Name: DEXTROMETHORPHAN HBR, GUAIFENESIN, PHENYLEPHRINE HCL
Brand Name: Mucus Relief Severe Congestion and Cough Maximum Strength
  • Substance Name(s):
  • PHENYLEPHRINE HYDROCHLORIDE
  • GUAIFENESIN
  • DEXTROMETHORPHAN HYDROBROMIDE

WARNINGS

Warnings Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. for children under 12 years of age Ask a doctor before use if you have heart disease thyroid disease diabetes high blood pressure trouble urinating due to an enlarged prostate gland persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis or emphysema cough that occurs with too much phlegm (mucus) When using this product, do not use more than directed. Stop use and ask a doctor if nervousness, dizziness or sleeplessness occur symptoms do not get better within 7 days or occur with a fever cough comes back, or occurs with fever, rash or headache that lasts These could be signs of a serious condition. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away.

INDICATIONS AND USAGE

Uses helps loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive temporarily relieves: cough due to minor throat and bronchial irritation as may occur with the common cold or inhaled irritants the intensity of coughing the impulse to cough to help you get to sleep nasal congestion due to a cold

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, EDTA disodium, FD&C blue #1, FD&C red #40, flavor, glycerin, propyl gallate, propylene glycol, purified water, sodium benzoate, sorbitol, sucralose, trisodium citrate dihydrate, xanthan gum

PURPOSE

Purposes Cough suppressant Expectorant Nasal Decongestant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center (1-800-222-1222) right away.

ASK DOCTOR

Ask a doctor before use if you have heart disease thyroid disease diabetes high blood pressure trouble urinating due to an enlarged prostate gland persistent or chronic cough such as occurs with smoking, asthma, chronic bronchitis or emphysema cough that occurs with too much phlegm (mucus)

DOSAGE AND ADMINISTRATION

Directions do not take more than 6 doses in a 24-hour period measure only with dosing cup provided Do not use any other dosing device. keep dosing cup with product mL=milliliter shake well before using adults and children 12 years of age and older: 20 mL in dosing cup provided every 4 hours children under 12 years of age: do not use

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use if you are now taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for depression, psychiatric or emotional conditions, or Parkinson’s disease), or for 2 weeks after stopping the MAOI drug. If you do not know if your prescription drug contains an MAOI, ask a doctor or pharmacist before taking this product. for children under 12 years of age

STOP USE

Stop use and ask a doctor if nervousness, dizziness or sleeplessness occur symptoms do not get better within 7 days or occur with a fever cough comes back, or occurs with fever, rash or headache that lasts These could be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredients (in each 20 mL) Dextromethorphan HBr 20 mg Guaifenesin 400 mg Phenylephrine HCl 10 mg

Ambrosia artemisiifolia pollen extract 1 GM per 10 ML Injectable Solution

Generic Name: AMBROSIA ARTEMISIIFOLIA
Brand Name: Short Ragweed
  • Substance Name(s):
  • AMBROSIA ARTEMISIIFOLIA POLLEN

WARNINGS

Physicians who elect to administer ragweed pollen extract should be familiar with the clinical use of allergenic extracts and have the necessary emergency equipment and medication available to treat systemic allergic reactions. The injection of ragweed pollen extract may cause severe local and/ or systemic anaphylactic reactions in some individuals. To minimize this potential hazard, the relative sensitivity of the patient must be assessed from the allergic history and from clinical observations. Patients should be informed of this risk prior to skin testing and immunotherapy (see adverse reactions). The dosage must be reduced when starting a patient on fresh standardized (Antigen E) extract or when transferring a patient from non-standardized to standardized extract, even though the labeled strength of the old and new vials may be the same. This is necessary due to a loss of extract potency during storage in the physician’s office. The antigen E content of old and new extract must be compared and adjusted by dosage reduction and/or dilution before new extract is administered. The amount of new extract given from the old vial, assuming both extracts contain comparable amounts of antigen E. Any evidence of a local or generalized reaction requires a reduction in dosage during the initial stages of hyposensitization as well as during maintenance therapy.

