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butalb-acetaminophen-caff 50-325-40 tab

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Uses

CNS Stimulation

Caffeine is used orally as a mild CNS stimulant to aid in staying awake and to restore mental alertness in fatigued patients.

Caffeine also is used orally in combination with antihistamines to overcome the sedative properties of the latter drugs, but the efficacy of caffeine and the dosage required have not been adequately established.

Caffeine and sodium benzoate injection has been used in conjunction with supportive measures to treat respiratory depression associated with overdosage of CNS depressant drugs (e.g., opiate analgesics, alcohol) and with electric shock. However, because of the questionable benefit and transient action, most authorities believe caffeine and other analeptics should not be used in these conditions and recommend other supportive therapy.

Apnea of Prematurity

Caffeine citrate is used IV or orally in the short-term (10-12 days) treatment of apnea of prematurity in neonates who are between 28 and less than 33 weeks of gestational age. Caffeine is designated an orphan drug by the US Food and Drug Administration (FDA) for use in apnea in premature neonates.

The use of caffeine citrate in apnea of prematurity was established in a randomized, placebo-controlled clinical trial of the drug in premature neonates (gestational age 28 to less than 33 weeks) with apnea of prematurity (defined as having at least 6 episodes of apnea of greater than 20 seconds' duration in a 24-hour period with no other identifiable causes of apnea). A 20-mg/kg loading dose of caffeine citrate (10 mg/kg of caffeine) was administered IV, followed by a daily maintenance dose of 5 mg/kg of caffeine citrate (2.5 mg/kg of caffeine) IV or orally (generally via a feeding tube). Patients randomized to placebo were allowed to cross over to caffeine treatment if their apnea became uncontrolled during the double-blind phase of the trial; the study period lasted 10-12 days. The percentage of patients without apnea on the second day of treatment (i.e., 24-48 hours after the loading dose) was greater in the caffeine-treated patients compared with placebo-treated patients (26.7 versus 8.1%, respectively). The mean number of days with zero apnea events was 3 in the caffeine-treated group and 1.2 in the placebo group, while the mean number of days with a 50% reduction from baseline in apnea events was 6.8 in the caffeine-treated group and 4.6 in the placebo group. Serum caffeine concentrations ranged from 8-40 mcg/mL in treated patients; however, a therapeutic plasma concentration could not be determined from this clinical trial. In low-birthweight neonates, the drug has decreased the frequency of apneic episodes without any substantial effect on heart rate. Some clinicians recommend that when conservative measures (e.g., tactile stimulation, flotation on a waterbed) are ineffective in preventing severe, recurrent apnea in neonates, caffeine may be used as an alternative to mechanical ventilation. The manufacturer states that the safety and efficacy of treatment with caffeine citrate in neonates with apnea of prematurity for longer than 10-12 days have not been established. The manufacturer also states that use of caffeine citrate in the prevention of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated neonates also has not been established. Use of the combination preparation containing caffeine and sodium benzoate in neonates is generally avoided because of the potential for sodium benzoate to produce kernicterus. (See Cautions: Pediatric Precautions.)

Headache

Caffeine is used orally or rectally in combination with ergotamine tartrate to abort vascular headaches such as migraine and cluster headaches (histamine cephalalgia). There is conflicting evidence regarding the efficacy of this combination in the treatment of acute migraine attacks. Caffeine's cerebral vasoconstrictor effect is reportedly additive with that of ergotamine, but the results of one study suggest that the principal value of caffeine in this combination is related to its ability to increase GI absorption of ergotamine tartrate. Some clinicians question the value of the combination because caffeine may keep patients awake and sleep can contribute to the relief of migraine.

Caffeine is used orally alone and in combination with analgesics (e.g., acetaminophen, aspirin) for the treatment of headache. Some experts state that the combination of acetaminophen, aspirin, and caffeine is a reasonable first-line therapy for mild to moderate migraine attacks or for severe migraine attacks that have responded in the past to similar nonsteroidal anti-inflammatory agents (NSAIAs) or non-opiate analgesics. Caffeine exerts no intrinsic analgesic activity. Although analgesic-caffeine combinations have been reported to produce slightly more analgesia than analgesic agents alone and to have a beneficial effect on mood, which may be clinically important in some patients with headache, these results have not always been reproducible in well-controlled studies and additional studies are needed to determine the role, if any, of caffeine as an analgesic adjuvant.

