Butalbital, Aspirin, Caffeine and Codeine Phosphate

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Overview

What is Butalbital, Aspirin, Caffeine and Codeine Phosphate?

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is supplied in capsule form for oral administration.

Each capsule contains the following active ingredients:butalbital, USP ……………………..50 mgaspirin, USP ……………………....325 mgcaffeine, USP ………………………40 mgcodeine phosphate, USP …………30 mg

Butalbital (5-allyl-5-isobutylbarbituric acid) is a short- to intermediate-acting barbiturate. It has the following structural formula:

CHNO                                              molecular weight 224.26

Aspirin (benzoic acid, 2-(acetyloxy)-) is an analgesic, antipyretic, and anti-inflammatory. It has the following structural formula:

CHO                                              molecular weight 180.16

Caffeine (1,3,7-trimethylxanthine) is a central nervous system stimulant. It has the following structural formula:

CHNO                                       molecular weight 194.19

Codeine phosphate (7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol phosphate (1:1) (salt) hemihydrate) is a narcotic analgesic and antitussive. It has the following structural formula:

CHNOP                                 anhydrous molecular weight 397.37

Inactive Ingredients:

What does Butalbital, Aspirin, Caffeine and Codeine Phosphate look like?

What are the available doses of Butalbital, Aspirin, Caffeine and Codeine Phosphate?

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What should I talk to my health care provider before I take Butalbital, Aspirin, Caffeine and Codeine Phosphate?

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How should I use Butalbital, Aspirin, Caffeine and Codeine Phosphate?

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is indicated for the relief of the symptom complex of tension (or muscle contraction) headache.

Evidence supporting the efficacy of butalbital, aspirin, caffeine, and codeine phosphate capsules is derived from 2 multi-clinic trials that compared patients with tension headache randomly assigned to 4 parallel treatments: butalbital, aspirin, caffeine, and codeine phosphate capsules; codeine; Butalbital, Aspirin, and Caffeine Capsules, USP; and placebo. Response was assessed over the course of the first 4 hours of each of 2 distinct headaches, separated by at least 24 hours. Butalbital, aspirin, caffeine, and codeine phosphate capsules proved statistically significantly superior to each of its components (Butalbital, Aspirin, and Caffeine Capsules, USP and codeine) and to placebo on measures of pain relief.

Evidence supporting the efficacy and safety of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in the treatment of multiple recurrent headaches is unavailable. Caution in this regard is required because codeine and butalbital are habit-forming and potentially abusable.

One or 2 capsules every 4 hours. Total daily dosage should not exceed 6 capsules.

Extended and repeated use of this product is not recommended because of the potential for physical dependence.

What interacts with Butalbital, Aspirin, Caffeine and Codeine Phosphate?

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated under the following conditions:

- Hypersensitivity or intolerance to aspirin, caffeine, butalbital or codeine.
- Patients with a hemorrhagic diathesis (e.g., hemophilia, hypoprothrombinemia, von Willebrand’s disease, the thrombocytopenias, thrombasthenia and other ill-defined hereditary platelet dysfunctions, severe vitamin K deficiency and severe liver damage).
- Patients with the syndrome of nasal polyps, angioedema and bronchospastic reactivity to aspirin or other nonsteroidal anti-inflammatory drugs. Anaphylactoid reactions have occurred in such patients.
- Peptic ulcer or other serious gastrointestinal lesions.
- Patients with porphyria.

What are the warnings of Butalbital, Aspirin, Caffeine and Codeine Phosphate?

A Lindane Shampoo Medication Guide must be given to the patient each time Lindane Shampoo is dispensed, as required by law.

Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking.

Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders.

Aspirin administered pre-operatively may prolong the bleeding time.

In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries.

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is not recommended.

Results from epidemiologic studies indicate an association between aspirin and Reye’s Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu.

What are the precautions of Butalbital, Aspirin, Caffeine and Codeine Phosphate?