OVERDOSAGE

A local reaction characterized by erythema and edema that persists for several hours or longer, or a recurrence of allergic symptoms following an injection requires that the dosage be reduced. Additional extract should not be given until all evidence of a previous reaction has disappeared. Severe generalized symptoms or anaphylaxis following an injection must be treated immediately with epinephrine HCL 1:1000 as follows: Usual Dosage – Children under 12 years 0.1 to 0.2 cc; persons over 12 years 0.3 to 0.5 cc, repeated as necessary every 10 to 15 minutes. Intravenous antihistamines and hydro-cortisone also may be used, but only after sufficient epinephrine has been give. (see Adverse Reaction Systemic). Immunotherapy after anaphylaxis should only be considered if the probable cause of anaphylaxis can be identified, such as accidental intravenous injection or failure to reduce the dosage after a previous local reaction or during periods of high external exposure to ragweed pollen.

DESCRIPTION

INGREDIENTS – Allergenic extract of short ragweed pollen is a clear, amber-colored solution prepared from the dry, defatted pollen of Ambrosia elatior. The extract contains the water extractables of the pollen, 0.25% sodium chloride, 0.125% sodium bicarbonate, 0.5% phenol and 50% glycerol by volume. Extract of mixed short-giant ragweed has the same appearance as short ragweed pollen extract and contains the same chemical ingredients. It is prepared from equal gram weights of the pollens of Ambrosia elatior and Ambrosia trifida. STANDARDIZATION – The potency of ragweed pollen extract is based on antigen E, a protein component which is believed to be the most important allergen of short ragweed pollen. Extracts of short ragweed pollen sold in the U.S. must have a minimum antigen E content of 67.5 units per ml for a 1:20 w/v concentrate. Extracts of mixed short-giant ragweed must have a minimum antigen E content of 33.75 units/ml for a 1:20 w/v concentrate. The importance of antigen E in ragweed allergy is based on the following observations: In vitro studies with antigen E have shown that it is capable of causing histamine release from peripheral leukocytes of ragweed sensitive persons 1. The antigen E content of short ragweed pollen extract has been found to correlate with extract potency when measured by skin test response in persons allergic to short ragweed pollen 2. Immunotherapy with antigen E has been shown to be comparably effective to whole short ragweed pollen extract in reducing symptoms related to ragweed pollen exposure 3. The weight by volume value shown on the label is a measurement of extract concentration, rather than extract potency. Weight by volume designations may be used to identify dilutions of extract for skin testing and immunotherapy, and are useful from a practical standpoint in identifying the relative strength of a given extract. However, studies have shown that the antigen E content varies in extracts with the same weight by volume concentration 4. EXPIRATION DATING – Expiration dating is based on the antigen E content of the extract. Extracts containing 50% glycerol by volume have longer dating periods due to the protective effects of glycerol on antigen E 5, 6. The expiration period of aqueous concentrate and saline dilutions of glycerinated concentrate is approximately one-half that of glycerinated extract containing comparable antigen E content. Ragweed extract should be kept at 2°C to 8°C during use and office storage to retain potency. Higher temperatures have an adverse affect on antigen E.

HOW SUPPLIED

SUPPLIED Short ragweed pollen extract and mixed short-giant ragweed pollen extract in concentrated form (w/v 1:20) are supplied in 1 ml dropper vials for scratch or prick testing and in 10 ml, and 50 ml vials for bulk use. Dilutions other than 1:20 w/v may be custom ordered.

INDICATIONS AND USAGE

INDICATIONS Studies have shown that properly performed an interpreted skin tests with ragweed pollen extract are useful in the diagnosis of allergy to ragweed pollen 7, 8, 20, 21. Immunotherapy with the appropriate dosage of short ragweed pollen extract is effective in reducing symptoms of hay fever and asthma resulting from exposure to short ragweed pollen (9, 10, 11), and it is believed to be effective with extract of giant ragweed, although carefully controlled studies are unavailable. However, clinical observations and known cross reactivity between short and giant ragweed pollens have led to the practice of using a mixture of the two species for skin testing and treatment 22, 23, 24, 25, 26, 27. This form of treatment is recommended for patients who cannot avoid exposure to pollen and who do not obtain satisfactory relief of symptoms from other medications, such as antihistamines. Immunologic changes resulting from treatment with short ragweed pollen extract are believed to include: The induction of specific anti-ragweed IgG antibodies commonly referred to as “blocking antibodies” 12, 13. A decrease in the elevation of ragweed specific IgE during and immediately following the ragweed pollen season 14. A reduction of circulating anti-ragweed IgE after long-term immunotherapy 15. A decrease in skin reactivity to the extract 16 and a decrease in leukocyte sensitivity to histamine release 17 after long-term immunotherapy.