Caffeine and sodium benzoate injection has been used for the symptomatic relief of headache following spinal puncture.

Other Uses

Caffeine is used orally alone and in combination with other drugs (e.g., analgesics, diuretics) to relieve tension, fatigue, and fluid retention associated with menstruation. However, because caffeine's diuretic activity in patients with fluid retention is minimal, its usefulness in this condition is questionable.

Caffeine (30% in a topical hydrophilic base) has been used effectively alone or in combination with topical hydrocortisone in the topical treatment of atopic dermatitis.

Caffeine also has been used in combination with ephedrine to promote weight loss in patients with exogenous obesity. It has been suggested that weight loss may be associated with increased energy expenditure (thermogenesis) and appetite suppression. However, the US Food and Drug Administration (FDA), which did not evaluate the efficacy of ephedrine dietary supplements in obesity therapy, has stated that such use of ephedrine may be associated with an unacceptable incidence of adverse effects.

Dosage and Administration

Administration

Caffeine may be administered orally. Caffeine citrate is administered orally or by slow IV infusion using a syringe infusion pump. Caffeine and sodium benzoate injection may be administered by IM or slow IV injection; the drug has also been administered subcutaneously.

The preservative-free commercially available injection is for single use only, and any unused portion should be discarded. It is important that such oral solution be measured accurately (e.g., using a 1-mL or other appropriate syringe).

Dosage

Some clinicians suggest that when used as a mild CNS stimulant to overcome fatigue, oral doses of 100-200 mg of anhydrous caffeine are required. The manufacturers state that adults and children 12 years of age or older may receive a dosage of 100-200 mg no more frequently than every 3-4 hours.

For the treatment of apnea of prematurity, commercially available caffeine citrate injection in a loading dose of 20 mg/kg (10 mg/kg when expressed in terms of anhydrous caffeine) is administered by slow IV infusion (i.e., over 30 minutes) using a syringe infusion pump. Beginning 24 hours after the loading dose, maintenance doses of caffeine citrate of 5 mg/kg (2.5 mg/kg when expressed as anhydrous caffeine) may be administered every 24 hours, either orally or via slow IV infusion (i.e., over 10 minutes) using a syringe infusion pump. The manufacturer states that the safety and efficacy of dosing periods exceeding 10-12 days have not been established. Other dosing regimens for the treatment of apnea of prematurity have used caffeine doses (in terms of anhydrous caffeine) of 5-10 mg/kg, given IV, IM, or orally as a loading dose, and followed by 2.5-5 mg/kg, given IV, IM, or orally once daily. Maintenance dosage has been adjusted according to the patient's response and tolerance and plasma caffeine concentrations.

When caffeine citrate is used for the treatment of apnea of prematurity in infants with hepatic or renal impairment, serum concentrations of caffeine should be monitored and dosage adjusted to avoid toxicity.

Analeptic use of caffeine is strongly discouraged by most clinicians. However, the manufacturers of caffeine and sodium benzoate injection recommend IM, or in emergency respiratory failure, IV injection of 500 mg of the drug (about 250 mg of anhydrous caffeine) or a maximum single dose of 1 g (about 500 mg of anhydrous caffeine) for the treatment of respiratory depression associated with overdosage of CNS depressants, including opiate analgesics and alcohol, and with electric shock.

Some clinicians recommend that when caffeine and sodium benzoate injection is used in children for CNS stimulation, an IM, IV, or subcutaneous dose of 8 mg/kg (about 4 mg of anhydrous caffeine per kg) (not to exceed 500 mg) or 250 mg/m (about 125 mg of anhydrous caffeine per m) be given up to every 4 hours if necessary.

