ASPIRIN: 92,524 Adverse Event Reports & Safety Profile

Aspirin and Extended-Release Dipyridamole Capsules are a combination of aspirin and dipyridamole, antiplatelet agents, intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole, USP in an extended-release form and 25 mg aspirin, USP as an immediate-release sugar-coated tablet. In addition, each capsule contains the following inactive ingredients: acacia milled powder, eudragit S-100, glyceryl behenate, hydroxy propyl methyl cellulose phthalate HP-55, hypromellose, hypromellose E3LV, hypromellose E50LV, lactose monohydrate, microcrystalline cellulose, micronized talc, povidone K 30, silicon dioxide, talc, tartatic acid pellets and triacetin. Each capsule shell contains FD & C blue 1, FD & C red 3, FD & C red 40, FD & C yellow 6, gelatin, iron oxide yellow, sodium lauryl sulphate and titanium dioxide. The imprinting ink contains black iron oxide, potassium hydroxide, and shellac.

Dipyridamole

Dipyridamole is an antiplatelet agent chemically described as 2,2',2'',2'''-[(4,8-Dipiperidinopyrimido[5,4- d ]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol. It has the following structural formula: Molecular formula: C 24 H 40 N 8 O 4 Mol. Wt. 504.63 g/mol Dipyridamole is an odorless yellow crystalline substance, having a bitter taste. It is soluble in dilute acids, methanol and chloroform, and is practically insoluble in water.

Aspirin

The antiplatelet agent aspirin (acetylsalicylic acid) is chemically known as benzoic acid, 2- (acetyloxy)-, and has the following structural formula: Molecular formula: C 9 H 8 O 4 Mol . Wt. 180.16 g/mol Aspirin has white crystals, commonly tubular or needle-like, or white, crystalline powder. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is slightly soluble in water; freely soluble in alcohol; soluble in chloroform and in ether; sparingly soluble in absolute ether. dipyridamole-structure.jpg asprin-structure.jpg

AND USAGE BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when non-opioid analgesic and alternative treatments are inadequate. BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE is a combination of butalbital, a barbiturate, aspirin, a nonsteroidal anti-inflammatory drug, caffeine, a methylxanthine, and codeine phosphate, an opioid agonist, and is indicated for the management of the symptom complex of tension (or muscle contraction) headache, when other non-opioid analgesics and alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain ( 1 , 5.1 ). BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions ( 5.1 ) ] , reserve opioid analgesics, including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

AND ADMINISTRATION Periodically reassess patients receiving BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse ( 2.1 , 5.1 ) Discuss availability of naloxone with the patient and caregiver and assess each patient's need for access to naloxone, both when initiating and renewing treatment with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider prescribing naloxone based on the patient's risk factors for overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Initiate treatment with one or two capsules every 4 hours as needed for pain and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Total daily dosage should not exceed 6 capsules. ( 2 , 5 ) Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.4 , 5.16 )

2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 ) ]</span>. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient&apos;s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) ]</span>. BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE. Consider this risk when selecting an initial dose and when making dose adjustments <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 ) ]</span>.

2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 ) ]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [ see Warnings and Precautions ( 5.2 ) ]. There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

2.3 Dosing Information One or two capsules every 4 hours as needed for pain. Total daily dosage should not exceed 6 capsules. Use the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient&apos;s response to their initial dose of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE.

2.4 Safe Reduction or Discontinuation of BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE Do not rapidly reduce or abruptly discontinue BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid dependent patient taking BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE, there are a variety of factors that should be considered, including the total daily dose of opioid (including BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on BUTALBITAL, ASPIRIN, CAFFEINE and CODEINE PHOSPHATE who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [ see Warnings and Precautions ( 5.16 ), Drug Abuse and Dependence ( 9.3 ) ].

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated for: All children younger than 12 years of age [see Warnings and Precautions ( 5.6 ) ] Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions ( 5.6 ) ]. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is also contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.9 ) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 ) ] Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days [see Warnings and Precautions ( 5.10 ),Drug Interactions ( 7 ) ]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.14 )] Hypersensitivity or intolerance to aspirin, caffeine, butalbital, or codeine. Hemophilia [see Warnings and Precautions ( 5.19 ) ] Reye’s Syndrome [see Warnings and Precautions ( 5.20 ) ] Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions ( 5.23 ) ] Syndrome of asthma, rhinitis, and nasal polyps [see Warnings and Precautions ( 5.23 ) ] Children younger than 12 years of age ( 4 ) Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy ( 4 ) Significant respiratory depression ( 4 ) Acute or severe bronchial asthma ( 4 ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to aspirin, caffeine, butalbital, or codeine ( 4 ) Hemophilia ( 4 ) Reye’s Syndrome ( 4 ) Known allergy to NSAIDs ( 4 ) Syndrome of asthma, rhinitis, and nasal polyps ( 4 )

REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Hypersensitivity [see Contraindications (4.1) ] Allergy [see Contraindications (4.2) ] Risk of Bleeding [see Warnings and Precautions (5.1) ] The most frequently reported adverse reactions (>10% and greater than placebo) were headache, dyspepsia, abdominal pain, nausea and diarrhea (6) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or www.avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The efficacy and safety of aspirin and extended-release dipyridamole was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind, placebo-controlled study that evaluated 6,602 patients over the age of 18 years who had a previous ischemic stroke or transient ischemic attack within ninety days prior to entry. Patients were randomized to either aspirin and extended-release dipyridamole, aspirin, ER-DP, or placebo <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> ; primary endpoints included stroke (fatal or nonfatal) and death from all causes.

This

24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of aspirin and extended-release dipyridamole with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in a total of 6,602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization.

Table

1 presents the incidence of adverse events that occurred in 1% or more of patients treated with aspirin and extended-release dipyridamole where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.

Table

1 Incidence of Adverse Events in ESPS2 a Individual Treatment Group Aspirin and Extended-release Dipyridamole ER-DP Alone ASA Alone Placebo Body System/Preferred Term 1,650 1,654 1,649 1,649 Total Number of Patients Total Number (%) of Patients With at Least One On-Treatment Adverse Event 1,319 (80%) 1,305 (79%) 1,323 (80%) 1,304 (79%) Central and Peripheral Nervous System Disorders Headache 647 (39%) 634 (38%) 558 (34%) 543 (33%)

Convulsions

28 (2%) 15 (1%) 28 (2%) 26 (2%)

Gastrointestinal System Disorders Dyspepsia

303 (18%) 288 (17%) 299 (18%) 275 (17%)

Abdominal Pain

289 (18%) 255 (15%) 262 (16%) 239 (14%)

Nausea

264 (16%) 254 (15%) 210 (13%) 232 (14%)

Diarrhea

210 (13%) 257 (16%) 112 (7%) 161 (10%)

Vomiting

138 (8%) 129 (8%) 101 (6%) 118 (7%)

Hemorrhage Rectum

26 (2%) 22 (1%) 16 (1%) 13 (1%)

Melena

31 (2%) 10 (1%) 20 (1%) 13 (1%)

Hemorrhoids

16 (1%) 13 (1%) 10 (1%) 10 (1%) GI Hemorrhage 20 (1%) 5 (0%) 15 (1%) 7 (0%) Body as a Whole - General Disorders Pain 105 (6%) 88 (5%) 103 (6%) 99 (6%)

Fatigue

95 (6%) 93 (6%) 97 (6%) 90 (5%)

Back Pain

76 (5%) 77 (5%) 74 (4%) 65 (4%)

Accidental Injury

42 (3%) 24 (1%) 51 (3%) 37 (2%)

Malaise

27 (2%) 23 (1%) 26 (2%) 22 (1%)

Asthenia

29 (2%) 19 (1%) 17 (1%) 18 (1%)

Syncope

17 (1%) 13 (1%) 16 (1%) 8 (0%)

Psychiatric Disorders Amnesia

39 (2%) 40 (2%) 57 (3%) 34 (2%)

Confusion

18 (1%) 9 (1%) 22 (1%) 15 (1%)

Anorexia

19 (1%) 17 (1%) 10 (1%) 15 (1%)

Somnolence

20 (1%) 13 (1%) 18 (1%) 9 (1%)

Musculoskeletal System Disorders Arthralgia

91 (6%) 75 (5%) 91 (6%) 76 (5%)

Arthritis

34 (2%) 25 (2%) 17 (1%) 19 (1%)

Arthrosis

18 (1%) 22 (1%) 13 (1%) 14 (1%)

Myalgia

20 (1%) 16 (1%) 11 (1%) 11 (1%)

Respiratory System Disorders Coughing

25 (2%) 18 (1%) 32 (2%) 21 (1%)

Upper Respiratory Tract Infection

16 (1%) 9 (1%) 16 (1%) 14 (1%)

Cardiovascular

Disorders, General Cardiac Failure 26 (2%) 17 (1%) 30 (2%) 25 (2%) Platelet, Bleeding and Clotting Disorders Hemorrhage NOS 52 (3%) 24 (1%) 46 (3%) 24 (1%)

Epistaxis

39 (2%) 16 (1%) 45 (3%) 25 (2%)

Purpura

23 (1%) 8 (0%) 9 (1%) 7 (0%)

Neoplasm

Neoplasm NOS 28 (2%) 16 (1%) 23 (1%) 20 (1%)

Red Blood Cell Disorders Anemia

27 (2%) 16 (1%) 19 (1%) 9 (1%) a Reported by ≥1% of patients during aspirin and extended-release dipyridamole treatment where the incidence was greater than in those treated with placebo. Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. NOS = not otherwise specified. Discontinuation due to adverse events in ESPS2 was 25% for aspirin and extended-release dipyridamole, 25% for extended-release dipyridamole, 19% for aspirin and 21% for placebo (refer to Table 2).