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be prescribed with caution for certain special-risk patients such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, coagulation disorders, or head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, prostatic hypertrophy, and peptic ulcer.

Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects.

Precautions should be taken when administering salicylates to persons with known allergies. Hypersensitivity to aspirin is particularly likely in patients with nasal polyps, and relatively common in those with asthma.

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See)

Patients should be informed that Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains aspirin and should not be taken by patients with an aspirin allergy.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, and should be avoided.

Codeine and butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

For information on use in geriatric patients, refer to.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.

In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may enhance the effects of:

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may diminish the effects of:

Uricosuric agents such as probenecid and sulfinpyrazone, reducing their effectiveness in the treatment of gout. Aspirin competes with these agents for protein binding sites.

Aspirin:

Codeine:

Adequate long-term studies have been conducted in mice and rats with aspirin, alone or in combination with other drugs, in which no evidence of carcinogenesis was seen. No adequate studies have been conducted in animals to determine whether aspirin has a potential for mutagenesis or impairment of fertility. No adequate studies have been conducted in animals to determine whether butalbital has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Pregnancy Category C.

Although Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP was not implicated in the birth defect, a female infant was born with lissencephaly, pachygyria and heterotopic gray matter. The infant was born 8 weeks prematurely to a woman who had taken an average of 90 butalbital, aspirin, caffeine, and codeine phosphate capsules each month from the first few days of pregnancy. The child’s development was mildly delayed and from one year of age she had partial simple motor seizures.

Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital-containing drug during the last 2 months of pregnancy. Butalbital was found in the infant’s serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms.

Studies of aspirin use in pregnant women have not shown that aspirin increases the risk of abnormalities when administered during the first trimester of pregnancy. In controlled studies involving 41,337 pregnant women and their offspring, there was no evidence that aspirin taken during pregnancy caused stillbirth, neonatal death or reduced birth weight. In controlled studies of 50,282 pregnant women and their offspring, aspirin administration in moderate and heavy doses during the first four lunar months of pregnancy showed no teratogenic effect.

Reproduction studies have been performed in rabbits and rats at doses up to 150 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to codeine.

Therapeutic doses of aspirin in pregnant women close to term may cause bleeding in mother, fetus, or neonate. During the last 6 months of pregnancy, regular use of aspirin in high doses may prolong pregnancy and delivery.

Ingestion of aspirin prior to delivery may prolong delivery or lead to bleeding in the mother or neonate. Use of codeine during labor may lead to respiratory depression in the neonate.

Aspirin, caffeine, barbiturates and codeine are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of potential for serious adverse reactions in nursing infants from Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, 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.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See)

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of butalbital, aspirin, caffeine, and codeine phosphate 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.

Butalbital 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.

Oral anticoagulants, causing bleeding by inhibiting prothrombin formation in the liver and displacing anticoagulants from plasma protein binding sites.

Oral antidiabetic agents and insulin, causing hypoglycemia by contributing an additive effect, if dosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP exceeds maximum recommended daily dosage.

6-mercaptopurine and methotrexate, causing bone marrow toxicity and blood dyscrasias by displacing these drugs from secondary binding sites, and, in the case of methotrexate, also reducing its excretion.

Non-steroidal anti-inflammatory agents, increasing the risk of peptic ulceration and bleeding by contributing additive effects.

Other narcotic analgesics, alcohol, general anesthetics, tranquilizers such as chlordiazepoxide, sedative-hypnotics, or other CNS depressants, causing increased CNS depression.

What are the side effects of Butalbital, Aspirin, Caffeine and Codeine Phosphate?

The most commonly reported adverse events associated with the use of butalbital, aspirin, caffeine, and codeine phosphate capsules and not reported at an equivalent incidence by placebo-treated patients were nausea and/or abdominal pain, drowsiness, and dizziness.