DOSAGE AND ADMINISTRATION

DIAGNOSIS. If the extract supplied in this package is concentrated product (w/v 1:20), it should not be used for intradermal testing. Concentrated extract may be used for scratch or prick testing providing the patient is not exposed to high levels of ragweed pollen and experiencing pronounced symptoms of hay fever or asthma at the time of testing. Extract for intradermal testing must be diluted to a strength of 0.25 units of antigen E per ml 7. Skin tests should not be performed if the patient has taken antihistamine within 24 hours prior to testing. PROCEDURES Scratch Test: 1 drop of extract concentrate applied to a small scratch or scarification of the volar surface of the forearm or the flat aspect of the back. Prick Test: 1 drop of extract concentrate applied to the unbroken skin of the forearm or the back followed by pricking the skin under the drop. Intradermal Test: 0.05 ml of extract containing 0.25 antigen E units per ml given intradermally on the volar surface of the forearm or outer aspect of the upper arm. This test should not be performed unless the patient is negative to a properly administered and interpreted scratch or prick test. A final intradermal test using 0.05 ml of extract containing 2.5 antigen E units per ml may be used to rule out skin sensitivity to ragweed allergen. INTERPRETATION OF RESULTS Scratch and Prick Test A negative test shows only a slight red area at the site of scarification or prick penetration. Positive tests are scored as follows: 1+ Erythema with 5 mm wheal 2+ Erythema with 5 – 10 mm wheal 3+ Erythema with a 10 – 15 mm wheal 4+ Erythema with a wheal 15 mm (or larger) with pseudopodia Intradermal Test A negative test shows no change in the appearance and size of the 5 mm wheal created by the I.D. injection of 0.05 ml of extract. Positive tests are scored as follows: 1+ Erythema with 10-20 mm with a 5-10 mm wheal 2+ Erythema with 20-30 mm with a 5-10 mm wheal 3+ Erythema with 30-40 mm with a 10-15 mm wheal 4+ Erythema greater than 40 mm with a 15 mm wheal (or larger) with pseudopodia IMMUNOTHERAPY Concentrated ragweed extract must be diluted before administration to new patients. As a rule, extract containing 0.01 to 0.05 units of antigen E per ml are safe to initiate immunotherapy. An intradermal skin test with the intended starting dose may be done as an additional precaution in evaluating the patient’s sensitivity. Injections should be given subcutaneously in the outer aspect of the upper arm. Care must be taken to avoid injecting the extract into a blood vessel, because of the potential hazard of anaphylaxis. Concentrated extract is usually administered once every two to four weeks at a maximum dose of 0.2 ml. A mild burning sensation immediately following the injection of concentrated extract is due to the glycerol in the extract. It should not be interpreted as an adverse allergic response. A suggested dosage schedule is shown in the Table below. Patients who have received allergenic extract for maintenance therapy should not be given the same dose from a fresh vial of extract. The antigen E content of ragweed pollen extract varies from lot to lot. Although the potency of fresh extract can be compared with that of previously administered product and adjusted accordingly, it is advisable to reduce the dosage of fresh extract to one-half the amount give from a previous lot. The antigen E content of ragweed pollen extract diminishes during storage and use in the physician’s office, and, therefore, may be less than that specified on the vial label. In addition, ragweed pollen extract contains other components which may contribute to the overall allergenicity of the product 18. SUGGESTED DOSAGE SCHEDULE FOR RAGWEED EXTRACT BASED ON ANTIGEN E CONCENTRATION (units per ml) Concentrated extracts (w/v 1:20) of short ragweed pollen usually contain between 100 and 300 units antigen E per ml. Mixed short-giant ragweed pollen extracts contain approximately one-half these values. AgE Units 0.01/ml frequency twice weekly AgE Units 0.1/ml frequency twice weekly AgE Units 1.0/ml frequency twice weekly AgE Units 10/ml frequency twice weekly AgE Units 100/ml frequency twice weekly No. ml No. ml No. ml No. ml No. ml 1 0.025 1 0.025 1 0.025 1 0.025 1 0.025 2 0.05 2 0.05 2 0.05 2 0.05 2 0.05 3 0.10 3 0.10 3 0.10 3 0.10 3 0.10 4 0.15 4 0.15 4 0.15 4 0.15 4 0.15 5 0.20 5 0.20 5 0.20 5 0.20 5 0.20 6 0.25 6 0.25 6 0.25 6 0.25 6 0.25 7 0.30 7 0.30 7 0.30 7 0.30 7 0.30 Note: Do not exceed a dose of 0.2 ml if the extract being administered contains 50% glycerol by volume Studies 10, 11 have shown that the accumulated pre-seasonal dose of short ragweed pollen extract should be in the range of 250 to 1000 units of antigen E to effectively reduce ragweed-related symptoms 3, 19. This dosage of antigen E is contained in 2.5 ml to 10.0 ml of extract containing 100 antigen E units/ml. Treatment with a maximum tolerated dose is recommended for both short ragweed pollen extract and mixed short-giant ragweed extract. The maintenance dose of ragweed pollen extract is defined as the highest tolerated dose that is consistently well tolerated without undue pain or swelling and which provides maximum relief to symptoms. The interval between maintenance injections should not exceed 4 weeks, since tolerance to the extract may be lost at longer intervals. If the interval exceeds 4 weeks, the dosage should be reduced by one-half for every additional two week period. A reduction in the maintenance dose also may be necessary during the ragweed season, due to the overdosing effects of inhaled allergen combined with injected allergen. As a rule, it is advisable to reduce the dosage by one-half during ragweed pollination and to increase the frequency of injections as needed to provide adequate relief symptoms. The dosage of ragweed pollen extract given to children is the same as the adult dose except for slight modifications due to body size and weight. A child’s dose of 0.2 ml is considered comparable to an adult dose of 0.5 ml of the same dilution. Maintenance injection should be continued for a period of two to three years or longer, depending upon patient tolerance and clinical response.