Table

2 Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥1% in the Aspirin and Extended-release Dipyridamole Group Treatment Groups Aspirin and Extended-release Dipyridamole ER-DP ASA Placebo Total Number of Patients 1,650 1,654 1,649 1,649 Patients with at least one Adverse Event that led to treatment discontinuation 417 (25%) 419 (25%) 318 (19%) 352 (21%)

Headache

165 (10%) 166 (10%) 57 (3%) 69 (4%)

Dizziness

85 (5%) 97 (6%) 69 (4%) 68 (4%)

Nausea

91 (6%) 95 (6%) 51 (3%) 53 (3%)

Abdominal Pain

74 (4%) 64 (4%) 56 (3%) 52 (3%)

Dyspepsia

59 (4%) 61 (4%) 49 (3%) 46 (3%)

Vomiting

53 (3%) 52 (3%) 28 (2%) 24 (1%)

Diarrhea

35 (2%) 41 (2%) 9 (<1%) 16 (<1%)

Stroke

39 (2%) 48 (3%) 57 (3%) 73 (4%)

Transient Ischemic Attack

35 (2%) 40 (2%) 26 (2%) 48 (3%)

Angina Pectoris

23 (1%) 20 (1%) 16 (<1%) 26 (2%) Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. Headache was most notable in the first month of treatment.

Other Adverse Events

Adverse reactions that occurred in less than 1% of patients treated with aspirin and extended-release dipyridamole in the ESPS2 study and that were medically judged to be possibly related to either dipyridamole or aspirin are listed below. Body as a Whole: Allergic reaction, fever Cardiovascular: Hypotension Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage Gastrointestinal: Gastritis, ulceration and perforation Hearing and Vestibular Disorders: Tinnitus and deafness. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism Heart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormal Metabolic and Nutritional Disorders: Hyperglycemia, thirst Platelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding Psychiatric Disorders: Agitation Reproductive: Uterine hemorrhage Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema Special Senses Other Disorders: Taste loss Skin and Appendages Disorders: Pruritus, urticaria Urogenital: Renal insufficiency and failure, hematuria Vascular (Extracardiac) Disorders: Flushing Laboratory Changes Over the course of the 24-month study (ESPS2), patients treated with aspirin and extended-release dipyridamole showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75% and erythrocyte count of 0.13x10 6 /mm 3 .

6.2 Post-Marketing Experience The following is a list of additional adverse reactions that have been reported either in the literature or are from post-marketing spontaneous reports for either dipyridamole or aspirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to aspirin and extended-release dipyridamole. Body as a Whole: Hypothermia, chest pain Cardiovascular: Angina pectoris Central Nervous System: Cerebral edema Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis Hearing and Vestibular Disorders: Hearing loss Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema Liver and Biliary System Disorders: Hepatitis, hepatic failure Musculoskeletal: Rhabdomyolysis Metabolic and Nutritional Disorders: Hypoglycemia, dehydration Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding Respiratory: Tachypnea, dyspnea Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis and hematoma Urogenital: Interstitial nephritis, papillary necrosis, proteinuria Vascular (Extracardiac) Disorders: Allergic vasculitis Other Adverse Events: anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected] ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.2 Post-Marketing Experience The following is a list of additional adverse reactions that have been reported either in the literature or are from post-marketing spontaneous reports for either dipyridamole or aspirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to aspirin and extended-release dipyridamole. Body as a Whole: Hypothermia, chest pain Cardiovascular: Angina pectoris Central Nervous System: Cerebral edema Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis Hearing and Vestibular Disorders: Hearing loss Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema Liver and Biliary System Disorders: Hepatitis, hepatic failure Musculoskeletal: Rhabdomyolysis Metabolic and Nutritional Disorders: Hypoglycemia, dehydration Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding Respiratory: Tachypnea, dyspnea Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis and hematoma Urogenital: Interstitial nephritis, papillary necrosis, proteinuria Vascular (Extracardiac) Disorders: Allergic vasculitis Other Adverse Events: anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected] ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. ( 5.9 )

Adrenal

Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off the opioid. ( 5.11 )

Severe

Hypotension : Regularly evaluate during dose initiation and titration. Avoid use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients with circulatory shock. ( 5.12 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Reguarly evaluate for sedation and respiratory depression. Avoid use of Butalbital, Aspirin, Caffeine, and Codeine Capsules, USP in patients with impaired consciousness or coma. ( 5.13 )

Fetal

Toxicity : Limit use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.17 , 8.1 ).