Of the 382 patients treated with butalbital, aspirin, caffeine, and codeine phosphate capsules in controlled clinical trials, three (0.8%) discontinued treatment with butalbital, aspirin, caffeine, and codeine phosphate capsules because of adverse events. One patient each discontinued treatment for the following reasons: gastrointestinal upset; lightheadedness and heavy eyelids; and drowsiness and generalized tingling.

The following table summarizes the incidence rates of the adverse events reported by at least 1% of the butalbital, aspirin, caffeine, and codeine phosphate capsules treated patients in controlled clinical trials comparing butalbital, aspirin, caffeine, and codeine phosphate capsules to placebo, and provides a comparison to the incidence rates reported by the placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.

The listing that follows represents the proportion of the 382 patients exposed to butalbital, aspirin, caffeine, and codeine phosphate capsules while participating in the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited. All reported adverse events, except those already presented in the previous table, are included. It is important to emphasize that, although the adverse events reported did occur while the patient was receiving butalbital, aspirin, caffeine, and codeine phosphate capsules, the adverse events were not necessarily caused by butalbital, aspirin, caffeine, and codeine phosphate capsules.

Adverse events are classified by body system and frequency. “Frequent” is defined as an adverse event which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are frequent. “Infrequent” is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000 patients. All adverse events tabulated below are classified as infrequent.

Central Nervous:

Autonomic Nervous:

Gastrointestinal:

Cardiovascular:

Musculoskeletal:

Genitourinary:

Miscellaneous:

Voluntary reports of adverse drug events, temporally associated with butalbital, aspirin, caffeine, and codeine phosphate capsules, that have been received since market introduction and that were not reported in clinical trials by the patients treated with butalbital, aspirin, caffeine, and codeine phosphate capsules, are listed below. Many or most of these events may have no causal relationship with the drug and are listed according to body system.

Central Nervous:

Autonomic Nervous:

Gastrointestinal:

Cardiovascular:

Skin:

Urinary:

Miscellaneous:

The following adverse drug events may be borne in mind as potential effects of the components of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Potential effects of high dosage are listed in the section of this insert.

Aspirin:

Caffeine:

Codeine:

**Adverse Events Reported by at Least 1% of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules Treated Patients During Placebo Controlled Clinical Trials Incidence Rate of Adverse Events**
	Body System/Adverse Event		Butalbital, Aspirin, Caffeine, andCodeine Phosphate Capsules(N = 382)	Placebo(N = 377)
	Central Nervous
Dizziness/Lightheadedness	2.6%	0.5%
Intoxicated Feeling	1.0%	0%
	Gastrointestinal

What should I look out for while using Butalbital, Aspirin, Caffeine and Codeine Phosphate?

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated under the following conditions:

Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking.

Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders.

Aspirin administered pre-operatively may prolong the bleeding time.

In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries.

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is not recommended.

Results from epidemiologic studies indicate an association between aspirin and Reye’s Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu.

What might happen if I take too much Butalbital, Aspirin, Caffeine and Codeine Phosphate?

The toxic effects of acute overdosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are attributable mainly to the barbiturate and codeine components, and, to a lesser extent, aspirin. Because toxic effects of caffeine occur in very high dosages only, the possibility of significant caffeine toxicity from Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP overdosage is unlikely.

Symptoms attributable to include drowsiness, confusion, and coma; respiratory depression; hypotension; hypovolemic shock. Symptoms attributable to include hyperpnea; acid-base disturbances with development of metabolic acidosis; vomiting and abdominal pain; tinnitus, hyperthermia; hypoprothrombinemia; restlessness; delirium; convulsions. may cause insomnia, restlessness, tremor, and delirium; tachycardia and extrasystoles. Symptoms of include the opioid triad of: pinpoint pupils, marked depression of respiration, and loss of consciousness. Convulsions may occur.

The following paragraphs describe one approach to the treatment of overdose with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. However, because strategies for the management of an overdose continually evolve, consultation with a regional poison control center is strongly encouraged.

