Data from FDA - Curated by EPG Health - Last updated 22 November 2019

Indication(s)

INDICATIONS AND USAGE Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are indicated for the relief of discomfort associated with acute, painful musculoskeletal conditions in adults. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses (see WARNINGS ), reserve Carisoprodol, Aspirin and Codeine Phosphate Tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics): Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP should only be used for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use has not been established and because acute, painful musculoskeletal conditions are generally of short duration (see DOSAGE AND ADMINISTRATION ).

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Advisory information

contraindications
CONTRAINDICATIONS Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for: All children younger than 12 years of age (see WARNINGS ) Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see WARNINGS ) Carisoprodol, Aspirin and Codeine Phosphate Tablets are also contraindicated in patients with: Significant respiratory depression (see WARNINGS ) Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (see WARNINGS ) Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see WARNINGS and PRECAUTIONS; Drug Interactions ). Known or suspected gastrointestinal obstruction, including paralytic ileus (see WARNINGS ) Hypersensitivity to codeine, aspirin, or a carbamate such as meprobamate (e.g., anaphylaxis) Hemophilia (see WARNINGS ) Reye’s Syndrome (see WARNINGS ) Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) (see WARNINGS ) Syndrome of asthma, rhinitis, and nasal polyps (see WARNINGS ) Acute intermittent porphyria
Special warnings and precautions
PRECAUTIONS This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Information for Patients Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Carisoprodol, Aspirin, and Codeine Phosphate Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home (see WARNINGS , DRUG ABUSE AND DEPENDENCE ). Inform patients that leaving Carisoprodol, Aspirin, and Codeine Phosphate Tablets unsecured can pose a deadly risk to others in the home. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or DEA-registered collectors are available, instruct patients to dispose of Carisoprodol, Aspirin, and Codeine Phosphate Tablets by following these four steps: Mix Carisoprodol, Aspirin, and Codeine Phosphate Tablets (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds; Place the mixture in a container such as a sealed plastic bag; Throw the container in the household trash; Delete all personal information on the prescription label of the empty bottle Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of Carisoprodol, Aspirin, and Codeine Phosphate 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets with others and to take steps to protect Carisoprodol, Aspirin, and Codeine Phosphate 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets or when the dosage is increased, and that it can occur even at recommended dosages (see WARNINGS ). Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death. Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children Advise caregivers that Carisoprodol, Aspirin and Codeine Phosphate Tablets is contraindicated in all children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to 18 years of age receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets to monitor for signs of respiratory depression (see WARNINGS ). Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Carisoprodol, Aspirin, and Codeine Phosphate 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 ). Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition 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 healthcare providers if they are taking, or plan to take serotonergic medications. (see PRECAUTIONS; Drug Interactions ). MAOI Interaction Inform patients not to take Carisoprodol, Aspirin, and Codeine Phosphate Tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Carisoprodol, Aspirin, and Codeine Phosphate Tablets (see PRECAUTIONS; Drug Interactions ). Adrenal Insufficiency Inform patients that opioids 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 ). Important Administration Instructions Instruct patients how to properly take Carisoprodol, Aspirin, and Codeine Phosphate Tablets. (see DOSAGE AND ADMINISTRATION ). Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Carisoprodol, Aspirin, and Codeine Phosphate Tablets without first discussing a tapering plan with the prescriber (see DOSAGE AND ADMINISTRATION ). Hypotension Inform patients that Carisoprodol, Aspirin, and Codeine Phosphate 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) (see WARNINGS ). Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Advise patients how to recognize such a reaction and when to seek medical attention (see CONTRAINDICATIONS, ADVERSE REACTIONS ). Aspirin Allergy: Patients should be informed that Carisoprodol, Aspirin, and Codeine Phosphate Tablets contains aspirin and should not be taken by patients with an aspirin or NSAIDs allergy (see WARNINGS ). Pregnancy Neonatal Opioid Withdrawal Syndrome: Inform female patients of reproductive potential that prolonged use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets can (or may) cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy (see PRECAUTIONS; Pregnancy ). Lactation Advise women that breastfeeding is not recommended during treatment with Carisoprodol, Aspirin, and Codeine Phosphate Tablets (see PRECAUTIONS; Nursing Mothers ). Infertility Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible (see PRECAUTIONS; Females and Males of Reproductive Potential ). Risk of Bleeding Inform patients about the signs and symptoms of bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding. Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin (see WARNINGS ). Driving or Operating Heavy Machinery Inform patients that Carisoprodol, Aspirin, and Codeine Phosphate 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 ). Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of Carisoprodol, Aspirin and Codeine Phosphate Tablets with NSAIDs or other salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS, PRECAUTIONS; Drug Interactions ). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Disposal of Unused Carisoprodol, Aspirin, and Codeine Phosphate Tablets Advise patients to properly dispose of unused Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Advise patients to throw the drug in the household trash following these steps. 1) Remove them from their original containers and mix them with an undesirable substance, such as used coffee grounds or kitty litter (this makes the drug less appealing to children and pets, and unrecognizable to people who may intentionally go through the trash seeking drugs). 2) Place the mixture in a sealable bag, empty can, or other container to prevent the drug from leaking or breaking out of a garbage bag, or to dispose of in accordance with the local state guidelines and/or regulations. Carisoprodol Should Only Be Used for Short-Term Treatment Patients should be advised that treatment with carisoprodol should be limited to acute use (up to two or three weeks) for the relief of acute, musculoskeletal discomfort. In the post-marketing experience with carisoprodol, cases of dependence, withdrawal, and abuse have been reported with prolonged use. If musculoskeletal symptoms still persist, patients should contact their healthcare provider for further evaluation. Drug Interactions Table 1 includes clinically significant drug interactions with Carisoprodol, Aspirin and Codeine Phosphate Tablets. Table 1: Clinically Significant Drug Interactions with Carisoprodol, Aspirin and Codeine Phosphate Tablets. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets is achieved (see WARNINGS ). 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; Pharmacokinetics ), 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage until stable drug effects are achieved. Monitor 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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; Pharmacokinetics ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence (see WARNINGS ). 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; Pharmacokinetics ), 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, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage as needed. If a CYP3A4 inducer is discontinued, consider Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage reduction, and monitor for signs of respiratory depression and sedation at frequent intervals. Examples: Rifampin, carbamazepine, phenytoin. Inhibitors of CYP2D6 Clinical Impact: Codeine in Carisoprodol, Aspirin, and Codeine Phosphate Tablets is metabolized by CYP2D6 to form morphine. The concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets is achieved (see CLINICAL PHARMACOLOGY; Pharmacokinetics ). 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; Pharmacokinetics ). Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Carisoprodol, Aspirin, and Codeine Phosphate Tablets and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets and monitor the patient 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. Follow patients closely for signs of respiratory depression and sedation (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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Carisoprodol, Aspirin, and Codeine Phosphate 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 affect 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: Do not use Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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, hydrocodone, 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 respiratorydepression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Carisoprodol, Aspirin, and Codeine Phosphate Tablets and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor 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: Monitor patients for signs of urinary retention or reduced gastric motility when Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 sides, leading to prolongation of both the prothrombin time and the bleeding time. Intervention: Monitor 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 and monitor patient 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. Monitor 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets with caution if used concomitantly with nephrotoxic agents. Closely monitor 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. Monitor 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. Monitor 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. Drug/Drug Interactions with Carisoprodol The sedative effect of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS ). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY ). Co-administration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John's Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect on CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long term studies in animals have not been performed to evaluate the carcinogenic potential of Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Administration of aspirin for 68 weeks at 0.5 percent in the feed of rats was not carcinogenic. Two-year carcinogenicity studies with codeine sulfate have been conducted in F344/N rats and B6C3F1 mice. There was no evidence of carcinogenicity in male and female rats, respectively, at dietary doses up to 70 and 80 mg/kg/day of codeine sulfate (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) for two years. Similarly there was no evidence of carcinogenicity activity in male and female mice at dietary doses up to 400 mg/kg/day of codeine sulfate (approximately 10 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) for two years. Mutagenesis Codeine was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro Chinese hamster ovary cell chromosome aberration assay. Aspirin is not mutagenic in the Ames Salmonella assay; however, aspirin did induce chromosome aberrations in cultured human fibroblasts. Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vitro mouse micronucleus assay of circulating blood cells. Impairment of Fertility No adequate studies have been conducted in animals to characterize the impact of the combinations of carisoprodol, aspirin, and codeine on fertility. There are also no data on codeine alone. Aspirin inhibits ovulation in rats. Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spent in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known. Pregnancy Pregnancy Category D Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Use of aspirin, including Carisoprodol, Aspirin, and Codeine Phosphate Tablets, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Carisoprodol, Aspirin, and Codeine Phosphate Tablets, in pregnant women starting at 30 weeks of gestation (third trimester). Available data with Carisoprodol, Aspirin, and Codeine Phosphate Tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies have not been conducted with the combination of carisoprodol, aspirin and caffeine, and codeine phosphate. In animal reproduction studies, codeine administration during organogenesis has been shown to produce delayed ossification in the offspring of mice at 2.8 times maximum recommended human dose (MRHD) of 180 mg/day, embryo-lethal and fetotoxic effects in the offspring of rats and hamsters at approximately 4 to 6 times the MRHD, and cranial malformations/ cranioschisis in the offspring of hamsters between 2 and 8 times the MRHD (see Data). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. Studies of aspirin use in pregnant women have not shown that aspirin increases the risk of abnormalities when administered during the first trimester of pregnancy. In controlled studies involving 41,337 pregnant women and their offspring, there was no evidence that aspirin taken during pregnancy caused stillbirth, neonatal death or reduced birth weight. In controlled studies of 50,282 pregnant women and their offspring, aspirin administration in moderate and heavy doses during the first four lunar months of pregnancy showed no teratogenic effect. Therapeutic doses of aspirin in pregnant women close to term may cause bleeding in mother, fetus, or neonate. During the last 6 months of pregnancy, regular use of aspirin in high doses may prolong pregnancy and delivery. There are no data on the use of carisoprodol during human pregnancy. Animal studies indicate that carisoprodol crosses the placenta and results in adverse effects on fetal growth and postnatal survival. The primary metabolite of carisoprodol, meprobamate, is an approved anxiolytic. Retrospective, post-marketing studies do not show a consistent association between maternal use of meprobamate and an increased risk for particular congenital malformations. Animal studies have not adequately evaluated the teratogenic effects of carisoprodol. There was no increase in the incidence of congenital malformations noted in the reproductive studies in rats, rabbits, and mice treated with meprobamate. Retrospective, post-marketing studies of meprobamate during human pregnancy were equivocal for demonstrating an increased risk of congenital malformations following the first trimester exposure. Across studies that indicated an increased risk, the types of malformations were inconsistent. In animal studies, carisoprodol reduced fetal weights, postnatal weight gain, and postnatal survival at maternal doses equivalent to 1 to 1.5 times the human dose (based on a body surface area comparison). Rats exposed to meprobamate in utero showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate in utero, one study found no adverse effects on mental or motor development or IQ scores. Carisoprodol should be used during pregnancy only if the potential benefit justifies the risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population 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 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reaction Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid 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, t
Adverse reactions
ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse (see WARNINGS ) Life-Threatening Respiratory Depression (see WARNINGS ) Interactions with Benzodiazepines and Other CNS Depressants (see WARNINGS ) Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children (see WARNINGS ) Neonatal Opioid Withdrawal Syndrome (see WARNINGS ) Adrenal Insufficiency (see WARNINGS ) Severe Hypotension (see WARNINGS ) Gastrointestinal Adverse Reactions (see WARNINGS ) Seizures (see WARNINGS ) Withdrawal (see WARNINGS ) Coagulation Abnormalities and Bleeding (see WARNINGS ) Reye’s Syndrome (see WARNINGS ) Allergy (see WARNINGS ) The following adverse reactions which have occurred with the administration of the individual products alone may also occur with the use of Carisoprodol, Aspirin and Codeine Phosphate Tablets. The following events have been reported during post-approval individual use of carisoprodol, aspirin, and codeine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Carisoprodol Cardiovascular: Tachycardia, postural hypotension, and facial flushing (see OVERDOSAGE ). Central Nervous System: Drowsiness, dizziness, vertigo, ataxia, tremor, agitation, irritability, headache, depressive reactions, syncope, insomnia, and seizures (see OVERDOSAGE ). Gastrointestinal: Nausea, vomiting, and epigastric discomfort. Hematologic: Leukopenia, pancytopenia. Aspirin The most common adverse reactions associated with the use of aspirin have been gastrointestinal, including both abdominal pain, anorexia, nausea, vomiting, gastritis, and occult bleeding (see WARNINGS ). Other adverse reactions associated with the use of aspirin include elevated liver enzymes, rash, pruritus, purpura, intracranial hemorrhage, interstitial nephritis, acute renal failure, and tinnitus. Tinnitus may be a sign of high serum salicylate levels (see OVERDOSAGE ). Codeine Phosphate Nausea, vomiting, constipation, miosis, sedation, dizziness. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Carisoprodol, Aspirin and Codeine Phosphate Tablets. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see CLINICAL PHARMACOLOGY ). To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals NJ, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse (see WARNINGS ). Dosing Information The recommended daily dose of Carisoprodol, Aspirin and Codeine Phosphate Tablets is 1 or 2 tablets, four times daily in adults. One Carisoprodol, Aspirin and Codeine Phosphate Tablet contains 200 mg of carisoprodol, 325 mg of aspirin, and 16 mg of codeine phosphate. The maximum daily dose (i.e., two tablets taken four times daily) will provide 1600 mg of carisoprodol, 2600 mg of aspirin, and 128 mg of codeine phosphate per day. The recommended maximum duration of Carisoprodol, Aspirin and Codeine Phosphate Tablet, USP use is up to two or three weeks. Safe Reduction or Discontinuation of Carisoprodol, Aspirin and Codeine Phosphate Tablets Do not abruptly discontinue Carisoprodol, Aspirin and Codeine Phosphate Tablets in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid 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 Carisoprodol, Aspirin and Codeine Phosphate Tablets, there are a variety of factors that should be considered, including the dose of Carisoprodol, Aspirin and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin and Codeine Phosphate Tablets 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, monitor 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 a long duration 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; Withdrawal , DRUG ABUSE AND DEPENDENCE ).
Pregnancy and lactation
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 Carisoprodol, Aspirin and Codeine Phosphate Tablets (see PRECAUTIONS, Nursing Mothers ). 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 Americans), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain ethnic groups (i.e., Oceanian, North 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) (see OVERDOSAGE ). Therefore, individuals who are ultra-rapid metabolizers should not use codeine. Neonatal Opioid Withdrawal Syndrome Prolonged use of Carisoprodol, Aspirin and Codeine Phosphate Tablets 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see PRECAUTIONS; Pregnancy, Information for Patients ). 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets requires careful consideration of the effects on codeine and the active metabolite, morphine. Cytochrome P450 3A4 Interaction The concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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. Follow patients receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. (see PRECAUTIONS; Drug Interactions ). Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors The concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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. Follow patients receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when Carisoprodol, Aspirin, and Codeine Phosphate Tablets are used in conjunction with inhibitors of CYP2D6. If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage and follow the patient for signs and symptoms of respiratory depression or sedation (see PRECAUTIONS; Drug Interactions ). Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). 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 PRECAUTIONS ; Drug Interactions ). 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. Follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 PRECAUTIONS, Drug Interactions, Information for Patients ). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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: Carisoprodol, Aspirin, and Codeine Phosphate Tablets-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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets (see WARNINGS ). 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 (see WARNINGS ). Monitor such patients closely, particularly when initiating and titrating Carisoprodol, Aspirin, and Codeine Phosphate Tablets and when Carisoprodol, Aspirin, and Codeine Phosphate Tablets is given concomitantly with other drugs that depress respiration (see WARNINGS ). Alternatively, consider the use of non-opioid analgesics in these patients. 