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.22 ).

5.1 Addiction, Abuse, and Misuse Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains codeine. Codeine in combination with butalbital, aspirin, and caffeine is a Schedule III controlled substance.

As

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP contains butalbital and codeine, it exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 ) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 )] . Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP, and reassess all patients receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, but use in such patients necessitates intensive counseling about the risks and proper use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and P recautions ( 5.2 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5. 2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid reversal agents, depending on the patient’s clinical status [see Overdosage ( 10 ) ] . Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are essential [see Dosage and Administration ( 2.1 )]. Overestimating the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, especially by children, can result in respiratory depression and death due to an overdose of codeine and butalbital. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17 )] . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.4 )] .

Patient

Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] . 5. 3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [ see Drug Interactions ( 7 ) ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ) , Overdosage ( 10 ) ] . Advise both patients and caregivers about the risks of respiratory depression and sedation when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [ see Drug Interactions ( 7 ) and Patient Counseling Information ( 17 ) ].

5.4 Neonatal Opioid Withdrawal Syndrome Use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 ), Patient Counseling Information ( 17 )]</span> .

5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Healthcare Providers Involved in the Management of Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed.

The Patient Counseling

Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG . Emphasize to patient and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioid analgesicrems.com . The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . 5. 6 Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon postmarketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death: Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated for all children younger than 12 years of age [see Contraindications ( 4 ) ]. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications ( 4 ) ]. Avoid the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression. As with adults, when prescribing Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose [see Use in Specific Populations ( 8.4 ), Overdosage ( 10 )] .

Nursing

Mothers At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP [ see Use in Specific Populations ( 8.2 ) ] . CYP2D6 Genetic Variability: Ultra-rapid metabolizer Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). 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 have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) [se e Overdosage ( 10 ) ] . Therefore, individuals who are ultra-rapid metabolizers should not use Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

5.7 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzymes The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP requires careful consideration of the effects on codeine and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Evaluate patients receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and any CYP3A4 inhibitor or inducer at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is used in conjunction with inhibitors and inducers of CYP3A4. If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage until stable drug effects are achieved. Evaluate patients at frequent intervals for signs of opioid withdrawal. <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) ]</span> . Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal. Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in codeine plasma concentration and an increase in active metabolite morphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. Evaluate patients receiving Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and any CYP2D6 inhibitor at frequent intervals for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP are used in conjunction with inhibitors of CYP2D6. If concomitant use with a CYP2D6 inhibitor is necessary, evaluate patients at frequent intervals for signs of reduced efficacy or opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation. <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) ]</span> .

5.8 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect <span class="opacity-50 text-xs">[see Dependence ( 9.3 )]</span> . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Causes of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ); Warnings and Precautions ( 5.16 )]</span> . 5. 9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP -treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.9 ) ]</span>. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.9 ) ]</span>. Regularly evaluate patients, particularly when initiating and titrating Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is given concomitantly with other drugs that depress respiration <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5 ) , Drug Interactions ( 7 ) ]</span> . Alternatively, consider the use of non-opioid analgesics in these patients. 5. 10 Interaction with Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of morphine, codeine’s active metabolite, including respiratory depression, coma, and confusion. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 5.1 1 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.1 2 Severe Hypotension Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) <span class="opacity-50 text-xs">[see Drug Interactions ( 7 ) ]</span> . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. In patients with circulatory shock, Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients with circulatory shock. 5.1 3 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients with impaired consciousness or coma. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. 5.1 4 Risks of Use in Patients with Gastrointestinal Complications The codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regulatory evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. The aspirin in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP can cause GI side effects including stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. 5.1 5 Increased Risk of Seizures in Patients with Seizure Disorders The codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP therapy. 5.1 6 Withdrawal Do not rapidly reduce or abruptly discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in a patient physically dependent on opioids. Rapid tapering of butalbital, aspirin, caffeine, and codeine phosphate capsules in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Drug Abuse and Dependence ( 9.3 )]</span> . Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> . When discontinuing Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in a physically-dependent patient, gradually taper the dosage <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) ]</span>. Abrupt discontinuation of butalbital can cause seizures <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.3 )]</span>. 5.1 7 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, in pregnant women about 30 weeks gestation and later. NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs, including Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP treatment extends beyond 48 hours.

Discontinue

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations ( 8.1 )] . 5.1 8 Risks of Driving and Operating Machinery Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and know how they will react to the medication. 5.1 9 Coagulation Abnormalities and Bleeding Risks Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (i.e. hemophilia) or acquired (i.e. liver disease or vitamin K deficiency) bleeding disorders. Aspirin is contraindicated in patients with hemophilia. Aspirin administered pre-operatively may prolong the bleeding time. Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. 5. 20 Reye’s Syndrome Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye’s syndrome with concomitant use of aspirin in certain viral illnesses.