Treatment consists primarily of management of barbiturate intoxication, reversal of the effects of codeine, and the correction of the acid-base imbalance due to salicylism. Vomiting should be induced mechanically or with emetics in the conscious patient. Gastric lavage may be used if the pharyngeal and laryngeal reflexes are present and if less than 4 hours have elapsed since ingestion. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and when necessary to provide assisted respiration. Diuresis, alkalinization of the urine, and correction of electrolyte disturbances should be accomplished through administration of intravenous fluids such as 1% sodium bicarbonate and 5% dextrose in water.

Meticulous attention should be given to maintaining adequate pulmonary ventilation. The value of vasopressor agents such as Norepinephrine or Phenylephrine Hydrochloride in treating hypotension is questionable since they increase vasoconstriction and decrease blood flow. However, if prolonged support of blood pressure is required, Norepinephrine Bitartrate (Levophed®) may be given I.V. with the usual precautions and serial blood pressure monitoring. In severe cases of intoxication, peritoneal dialysis, hemodialysis, or exchange transfusion may be lifesaving. Hypoprothrombinemia should be treated with vitamin K, intravenously.

Methemoglobinemia over 30% should be treated with methylene blue by slow intravenous administration.

Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Typically, a dose of 0.4-2 mg is given parenterally and may be repeated if an adequate response is not achieved. Since the duration of action of codeine may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression.

Up-to-date information about the treatment of overdose can be obtained from a Certified Regional Poison Control Center. Telephone numbers of Certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®.

Butalbital:

Aspirin:

Caffeine:

Codeine:

How should I store and handle Butalbital, Aspirin, Caffeine and Codeine Phosphate?

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146 Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USPbottles of 20 NDC 54868-1037-1bottles of 30 NDC 54868-1037-3 bottles of 60 NDC 54868-1037-5bottles of 120 NDC 54868-1037-4which are supplied with child-resistant closures.Below 25°C (77°F); tight container. Protect from moisture.Rx onlyWatson Laboratories, Inc.Revised: January 2007BASPCC01/07S0107Relabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK 74146

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is a combination drug product intended as a treatment for tension headache.

Butalbital, Aspirin, and Caffeine Capsules, USP consists of a fixed combination of caffeine 40 mg, butalbital 50 mg, and aspirin 325 mg. The role each component plays in the relief of the complex of symptoms known as tension headache is incompletely understood.

Bioavailability:

The behavior of the individual components is described below.

The systemic availability of aspirin after an oral dose is highly dependent on the dosage form, the presence of food, the gastric emptying time, gastric pH, antacids, buffering agents, and particle size. These factors affect not necessarily the extent of absorption of total salicylates but more the stability of aspirin prior to absorption.

During the absorption process and after absorption, aspirin is mainly hydrolyzed to salicylic acid and distributed to all body tissues and fluids, including fetal tissues, breast milk, and the central nervous system (CNS). Highest concentrations are found in plasma, liver, renal cortex, heart, and lung. In plasma, about 50%-80% of the salicylic acid and its metabolites are loosely bound to plasma proteins.

The clearance of total salicylates is subject to saturable kinetics; however, first-order elimination kinetics are still a good approximation for doses up to 650 mg. The plasma half-life for aspirin is about 12 minutes and for salicylic acid and/or total salicylates is about 3 hours.

The elimination of therapeutic doses is through the kidneys either as salicylic acid or other biotransformation products. The renal clearance is greatly augmented by an alkaline urine as is produced by concurrent administration of sodium bicarbonate or potassium citrate.

The biotransformation of aspirin occurs primarily in the hepatocytes. The major metabolites are salicyluric acid (75%), the phenolic and acyl glucuronides of salicylate (15%), and gentisic and gentisuric acid (1%). The bioavailability of the aspirin component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution except for a slower rate of absorption. A peak concentration of 8.8 mcg/mL was obtained at 40 minutes after a 650 mg dose.

See for toxicity information.