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. Carisoprodol, Aspirin, and Codeine Phosphate Tablets should not be used in patients taking MAOIs or within 14 days of stopping such treatment. 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. Severe Hypotension Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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) (see PRECAUTIONS; Drug Interactions ). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Carisoprodol, Aspirin, and Codeine Phosphate Tablets. In patients with circulatory shock, Carisoprodol, Aspirin, and Codeine Phosphate Tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets in patients with circulatory shock. 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 CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Carisoprodol, Aspirin, and Codeine Phosphate Tablets may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions Including Peptic Ulcer Disease Carisoprodol, Aspirin, and Codeine Phosphate Tablets is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The codeine in Carisoprodol, Aspirin, and Codeine Phosphate Tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding. Aspirin can cause serious gastrointestinal (GI) adverse reactions including bleeding, perforation, and obstruction of the stomach, small intestine, or large intestine, which can be fatal. Aspirin-associated serious GI adverse reactions can occur anywhere along the GI tract, at any time, with or without warning symptoms. Patients at higher risk of aspirin-associated serious upper GI adverse reactions include patients with a history of aspirin-associated GI bleeding from ulcers (complicated ulcers), a history of aspirin-associated ulcers (uncomplicated ulcers), geriatric patients, patients with poor baseline health status, patients taking higher doses of aspirin, and patients taking concomitant anticoagulants, NSAIDs, and/or large amounts of alcohol. To minimize the risk for aspirin-associated GI serious adverse reactions, the lowest effective aspirin dose should be used for the shortest possible duration. Increased Risk of Seizures in Patients with Seizure Disorders The codeine in Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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. Monitor patients with a history of seizure disorders for worsened seizure control during Carisoprodol, Aspirin, and Codeine Phosphate Tablets therapy. There have been post-marketing reports of seizures in patients who received carisoprodol. Most of these cases have occurred in the setting of multiple drug overdoses (including drugs of abuse, illegal drugs, and alcohol) (see OVERDOSAGE ). Withdrawal Do not abruptly discontinue Carisoprodol, Aspirin, and Codeine Phosphate Tablets in a patient physically dependent on opioids. When discontinuing Carisoprodol, Aspirin, and Codeine Phosphate Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of Carisoprodol, Aspirin, and Codeine Phosphate Tablets in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain (see DOSAGE AND ADMINISTRATION , DRUG ABUSE AND DEPENDENCE ). 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms (see Drug Interactions ). Risks of Driving and Operating Machinery Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets and know how they will react to the medication. 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. Rey's Syndrome Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses. 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).

Interactions

Drug Interactions Table 1 includes clinically significant drug interactions with Carisoprodol, Aspirin and Codeine Phosphate Tablets. Table 1: Clinically Significant Drug Interactions with Carisoprodol, Aspirin and Codeine Phosphate Tablets. Inhibitors of CYP3A4 Clinical Impact: The concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets is achieved (see WARNINGS ). 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; Pharmacokinetics ), 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage until stable drug effects are achieved. Monitor 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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; Pharmacokinetics ), resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence (see WARNINGS ). 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; Pharmacokinetics ), 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, follow the patient for reduced efficacy and signs of opioid withdrawal and consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage as needed. If a CYP3A4 inducer is discontinued, consider Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage reduction, and monitor for signs of respiratory depression and sedation at frequent intervals. Examples: Rifampin, carbamazepine, phenytoin. Inhibitors of CYP2D6 Clinical Impact: Codeine in Carisoprodol, Aspirin, and Codeine Phosphate Tablets is metabolized by CYP2D6 to form morphine. The concomitant use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets is achieved (see CLINICAL PHARMACOLOGY; Pharmacokinetics ). 