5.21 Serious Skin Reactions NSAIDs, including aspirin, a component of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP at the first appearance of skin rash or any other sign of hypersensitivity. Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is contraindicated in patients with previous serious skin reactions to NSAIDs <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . 5.2 2 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP. Some of these events have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities. myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate the patient immediately. 5.2 3 Allergy Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma). 5.2 4 Drug/Laboratory Test Interactions Aspirin: Aspirin may interfere with the following laboratory determinations in blood: serum amylase, fasting blood glucose, cholesterol, protein, serum glutamic-oxalacetic transaminase (SGOT), uric acid, prothrombin time and bleeding time. Aspirin may interfere with the following laboratory determinations in urine: glucose, 5-hydroxy-indoleacetic acid, Gerhardt ketone, vanillylmandelic acid (VMA), uric acid, diacetic acid, and spectrophotometric detection of barbiturates. Codeine: Codeine may increase serum amylase levels.

PRECAUTIONS General Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.

Hemorrhage

Aspirin may increase the likelihood of hemorrhage due to its effect on the gastric mucosa and platelet function (prolongation of bleeding time). Salicylates should be used with caution in the presence of peptic ulcer or coagulation abnormalities.

Ambulatory

Surgery and Postoperative Use Oxycodone and other morphine-like opioids have been shown to decrease bowel motility. Ileus is a common postoperative complication, especially after intra-abdominal surgery with use of opioid analgesia. Caution should be taken to monitor for decreased bowel motility in postoperative patients receiving opioids. Standard supportive therapy should be implemented. Information for Patients/Caregivers Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store oxycodone and aspirin tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving oxycodone and aspirin tablets unsecured can pose a deadly risk to others in the home (see WARNINGS , DRUG ABUSE AND DEPENDENCE ). Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused oxycodone and aspirin tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of oxycodone and aspirin tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death (see WARNINGS ). Instruct patients not to share oxycodone and aspirin tablets with others and to take steps to protect oxycodone and aspirin tablets from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting oxycodone and aspirin tablets or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see WARNINGS ].

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death (see WARNINGS ). Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if oxycodone and aspirin tablets is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a health care provider (see WARNINGS , PRECAUTIONS ; Drug Interactions ).

Patient

Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with oxycodone and aspirin tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see WARNINGS , DOSAGE AND ADMINISTRATION ]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see OVERDOSAGE ]. If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose
• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency
• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including sensitivity to pain, or new pain [see WARNINGS ; ADVERSE REACTIONS ].

Serotonin Syndrome

Inform patients that oxycodone and aspirin tablets could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.

Maoi

Interaction Inform patients to avoid taking oxycodone and aspirin tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking oxycodone and aspirin tablets (see PRECAUTIONS ; Drug Interactions ).

Important Administration Instructions

Instruct patients how to properly take oxycodone and aspirin tablets. The usual dosage is one tablet every 6 hours as needed for pain. The maximum daily dose of aspirin should not exceed 4 grams (see DOSAGE AND ADMINISTRATION , PRECAUTIONS )

Important Discontinuation

Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue oxycodone and aspirin tablets without first discussing a tapering plan with the prescriber (see DOSAGE AND ADMINISTRATION ). Driving or Operating Heavy Machinery Inform patients that oxycodone and aspirin tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see WARNINGS ].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY ].

Adrenal Insufficiency

Inform patients that oxycodone and aspirin tablets could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see WARNINGS ].

Hypotension

Inform patients that oxycodone and aspirin tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in oxycodone and aspirin tablets. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS , ADVERSE REACTIONS ).

Pregnancy Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of oxycodone and aspirin tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated (see WARNINGS, PRECAUTIONS; Pregnancy) Embryo-Fetal Toxicity Inform female patients of reproductive potential that oxycodone and aspirin tablets can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy. Inform pregnant women to avoid use of aspirin and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with oxycodone and aspirin tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see WARNINGS ; Fetal Toxicity , PRECAUTIONS; Pregnancy ].

Lactation

Advise breastfeeding women using oxycodone and aspirin tablets to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs.

Infertility

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible (see ADVERSE REACTIONS ).

Serious Skin

Reactions, including DRESS Advise patients to stop taking oxycodone and aspirin tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see WARNINGS ].