Magnesium Hydroxide 80 MG/ML Oral Suspension

Generic Name: MAGNESIUM HYDROXIDE
Brand Name: Milk of Magnesia
  • Substance Name(s):
  • MAGNESIUM HYDROXIDE

WARNINGS

Warnings Ask a doctor before use if you have •kidney disease •a magnesium-restricted diet •stomach pain, nausea, or vomiting •a sudden change in bowel habits that lasts more than 2 weeks Ask a doctor or pharmacist before use if you are taking any other drug. Take this product two or more hours before or after other drugs. Laxatives may affect how other drugs work. Stop use and ask a doctor if •you have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition. •you need to use a laxative for more than 1 week If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

INDICATIONS AND USAGE

Uses •relieves occasional constipation (irregularity) •generally produces bowel movement in ½ to 6 hours

INACTIVE INGREDIENTS

Inactive ingredients anhydrous citric acid, D&C red #28, flavor, glycerin, purified water, sorbitol solution, sucrose, xanthan gum

PURPOSE

Purpose Saline laxative

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

ASK DOCTOR

Ask a doctor before use if you have •kidney disease •a magnesium-restricted diet •stomach pain, nausea, or vomiting •a sudden change in bowel habits that lasts more than 2 weeks

DOSAGE AND ADMINISTRATION

Directions •do not exceed the maximum recommended daily dose in a 24 hour period •shake well before use •dose may be taken once a day preferably at bedtime, in divided doses, or as directed by a doctor •drink a full glass (8 oz) of liquid with each dose •for accurate dosing, use dose cup provided •mL = milliliter adults and children 12 years and older 30 mL to 60 mL children 6 to 11 years 15 mL to 30 mL children under 6 years ask a doctor

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

STOP USE

Stop use and ask a doctor if •you have rectal bleeding or no bowel movement after using this product. These could be signs of a serious condition. •you need to use a laxative for more than 1 week

ACTIVE INGREDIENTS

Active ingredient (in each 15 mL) Magnesium hydroxide 1200 mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking any other drug. Take this product two or more hours before or after other drugs. Laxatives may affect how other drugs work.