Codeine is readily absorbed from the gastrointestinal tract. It is rapidly distributed from the intravascular spaces to the various body tissues, with preferential uptake by parenchymatous organs such as the liver, spleen, and kidney. Codeine crosses the blood-brain barrier, and is found in fetal tissue and breast milk. The plasma concentration does not correlate with brain concentration or relief of pain, however, codeine is not bound to plasma proteins and does not accumulate in body tissues.

The plasma half-life is about 2.9 hours. The elimination of codeine is primarily via the kidneys, and about 90% of an oral dose is excreted by the kidneys within 24 hours of dosing. The urinary secretion products consist of free and glucuronide-conjugated codeine (about 70%), free and conjugated norcodeine (about 10%), free and conjugated morphine (about 10%), normorphine (4%), and hydrocodone (1%). The remainder of the dose is excreted in the feces.

At therapeutic doses, the analgesic effect reaches a peak within 2 hours and persists between 4 and 6 hours.

The bioavailability of the codeine component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution. Peak concentrations of 198 ng/mL were obtained at 1 hour after a 60 mg dose.

See for toxicity information.

Butalbital is well absorbed from the gastrointestinal tract and is expected to distribute to most of the tissues in the body. Barbiturates, in general, may appear in breast milk and readily cross the placental barrier. They are bound to plasma and tissue proteins to a varying degree and binding increases directly as a function of lipid solubility.

Elimination of butalbital is primarily via the kidney (59%-88% of the dose) as unchanged drug or metabolites. The plasma half-life is about 35 hours. Urinary excretion products included parent drug (about 3.6% of the dose), 5-isobutyl-5-(2,3-dihydroxypropyl) barbituric acid (about 24% of the dose), 5-allyl-5(3-hydroxy-2-methyl-1-propyl) barbituric acid (about 4.8% of the dose), products with the barbituric acid ring hydrolyzed with excretion of urea (about 14% of the dose), as well as unidentified materials. Of the material excreted in the urine, 32% was conjugated.

The bioavailability of the butalbital component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution except for a decrease in the rate of absorption. A peak concentration of 2,020 ng/mL is obtained at about 1.5 hours after a 100 mg dose.

The plasma protein binding of butalbital is 45% over the concentration range of 0.5-20 mcg/mL. This falls within the range of plasma protein binding (20%-45%) reported with other barbiturates such as phenobarbital, pentobarbital, and secobarbital sodium. The plasma-to-blood concentration ratio was almost unity indicating that there is no preferential distribution of butalbital into either plasma or blood cells.

See for toxicity information.

Like most xanthines, caffeine is rapidly absorbed and distributed in all body tissues and fluids, including the CNS, fetal tissues, and breast milk.

Caffeine is cleared rapidly through metabolism and excretion in the urine. The plasma half-life is about 3 hours. Hepatic biotransformation prior to excretion results in about equal amounts of 1-methylxanthine and 1-methyluric acid. Of the 70% of the dose that has been recovered in the urine, only 3% was unchanged drug.

The bioavailability of the caffeine component Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is equivalent to that of a solution except for a slightly longer time to peak. A peak concentration of 1,660 ng/mL was obtained in less than an hour for an 80 mg dose.

See for toxicity information.

Non-Clinical Toxicology

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated under the following conditions:

Therapeutic doses of aspirin can cause anaphylactic shock and other severe allergic reactions. It should be ascertained if the patient is allergic to aspirin, although a specific history of allergy may be lacking.

Significant bleeding can result from aspirin therapy in patients with peptic ulcer or other gastrointestinal lesions, and in patients with bleeding disorders.

Aspirin administered pre-operatively may prolong the bleeding time.

In the presence of head injury or other intracranial lesions, the respiratory depressant effects of codeine and other narcotics may be markedly enhanced, as well as their capacity for elevating cerebrospinal fluid pressure. Narcotics also produce other CNS depressant effects, such as drowsiness, that may further obscure the clinical course of patients with head injuries.

Codeine or other narcotics may obscure signs on which to judge the diagnosis or clinical course of patients with acute abdominal conditions.