Cautions

Adverse Effects

CNS stimulation and GI irritation usually occur with therapeutic dosages of caffeine. Adverse CNS effects, which are usually more severe in children than in adults, include insomnia, restlessness, nervousness, and mild delirium. Adverse GI effects include nausea, vomiting, and gastric irritation. Although chronic administration of caffeine in animals has been associated with gastric ulceration, such a causal relationship in humans has not been adequately established to date. Suppositories containing caffeine may produce rectal irritation. Large doses of caffeine may produce headache, excitement, agitation, a condition resembling anxiety neurosis, scintillating scotoma, hyperesthesia, tinnitus, muscle tremors or twitches, diuresis, tachycardia, extrasystoles, and possibly other cardiac arrhythmias.

Further CNS depression may occur when already depressed patients are too vigorously treated with caffeine and sodium benzoate.

In a placebo-controlled study, the most common adverse effects occurring more frequently in patients receiving caffeine citrate than in those receiving placebo included rash and feeding intolerance, each of which occurred in 8.7% of patients, and sepsis and necrotizing enterocolitis, each of which occurred in 4.3% of patients. In this same trial, accidental injury, hemorrhage, gastritis, GI hemorrhage, disseminated intravascular coagulation, acidosis, abnormal healing, cerebral hemorrhage, pulmonary edema, dyspnea, dry skin, skin breakdown, retinopathy of prematurity, and kidney failure each occurred in 2.2% of caffeine-treated patients. In addition, during the trial of caffeine citrate for the apnea of prematurity, 6 cases of necrotizing enterocolitis developed among the 85 neonates studied, 3 cases of which were fatal. Five of the 6 neonates had been randomized to treatment with or had been exposed to caffeine citrate. Adverse effects reported in the literature include CNS stimulation (i.e., irritability, restlessness, jitteriness), cardiovascular effects (i.e., tachycardia, increased left ventricular output, increased stroke volume), GI effects (i.e., increased gastric aspirate, GI intolerance), alterations in serum glucose (i.e., hyperglycemia or hypoglycemia), and renal effects (i.e., increased urine flow rate, increased creatinine clearance, increased sodium and calcium excretion).

Ingestion of large amounts of combinations containing aspirin, phenacetin, and caffeine (combinations containing phenacetin no longer are commercially available in the US) has been associated with analgesic nephropathy which is characterized by sterile pyuria, asymptomatic bacteriuria, pyelonephritis, papillary necrosis, interstitial fibrosis and nephritis, and increased excretion of renal tubular cells and erythrocytes. Caffeine's role in the etiology of this condition has not been conclusively established.

Precautions and Contraindications

Because it has been suggested that caffeine may promote gastric ulceration, the drug should be used cautiously in patients with a history of peptic ulcer. Because of its suspected arrhythmogenic potential, it is generally recommended that caffeine be avoided in patients with symptomatic cardiac arrhythmias and/or palpitations and during the first several days to weeks after an acute myocardial infarction.

When self-administered as a mild CNS stimulant to overcome fatigue or drowsiness, caffeine is intended for occasional use only and should not be used as a substitute for sleep.

When preparations containing caffeine in combination with other drugs (see Preparations) are used, the cautions, precautions, and contraindications applicable to each ingredient should be considered.

Caffeine is contraindicated in patients with a history of hypersensitivity to the drug.

Pediatric Precautions

Use of caffeine tablets for self-medication in children younger than 12 years of age is not recommended.

Adverse CNS effects of caffeine are usually more severe in children than in adults. (See Cautions: Adverse Effects.) The sodium benzoate component in caffeine and sodium benzoate injection reportedly produces kernicterus in neonates by uncoupling albumin-bilirubin binding. Long-term follow-up studies have not shown caffeine administration in premature neonates to affect adversely either neurologic development or growth parameters.

In neonates receiving caffeine citrate therapy, periodic monitoring of serum caffeine concentrations may be necessary to avoid toxicity. Prior to initiation of caffeine citrate therapy, baseline serum concentrations of caffeine should be measured in neonates previously treated with theophylline, since preterm neonates metabolize theophylline to caffeine. Similarly, baseline serum concentrations of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery since caffeine readily crosses the placenta. Serious toxicity has been reported when serum caffeine concentrations exceed 50 mcg/mL.