Excedrin Migraine (APAP 250 MG / ASA 250 MG / caffeine 65 MG) Oral Tablet

Generic Name: ACETAMINOPHEN, ASPIRIN (NSAID), AND CAFFEINE
Brand Name: Excedrin Extra Strength
  • Substance Name(s):
  • ASPIRIN
  • CAFFEINE
  • ACETAMINOPHEN

WARNINGS

Warnings Reye’s syndrome: Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye’s syndrome, a rare but serious illness. Allergy alert: Aspirin may cause a severe allergic reaction which may include: hives facial swelling asthma (wheezing) shock Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take more than 8 tables in 24 hours, which is the maximum daily amount with other drugs containing acetaminophen 3 or more alcoholic drinks every day while using this product Stomach bleeding warning: This product contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause stomach bleeding. The chance is higher if you are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing an NSAID (aspirin, ibuprofen, naproxen, or others have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Caffeine warning: The recommended dose of this product contains about as much caffeine as a cup of coffee. Limit the use of caffeine-containing medications, foods, or beverages while taking this product because too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heart beat. Do not use if you have ever had an allergic reaction to aspirin or any other pain reliever/fever reducer with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist. Ask Doctor before use if you have liver disease stomach bleeding warning applies to you you have a history of stomach problems, such as heartburnyou have high blood pressure, heart disease, liver cirrhosis. or kidney disease you are taking a diuretic high blood pressure you have asthma Ask a doctor or pharmacist before use any other drug containing an NSAID (prescription or nonprescription) a blood thinning (anticoagulant) or steroid drug a prescription drug for diabetes, gout, or arthritis any other drug, or are under a doctor’s care for any serious condition Stop use and ask doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs os stomach bleeding feel faint vomit blood have bloody or black stools have stomach pain that does not get better ringing in the ears or loss of hearing occurs painful area is red or swollen pain gets worse or lasts for more than 10 days fever gets worse or lasts for more than 3 days any new symptoms appear If pregnant or breast-feeding ask a health professional before use. It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery. Keep out of reach of children Overdose Warning In case of overdose, get medical help or contact a Poison Control Center right away. Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms.

OVERDOSAGE

Overdose Warning In case of overdose, get medical help or contact a Poison Control Center right away. Quick medical attention is critical for adults as well as for children even if you do not notice any signs or symptoms.

INDICATIONS AND USAGE

Uses temporarily relieves minor aches and pains due to: headache a cold arthritis muscular aches sinusitis toothache premenstrual & menstrual cramps

INACTIVE INGREDIENTS

Inactive ingredients benzoic acid, carnauba wax, FD&C blue #1, hydroxypropyl cellulose, hypromellose, light mineral oil, microcrystalline cellulose, polysorbate 20, povidone, propylene glycol, simethicone emulsion, sorbitan monolaurate, stearic acid, titanium dioxide

PURPOSE

Purpose Pain reliever Pain reliever Pain reliever aid

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children

ASK DOCTOR

Ask Doctor before use if you have liver disease stomach bleeding warning applies to you you have a history of stomach problems, such as heartburnyou have high blood pressure, heart disease, liver cirrhosis. or kidney disease you are taking a diuretic high blood pressure you have asthma

DOSAGE AND ADMINISTRATION

Directions do not use more than directed (see Overdose Warning) drink a full glass of water with each dose adults and children 12 years and over: take 2 tablets every 6 hours; not more than 8 tables in 24 hours children under 12 years: ask a doctor Other information store at controlled room temperature 200 – 250 C (680 – 770 F) read all product information before using. Keep this box for important information

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding ask a health professional before use. It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.

DO NOT USE

Do not use if you have ever had an allergic reaction to aspirin or any other pain reliever/fever reducer with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.

STOP USE

Stop use and ask doctor if an allergic reaction occurs. Seek medical help right away. you experience any of the following signs os stomach bleeding feel faint vomit blood have bloody or black stools have stomach pain that does not get better ringing in the ears or loss of hearing occurs painful area is red or swollen pain gets worse or lasts for more than 10 days fever gets worse or lasts for more than 3 days any new symptoms appear

ACTIVE INGREDIENTS

Active ingredient (in each tablet) Acetaminophen 250 mg Aspirin 250 mg (NSAID)* Caffeine 65 mg *nonsteroidal anti-inflammatory drug

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use any other drug containing an NSAID (prescription or nonprescription) a blood thinning (anticoagulant) or steroid drug a prescription drug for diabetes, gout, or arthritis any other drug, or are under a doctor’s care for any serious condition