Butalbital and codeine are both habit-forming and potentially abusable. Consequently, the extended use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is not recommended.

Results from epidemiologic studies indicate an association between aspirin and Reye’s Syndrome. Caution should be used in administering this product to children, including teenagers, with chicken pox or flu.

Oils may enhance absorption of lindane, therefore, patients and caregivers applying the shampoo to others should avoid using oil treatments, or oil-based hair dressings or conditioners immediately before and after applying Lindane Shampoo.

In addition, there are many drugs that may lower the seizure threshold, and Lindane Shampoo should be prescribed with caution in patients taking these medications. Drugs that may lower the seizure threshold include, but are not limited to the following:

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should be prescribed with caution for certain special-risk patients such as the elderly or debilitated, and those with severe impairment of renal or hepatic function, coagulation disorders, or head injuries, elevated intracranial pressure, acute abdominal conditions, hypothyroidism, urethral stricture, Addison’s disease, prostatic hypertrophy, and peptic ulcer.

Aspirin should be used with caution in patients on anticoagulant therapy and in patients with underlying hemostatic defects.

Precautions should be taken when administering salicylates to persons with known allergies. Hypersensitivity to aspirin is particularly likely in patients with nasal polyps, and relatively common in those with asthma.

Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and should inform their patients about these risks and the signs of morphine overdose. (See)

Patients should be informed that Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains aspirin and should not be taken by patients with an aspirin allergy.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may impair the mental and/or physical abilities required for performance of potentially hazardous tasks such as driving a car or operating machinery. Such tasks should be avoided while taking Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

Alcohol and other CNS depressants may produce an additive CNS depression when taken with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, and should be avoided.

Codeine and butalbital may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

For information on use in geriatric patients, refer to.

Caution patients that some people have a variation in a liver enzyme and change codeine into morphine more rapidly and completely than other people. These people are ultra-rapid metabolizers and are more likely to have higher-than-normal levels of morphine in their blood after taking codeine which can result in overdose symptoms such as extreme sleepiness, confusion, or shallow breathing. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer.

Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mothers to talk to the baby's doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

In patients with severe hepatic or renal disease, effects of therapy should be monitored with serial liver and/or renal function tests.

The CNS effects of butalbital may be enhanced by monoamine oxidase (MAO) inhibitors.

In patients receiving concomitant corticosteroids and chronic use of aspirin, withdrawal of corticosteroids may result in salicylism because corticosteroids enhance renal clearance of salicylates and their withdrawal is followed by return to normal rates of renal clearance.

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may enhance the effects of:

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may diminish the effects of:

Uricosuric agents such as probenecid and sulfinpyrazone, reducing their effectiveness in the treatment of gout. Aspirin competes with these agents for protein binding sites.

Aspirin:

Codeine:

Adequate long-term studies have been conducted in mice and rats with aspirin, alone or in combination with other drugs, in which no evidence of carcinogenesis was seen. No adequate studies have been conducted in animals to determine whether aspirin has a potential for mutagenesis or impairment of fertility. No adequate studies have been conducted in animals to determine whether butalbital has a potential for carcinogenesis, mutagenesis, or impairment of fertility.

Pregnancy Category C.

Although Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP was not implicated in the birth defect, a female infant was born with lissencephaly, pachygyria and heterotopic gray matter. The infant was born 8 weeks prematurely to a woman who had taken an average of 90 butalbital, aspirin, caffeine, and codeine phosphate capsules each month from the first few days of pregnancy. The child’s development was mildly delayed and from one year of age she had partial simple motor seizures.

Withdrawal seizures were reported in a two-day-old male infant whose mother had taken a butalbital-containing drug during the last 2 months of pregnancy. Butalbital was found in the infant’s serum. The infant was given phenobarbital 5 mg/kg, which was tapered without further seizure or other withdrawal symptoms.