Laboratory Tests

Although oxycodone may cross-react with some drug urine tests, no available studies were found which determined the duration of detectability of oxycodone in urine drug screens. However, based on pharmacokinetic data, the approximate duration of detectability for a single dose of oxycodone is roughly estimated to be one to two days following drug exposure. Urine testing for opiates may be performed to determine illicit drug use and for medical reasons such as evaluation of patients with altered states of consciousness or monitoring efficacy of drug rehabilitation efforts. The preliminary identification of opiates in urine involves the use of an immunoassay screening and thin-layer chromatography (TLC). Gas chromatography/mass spectrometry (GC/MS) may be utilized as a third-stage identification step in the medical investigational sequence for opiate testing after immunoassay and TLC. The identities of 6-keto opiates (e.g., oxycodone) can further be differentiated by the analysis of their methoxime-trimethylsilyl (MO-TMS) derivative.

Table

1: Clinically Significant Drug Interactions with Oxycodone and Aspirin Tablets Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of oxycodone and aspirin tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone and aspirin tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone and aspirin tablets is achieved (see WARNINGS ). After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease (see CLINICAL PHARMACOLOGY ), resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of oxycodone and aspirin tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone and aspirin tablets dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal.

Examples

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of oxycodone and aspirin tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone (see CLINICAL PHARMACOLOGY ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone (see WARNINGS ). After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase (see CLINICAL PHARMACOLOGY ), which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the oxycodone and aspirin tablets dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal and sedation. If a CYP3A4 inducer is discontinued, consider oxycodone and aspirin tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS)

Depressants Clinical

Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see WARNINGS ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical

Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone and aspirin tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), ), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase

Inhibitors (MAOIs)

Clinical

Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) (see WARNINGS ). Intervention: The use of oxycodone and aspirin tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of oxycodone and aspirin tablets and/or precipitate withdrawal symptoms Intervention: Avoid concomitant use. Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone and aspirin tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose.

Diuretics Clinical

Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical

Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when oxycodone and aspirin tablets is used concomitantly with anticholinergic drugs.

Analgesics Clinical

Impact: Analgesics may reduce the analgesic effect of oxycodone or may precipitate withdrawal symptoms Intervention: Should be administered with caution to a patient who has received or is receiving a full opioid agonist such as oxycodone. Examples: Pentazocine, nalbuphine, naltrexone, and butorphanol Drug/Drug Interactions with Aspirin Angiotensin Converting Enzyme (ACE) Inhibitors: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin-angiotensin conversion pathway. Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.

Anticoagulant

Therapy (Heparin and Warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and the effect on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. Anticonvulsants: Salicylate can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Beta

Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. Methotrexate: Aspirin may enhance the serious side and toxicity of methotrexate due to displacement from its plasma protein binding sites and/or reduced renal clearance.

Nonsteroidal

Anti-inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs should be avoided because this may increase bleeding or lead to decreased renal function. Aspirin may enhance the serious side effects and toxicity of ketorolac, due to displacement from its plasma protein binding sites and/or reduced renal clearance.

Oral Hypoglycemics

Agents: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia.

Uricosuric

Agents: Salicylates antagonize the uricosuric action of probenecid or sulfinpyrazone.

Drug/Laboratory

Test Interactions Depending on the sensitivity/specificity and the test methodology, the individual components of oxycodone and aspirin tablets may cross-react with assays used in the preliminary detection of cocaine (primary urinary metabolite, benzoylecgonine) or marijuana (cannabinoids) in human urine. A more specific alternate chemical method must be used in order to obtain a confirmed analytical result. The preferred confirmatory method is gas chromatography/mass spectrometry (GC/MS). Moreover, clinical considerations and professional judgment should be applied to any drug-of-abuse test result, particularly when preliminary positive results are used. Salicylates may increase the protein bound iodine (PBI) result by competing for the protein binding sites on pre-albumin and possibly thyroid-binding globulins. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone and aspirin have not been conducted.

Mutagenesis

The combination of oxycodone and aspirin has not been evaluated for mutagenicity. Oxycodone alone was negative in a bacterial reverse mutation assay (Ames), an in vitro chromosome aberration assay with human lymphocytes without metabolic activation and an in vivo mouse micronucleus assay. Oxycodone was clastogenic in the human lymphocyte chromosomal assay in the presence of metabolic activation and in the mouse lymphoma assay with or without metabolic activation. Aspirin induced chromosome aberrations in cultured human fibroblasts. Impairment of Fertility Animal studies to evaluate the effects of oxycodone on fertility have not been conducted. Aspirin has been shown to inhibit ovulation in rats.

Pregnancy Risk Summary

Use of opioid analgesics for extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome (see WARNINGS ). Available data with oxycodone and aspirin tablets are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. Use of NSAIDs, including aspirin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of oxycodone and aspirin tablets use between about 20 and 30 weeks of gestation, and avoid oxycodone and aspirin tablets use at about 30 weeks of gestation and later in pregnancy [see WARNINGS; Fetal Toxicity ] .