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; Pharmacokinetics ). Intervention: If concomitant use with a CYP2D6 inhibitor is necessary, or if a CYP2D6 inhibitor is discontinued after concomitant use, consider dosage adjustment of Carisoprodol, Aspirin, and Codeine Phosphate Tablets and monitor patients closely at frequent intervals. If concomitant use with CYP2D6 inhibitors is necessary, follow the patient for reduced efficacy or signs and symptoms of opioid withdrawal and consider increasing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets as needed. After stopping use of a CYP2D6 inhibitor, consider reducing the Carisoprodol, Aspirin, and Codeine Phosphate Tablets and monitor the patient 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. Follow patients closely for signs of respiratory depression and sedation (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, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Carisoprodol, Aspirin, and Codeine Phosphate 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 affect 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: Do not use Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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, hydrocodone, 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 respiratorydepression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Carisoprodol, Aspirin, and Codeine Phosphate Tablets and/or the muscle relaxant as necessary. Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor 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: Monitor patients for signs of urinary retention or reduced gastric motility when Carisoprodol, Aspirin, and Codeine Phosphate Tablets 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 sides, leading to prolongation of both the prothrombin time and the bleeding time. Intervention: Monitor 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 and monitor patient 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. Monitor 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets with caution if used concomitantly with nephrotoxic agents. Closely monitor 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. Monitor 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. Monitor 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. Drug/Drug Interactions with Carisoprodol The sedative effect of carisoprodol and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants) may be additive. Therefore, caution should be exercised with patients who take more than one of these CNS depressants simultaneously. Concomitant use of carisoprodol and meprobamate, a metabolite of carisoprodol, is not recommended (see WARNINGS ). Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see CLINICAL PHARMACOLOGY ). Co-administration of CYP2C19 inhibitors, such as omeprazole or fluvoxamine, with carisoprodol could result in increased exposure of carisoprodol and decreased exposure of meprobamate. Co-administration of CYP2C19 inducers, such as rifampin or St. John's Wort, with carisoprodol could result in decreased exposure of carisoprodol and increased exposure of meprobamate. Low dose aspirin also showed an induction effect on CYP2C19. The full pharmacological impact of these potential alterations of exposures in terms of either efficacy or safety of carisoprodol is unknown.

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Category Value
Authorisation number ANDA040860
Agency product number GSL05Y1MN6
Orphan designation No
Product NDC 50742-256
Date Last Revised 10-09-2019
Type HUMAN PRESCRIPTION DRUG
RXCUI 994226
Marketing authorisation holder Ingenus Pharmaceuticals, LLC
Warnings WARNING: ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse and Misuse Carisoprodol, Aspirin and Codeine Phosphate Tablets expose patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing Carisoprodol, Aspirin and Codeine Phosphate Tablets, and monitor all patients regularly for the development of these behaviors and conditions (see WARNINGS). 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 REMS for these products (see WARNINGS). Under the requirements of the REMS, drug companies with approved opioid analgesic product must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to complete a REMS-compliant education program, counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products, emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and consider other tools to improve patient, household, and community safety. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Carisoprodol, Aspirin and Codeine Phosphate Tablets. Monitor for respiratory depression, especially during initiation of Carisoprodol, Aspirin and Codeine Phosphate Tablets or following a dose increase (see WARNINGS). Accidental Ingestion Accidental ingestion of even one dose of Carisoprodol, Aspirin and Codeine Phosphate Tablets, especially by children, can result in a fatal overdose of Carisoprodol, Aspirin and Codeine Phosphate Tablets (see WARNINGS). 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. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism (see WARNINGS). Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS). Avoid the use of Carisoprodol, Aspirin and Codeine Phosphate Tablets 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. Neonatal Opioid Withdrawal Syndrome Prolonged use of Carisoprodol, Aspirin and Codeine Phosphate Tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see WARNINGS). 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 Carisoprodol, Aspirin and Codeine Phosphate Tablets requires careful consideration of the effects on codeine, and the active metabolite, morphine. (See WARNINGS, PRECAUTIONS; Drug Interactions). Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, PRECAUTIONS; Drug Interactions). Reserve concomitant prescribing of Carisoprodol, Aspirin and Codeine Phosphate Tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.