Because studies examining the pharmacokinetics of caffeine in neonates with renal or hepatic insufficiency have not been conducted, caffeine citrate should be administered with caution in premature neonates with impaired renal or hepatic function. Serum concentrations of caffeine should be monitored in these neonates, and dosage adjusted to avoid toxicity.

Few data exist on drug interactions with caffeine in premature neonates. Based on data in adults, lower doses of caffeine may be needed following concomitant use of drugs that are reported to decrease caffeine elimination (e.g., ketoconazole, cimetidine) and higher caffeine doses may be required following concomitant use of drugs that increase caffeine elimination (e.g., phenobarbital, phenytoin). Interconversion between caffeine and theophylline has been reported in premature neonates. The concurrent use of these drugs is not recommended. In healthy adults, concomitant administration of caffeine with ketoprofen resulted in decreased urinary volume; the clinical significance of this interaction in premature neonates is not known.

In clinical trials reported in the literature, cases of hypoglycemia and hyperglycemia have been reported in patients receiving caffeine; therefore, blood glucose concentration may need to be monitored periodically in neonates receiving caffeine citrate.

Although no cases of cardiac toxicity were reported in the placebo-controlled trial of caffeine citrate for the treatment of apnea of prematurity, caffeine has been shown to increase heart rate, left ventricular output, and stroke volume. Therefore, caffeine citrate should be used with caution in neonates with cardiovascular disease.

If signs of GI intolerance (e.g., abdominal distention, vomiting, bloody stools) or lethargy develops in premature neonates receiving caffeine citrate oral solution, a clinician should be consulted.

Because seizures have been reported in cases of caffeine overdose, caffeine citrate should be used with caution in neonates with seizure disorders.

The duration of treatment with caffeine citrate in neonates with apnea of prematurity was limited to 10-12 days in the placebo-controlled trial. The safety and efficacy of caffeine citrate for longer periods in this condition have not been established. If premature neonates receiving caffeine citrate oral solution continue to experience apnea events, dosage of the drug should not be increased without advice of a clinician. Safety and efficacy of caffeine citrate in the prevention of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated patients also have not been established.

Apnea of prematurity is a diagnosis of exclusion. Other causes of apnea (e.g., CNS disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, obstructive apnea) should be ruled out or treated appropriately prior to initiation of treatment with caffeine citrate.

During the placebo-controlled trial of caffeine citrate establishing efficacy in the US for apnea of prematurity, 6 cases of necrotizing enterocolitis developed among the 85 neonates studied, 3 cases of which were fatal. Five of the 6 neonates had been randomized to treatment with or had been exposed to caffeine citrate. Reports in the literature have raised the possibility of an association between the use of methylxanthines and the development of necrotizing enterocolitis, although a causal relationship between methylxanthine use and the development of necrotizing enterocolitis has not been established. Therefore, as with all premature neonates, patients being treated with caffeine citrate should be monitored carefully for the development of necrotizing enterocolitis.

Mutagenicity and Carcinogenicity

Although clastogenicity and mutagenicity have been demonstrated in some in vitro and animal studies, most clinicians believe that these effects are not important in relation to the amounts of caffeine consumed by humans.

In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2 and 4 times, respectively, the maximum IV loading dose for neonates on a mg/m basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses of up to 55 mg/kg (less than the maximum IV loading dose for neonates on a mg/m basis).

Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation fivefold in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/HGPRT gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay.

Although it has been suggested that coffee consumption is associated with an increased risk of lower urinary tract, renal, and pancreatic cancers, most studies conducted to date have had methodologic flaws and there is currently no clear evidence that coffee consumption is causally related to an increased risk of these cancers.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained-release pellets at 50 mg/kg (less than the maximum IV loading dose for neonates on a mg/m basis) during the period of organogenesis caused a low incidence of cleft palate and exencephaly in fetuses. Based on data from a large retrospective epidemiologic study and from a large retrospective case-control study in humans, it appears that use of caffeine during pregnancy has little, if any, effect on the outcome of pregnancy. Although caffeine use during pregnancy does not appear to be associated with substantial risk, most clinicians recommend that pregnant women avoid or limit their consumption of foods, beverages, and drugs containing caffeine, since caffeine crosses the placenta.