Premature

Closure of Fetal Ductus Arteriosus: Use of NSAIDs, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment: Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. 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 aspirin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions: Use of opioid analgesics for extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, and manage accordingly (see WARNINGS ).

Premature

Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including oxycodone and aspirin tablets, can cause premature closure of the fetal ductus arteriosus [see WARNINGS; Fetal Toxicity ] .

Oligohydramnios/Neonatal

Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If oxycodone and aspirin tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue oxycodone and aspirin tablets and follow up according to clinical practice [see WARNINGS; Fetal Toxicity ] . Labor and Delivery Opioids cross the placenta and may produce respiratory depression and pyscho-physiologic effects in neonates. An opioid antagonist, such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone and aspirin tablets are not recommended for use in women during and immediately prior to labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics, including oxycodone and aspirin tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Data Human Data Premature

Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Reproduction studies in rats and rabbits demonstrated that oral administration of oxycodone was not teratogenic or embryo-fetal toxic. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis).

Lactation Risk Summary

Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose (see Data ). In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression (see Clinical Considerations ). There are no data on the effects of the oxycodone on milk production. Salicylic acid has been detected in breast milk. Adverse effects on platelet function in the nursing infant exposed to aspiring in breast milk may be a potential risk. Furthermore, the risk of Reye Syndrome cause by salicylate in breast milk is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oxycodone and aspirin tablets and any potential adverse effects on the breastfed child from oxycodone and aspirin tablets or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to oxycodone and aspirin tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breastfeeding is stopped.

Data

Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20- 200 ng/mL). Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

Pediatric Use

Oxycodone and aspirin tablets should not be administered to pediatric patients.

Reye

Syndrome is a rare but serious disease which can follow flu or chicken pox in children and teenagers. While the cause of Reye Syndrome is unknown, some reports claim aspirin (or salicylates) may increase the risk of developing this disease.

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, 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. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of oxycodone and aspirin tablets slowly in geriatric patients and frequently reevaluate the patients for signs of central nervous system and respiratory depression. This drug is known to be substantially excreted by the kidney, and the risk of adverse 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 regularly evaluate renal function.

Hepatic

Impairment In a pharmacokinetic study of oxycodone in patients with end-stage liver disease, oxycodone plasma clearance decreased and the elimination half-life increased. Care should be exercised when oxycodone is used in patients with hepatic impairment. Avoid aspirin in patients with severe hepatic impairment.

Renal

Impairment In a study of patients with end stage renal impairment, mean elimination half-life of oxycodone was prolonged in uremic patients due to increased volume of distribution and reduced clearance. Oxycodone should be used with caution in patients with renal impairment. Avoid aspirin in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute).

INTERACTIONS Table 1 includes clinically significant drug interactions with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP.

Table

1: Clinically Significant Drug Interactions with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with CYP3A4 inhibitors may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, it may result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to codeine. Intervention: If concomitant use with CYP3A4 inhibitor is necessary, consider dosage reduction of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and CYP3A4 inducers can result in lower codeine levels, greater norcodeine levels, and less metabolism via 2D6 with resultant lower morphine levels [see Clinical Pharmacology ( 12.3 ) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence [see Warnings and Precautions ( 5.16 ) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the codeine plasma concentration may increase with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels [see Clinical Pharmacology ( 12.3 ) ] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use of a CYP3A4 inducer is necessary, evaluate patients at frequent intervals for reduced efficacy and signs of opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage as needed. If a CYP3A4 inducer is discontinued, consider Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP dosage reduction, and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Inhibitors of CYP2D6 Clinical Impact: Codeine in Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is metabolized by CYP2D6 to form morphine. The concomitant use of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and CYP2D6 inhibitors can increase the plasma concentration of codeine, but can decrease the plasma concentrations of active metabolite morphine which could result in reduced analgesic efficacy or symptoms of opioid withdrawal, particularly when an inhibitor is added after a stable dose of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is achieved [see Clinical Pharmacology ( 12.3 ) ]. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the codeine plasma concentration will decrease but the active metabolite morphine plasma concentration will increase, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3 ) ]. Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate patients at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, evaluate patients for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and evaluate patients at frequent intervals for signs and symptoms of respiratory depression or sedation. Examples: paroxetine, fluoxetine, bupropion, quinidine Benzodiazepines and other Central Nervous System (CNS)

Depressants Clinical

Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical

Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment.

Discontinue

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP immediately if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT 3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase

Inhibitors (MAOIs)

Clinical

Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions ( 5.10 ) ]. Intervention: Do not use Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine, Muscle Relaxants Clinical Impact: Codeine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Evaluate patients for signs of respiratory depression that may be greater than otherwise expected, decrease the dosage of Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 , 5.4 )] . Examples: Cyclobenzaprine, metaxalone.