Studies of aspirin use in pregnant women have not shown that aspirin increases the risk of abnormalities when administered during the first trimester of pregnancy. In controlled studies involving 41,337 pregnant women and their offspring, there was no evidence that aspirin taken during pregnancy caused stillbirth, neonatal death or reduced birth weight. In controlled studies of 50,282 pregnant women and their offspring, aspirin administration in moderate and heavy doses during the first four lunar months of pregnancy showed no teratogenic effect.

Reproduction studies have been performed in rabbits and rats at doses up to 150 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to codeine.

Therapeutic doses of aspirin in pregnant women close to term may cause bleeding in mother, fetus, or neonate. During the last 6 months of pregnancy, regular use of aspirin in high doses may prolong pregnancy and delivery.

Ingestion of aspirin prior to delivery may prolong delivery or lead to bleeding in the mother or neonate. Use of codeine during labor may lead to respiratory depression in the neonate.

Aspirin, caffeine, barbiturates and codeine are excreted in breast milk in small amounts, but the significance of their effects on nursing infants is not known. Because of potential for serious adverse reactions in nursing infants from Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, 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.

Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine's active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants.

The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1-10% in Caucasians, 3% in African Americans, and 16-28% in North Africans, Ethiopians and Arabs. Data is not available for other ethnic groups.

The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultra-rapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See)

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of butalbital, aspirin, caffeine, and codeine phosphate 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.

Butalbital 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.

The most commonly reported adverse events associated with the use of butalbital, aspirin, caffeine, and codeine phosphate capsules and not reported at an equivalent incidence by placebo-treated patients were nausea and/or abdominal pain, drowsiness, and dizziness.

Of the 382 patients treated with butalbital, aspirin, caffeine, and codeine phosphate capsules in controlled clinical trials, three (0.8%) discontinued treatment with butalbital, aspirin, caffeine, and codeine phosphate capsules because of adverse events. One patient each discontinued treatment for the following reasons: gastrointestinal upset; lightheadedness and heavy eyelids; and drowsiness and generalized tingling.

The following table summarizes the incidence rates of the adverse events reported by at least 1% of the butalbital, aspirin, caffeine, and codeine phosphate capsules treated patients in controlled clinical trials comparing butalbital, aspirin, caffeine, and codeine phosphate capsules to placebo, and provides a comparison to the incidence rates reported by the placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.

The listing that follows represents the proportion of the 382 patients exposed to butalbital, aspirin, caffeine, and codeine phosphate capsules while participating in the controlled clinical trials who reported, on at least one occasion, an adverse event of the type cited. All reported adverse events, except those already presented in the previous table, are included. It is important to emphasize that, although the adverse events reported did occur while the patient was receiving butalbital, aspirin, caffeine, and codeine phosphate capsules, the adverse events were not necessarily caused by butalbital, aspirin, caffeine, and codeine phosphate capsules.

Adverse events are classified by body system and frequency. “Frequent” is defined as an adverse event which occurred in at least 1/100 (1%) of the patients; all adverse events listed in the previous table are frequent. “Infrequent” is defined as an adverse event that occurred in less than 1/100 patients but at least 1/1000 patients. All adverse events tabulated below are classified as infrequent.

Central Nervous:

Autonomic Nervous:

Gastrointestinal:

Cardiovascular:

Musculoskeletal:

Genitourinary:

Miscellaneous:

Voluntary reports of adverse drug events, temporally associated with butalbital, aspirin, caffeine, and codeine phosphate capsules, that have been received since market introduction and that were not reported in clinical trials by the patients treated with butalbital, aspirin, caffeine, and codeine phosphate capsules, are listed below. Many or most of these events may have no causal relationship with the drug and are listed according to body system.

Central Nervous:

Autonomic Nervous:

Gastrointestinal:

Cardiovascular:

Skin:

Urinary:

Miscellaneous:

The following adverse drug events may be borne in mind as potential effects of the components of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Potential effects of high dosage are listed in the section of this insert.

Aspirin:

Caffeine:

Codeine:

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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