Fertility

Caffeine (as caffeine base) administered subcutaneously to male rats at 50 mg/kg daily (approximately equal to the maximum IV loading dose for neonates on a mg/m basis) for 4 days prior to mating with untreated females caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

Lactation

Caffeine is distributed into the milk of nursing women. Milk-to-plasma ratios of 0.5-0.76 have been reported. The amount of caffeine ingested from usual quantities of caffeinated beverages is considered compatible with breast-feeding; however, caffeine may accumulate in nursing infants following moderate to heavy maternal consumption of caffeine, resulting in irritability and poor sleeping patterns.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Caffeine is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by isoenzyme 1A2. Therefore, caffeine has the potential to interact with drugs that are metabolized by CYP1A2 or with drugs that induce or inhibit this isoenzyme.(See Cautions: Pediatric Precautions.) Caffeine has been reported to increase its own metabolism.

β-Adrenergic Agonists

Caffeine and other xanthines may enhance the cardiac inotropic effects of β-adrenergic stimulating agents.

Disulfiram

When caffeine and disulfiram are administered concomitantly in healthy individuals or recovering alcohol-dependent patients, the total blood clearance of caffeine is substantially decreased and its elimination half-life is increased. The exact mechanism of the interaction is not known, but disulfiram may inhibit hepatic metabolism of caffeine. The clinical importance of the interaction has not been established, but the possibility that exaggerated or prolonged effects of caffeine might occur in patients receiving disulfiram who also ingest substantial quantities of coffee, tea, or other caffeine-containing beverages should be considered. Further studies are needed.

Pharmacokinetics

Absorption

Caffeine and citrated caffeine are well absorbed following oral administration. Absorption of caffeine following oral administration may be more rapid than that following IM injection of caffeine and sodium benzoate. Absorption following rectal administration of caffeine in suppositories may be slow and erratic. Absolute bioavailability of caffeine in preterm neonates has not been fully determined. Following oral administration of 100 mg of caffeine (as coffee), peak plasma concentrations of about 1.5-1.8 mcg/mL are reached after 50-75 minutes. After oral administration of 10 mg/kg caffeine to preterm neonates, the peak plasma concentration for caffeine ranged from 6-10 mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours. The time to reach peak plasma concentration was not affected by formula feeding.

Distribution

Caffeine is rapidly distributed into body tissues, readily crossing the placenta and blood-brain barrier. Caffeine concentration in the CSF fluid of preterm neonates approximates the plasma concentration. The mean volume of distribution of caffeine in infants (0.8-0.9 L/kg) is slightly higher than that in adults (0.6 L/kg). Approximately 17-36% of the drug is bound to plasma proteins in adults. Plasma protein binding data are not available for neonates or infants. Caffeine has been shown to distribute into milk in a milk-to-plasma concentration ratio of 0.5-0.76.

Elimination

Caffeine has a plasma half-life of 3-5 hours in adults. In one study, when administered to pregnant women prior to delivery, caffeine had a prolonged mean half-life of 80 hours in the neonates after delivery. In young infants, the elimination of caffeine is much slower than that in adults because of immature hepatic and/or renal function. Mean half-life and fraction excreted unchanged in urine of caffeine in infants have been shown to be related inversely to gestational/postconceptional age. In neonates, the half-life of caffeine is approximately 3-4 days, and the mean fraction excreted unchanged in urine is approximately 86% (within 6 days). By 9 months of age, the metabolism of caffeine approximates that seen in adults. Hepatic cytochrome P-450 (CYP) isoenzyme 1A2 is involved in caffeine enzymatic metabolism. In adults, the drug is rapidly metabolized in the liver to 1-methyluric acid, 1-methylxanthine, and 7-methylxanthine. Interconversion between caffeine and theophylline has been reported in preterm neonates; caffeine concentrations are approximately 25% of theophylline concentration following theophylline administration and approximately 3-8% of an administered dose of caffeine would be expected to convert to theophylline. Caffeine and its metabolites are excreted mainly by the kidneys; approximately 1% of a dose of caffeine is excreted unchanged in urine in adults.

Studies examining the pharmacokinetics of caffeine in neonates with renal or hepatic insufficiency have not been conducted.

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