Diuretics Clinical

Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Anticholinergic Drugs Clinical

Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP is used concomitantly with anticholinergic drugs.

Anticoagulants Clinical

Impact: Aspirin may enhance the effects of anticoagulants. Concurrent use may increase the risk of bleeding. Aspirin can also displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Intervention: Evaluate patients for signs of bleeding. Examples: Warfarin, heparin, enoxaparin, clopidogrel, prasugrel, rivaroxaban, apixaban Uricosuric Agents Clinical Impact: Aspirin inhibits the uricosuric effects of uricosuric agents. Intervention: Avoid concomitant use. Examples: Probenecid Carbonic Anhydrase Inhibitors Clinical Impact: Concurrent use with aspirin can lead to high serum concentrations of the carbonic anhydrase inhibitor and cause toxicity due to competition at the renal tubule for secretion. Intervention: Consider reducing the dose of the carbonic anhydrase inhibitor. Evaluate the patients for any adverse effects from the carbonic anhydrase inhibitor. Examples: Acetazolamide, methazolamide Methotrexate Clinical Impact: Aspirin may enhance the toxicity of methotrexate by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Intervention: Use caution if using concomitantly, especially in elderly patients or patients with renal impairment. Evaluate patients for methotrexate toxicity.

Nephrotoxic Agents Clinical

Impact: Concomitant use with aspirin may lead to additive nephrotoxicity due to the inhibition of renal prostaglandins by aspirin. Also, the plasma concentration of aspirin is increased by conditions that reduce the glomerular filtration rate or tubular secretion. Intervention: Use Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP with caution if used concomitantly with nephrotoxic agents. Evaluate the renal function of patients. Examples: Aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin Angiotensin Converting Enzyme (ACE)

Inhibitors Clinical

Impact: The hyponatremic and hypotensive effects of ACE inhibitors may be diminished by the concomitant administration of aspirin due to its indirect effect on the renin- angiotensin conversion pathway. Intervention: Use caution if using concomitantly. Evaluate the blood pressure and renal function of patients. Examples: Ramipril, captopril Beta Blockers Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid retention. Intervention: Use caution if using concomitantly. Evaluate the blood pressure and renal function of patients. Examples: Metoprolol, propranolol Hypoglycemic Agents Clinical Impact: Aspirin may increase the serum glucose-lowering action of insulin and sulfonylureas leading to hypoglycemia. Intervention: Patients should be advised to consult a physician if any signs or symptoms of hypoglycemia occur. Examples: Insulin, glimepiride, glipizide Anticonvulsants Clinical Impact: Aspirin can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. Intervention: Use caution if using concomitantly. Examples: Phenytoin, valproic acid Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Clinical

Impact: Concurrent use with aspirin may increase the risk of bleeding or lead to decreased renal function. Aspirin may enhance serious side effects and toxicity of ketorolac by displacing it from its plasma protein binding sites and/or reducing its renal clearance. Intervention: Avoid concomitant use. Examples: Ketorolac, ibuprofen, naproxen, diclofenac Corticosteroids Clinical Impact: 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. Intervention: Avoid concomitant use.

Serotonergic

Drugs: Concomitant use may result in serotonin syndrome.

Discontinue

Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP if serotonin syndrome is suspected. ( 7 )

Mixed

Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Butalbital, Aspirin, Caffeine, and Codeine Phosphate Capsules, USP because they may reduce analgesic effect of Butalbital, Aspirin, Caffeine, and Codeine Phosphate, USP or precipitate withdrawal symptoms. ( 7 )

Drug Facts Active ingredients (in each effervescent tablet)

Purpose Aspirin

325 mg (NSAID)*. . . . . . . . . . . . . . . . . . . . . . .Pain reliever/fever reducer Chlorpheniramine maleate 2 mg . . . . . . . . . . . . . . . . .

Antihistamine Phenylephrine Bitartrate

7.8 mg . . . . . . . . . . . . . . . . . Nasal decongestant *Nonsteroidal anti-inflammatory drug

Inactive ingredients cellulose, D&C yellow #10 lake, FD&C yellow #6 lake, hypromellose, iron oxide, PEG, polydextrose, polyvinyl acetate phthalate, propylene glycol, shellac wax, silica, simethicone, sodium alginate, sodium bicarbonate, starch, stearic acid, talc, titanium dioxide, triacetin, triethyl citrate. May also contain acetylated monoglycerides, croscarmellose sodium, hypromellose phthalate, methacrylic acid, mineral oil, polysorbate 80, sodium lauryl sulfate. DISTRIBUTED BY: ALTANTIC BIOLOGICALS CORP. 20101 N.E 16TH PLACE MIAMI, FL 33179