Carisoprodol, Aspirin and Codeine Phosphate (carisoprodol 200 mg aspirin 325 mg codeine phosphate 16 mg) Dailymed

Precautions

Information for Patients

Patients should be advised to contact their health care provider if they experience any adverse reactions to Carisoprodol, Aspirin and Codeine Phosphate Tablets. Advise the patient to read theFDA-approved patient labeling (Medication Guide).

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. Instruct patients to take steps to store Carisoprodol, Aspirin, and Codeine Phosphate Tablets securely and to properly dispose of unused Carisoprodol, Aspirin, and Codeine Phosphate Tablets in accordance with the local state guidelines and/or regulations.

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 to18 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.

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.

• 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).
• 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 theCarisoprodol, 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. DiscontinueCarisoprodol, 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), 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 treatpain while closely monitoring blood pressure and signs and symptoms ofCNS 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 skeletalmuscle relaxants and produce an increased degree of respiratorydepression.
Intervention:	Monitor patients for signs of respiratory depression that may be greaterthan otherwise expected and decrease the dosage of Carisoprodol,Aspirin, and Codeine Phosphate Tablets and/or the muscle relaxant asnecessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release ofantidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on bloodpressure and increase the dosage of the diuretic as needed.The effectiveness of diuretics in patients with underlying renal orcardiovascular disease may be diminished by the concomitantadministration 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

Caricinogenesis

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. typhimuriumstrains 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 carisoproldol, 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, embryolethal 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 postimplantation 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, 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 ).

Labor and Delivery

There are no studies on the effects of Carisoprodol, Aspirin, and Codeine Phosphate Tablets during labor or delivery. In animal studies, NSAIDS, including aspirin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Opioids such as codeine cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Carisoprodol, Aspirin, and Codeine Phosphate Tablets is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Carisoprodol, Aspirin, and Codeine Phosphate 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 dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.

Aspirin should be avoided one week prior to and during labor and delivery because it can result in excessive blood loss at delivery. Prolonged gestation and prolonged labor due to prostaglandin inhibition have been reported.

Salicylates readily cross the placenta and by inhibiting prostaglandin synthesis, may cause constriction of ductus arteriosus resulting in pulmonary hypertension and increased fetal mortality and, possibly other untoward fetal effects. Aspirin use in pregnancy can also result in alteration in maternal and neonatal hemostasis mechanisms. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence of intracranial hemorrhage in premature infants, stillbirths and neonatal death. Use during pregnancy, especially in the third trimester, should be avoided.

There is no information about the effects of carisoprodol on the mother and the fetus during labor and delivery.

Data

Animal Data

Animal reproduction studies have not been conducted with the combination of carisoprodol, aspirin, and codeine phosphate.

• Codeine

In a study in which pregnant hamsters were administered 150 mg/kg twice daily of codeine (oral; approximately 14 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis cranial malformations (i.e., meningoencephalocele) in several fetuses were reported; as well as the observation of increases in the percentage of resorptions per litter. Doses of 50 and 150 mg/kg, bid resulted in fetotoxicity as demonstrated by decreased fetal body weight. In an earlier study in hamsters, single oral doses of 73 to 360 mg/kg level on Gestation Day 8 (oral; approximately 4 to 16 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis), reportedly produced cranioschisis in all of the fetuses examined.

In studies in rats, doses at the 120 mg/kg level (oral; approximately 6 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) during organogenesis, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation.

In pregnant mice, a single 100 mg/kg dose (subcutaneous; approximately 2.8 times the recommended daily dose of 180 mg/day for adults on a mg/mg2 basis) administered between Gestation Day 7 and 12 reportedly resulted in delayed ossification in the offspring.

No teratogenic effects were observed in rabbits administered up to 30 mg/kg (approximately 4 times the maximum recommended daily dose of 180 mg/day for adults on a mg/m2 basis) of codeine during organogenesis.

Codeine (30 mg/kg) administered subcutaneously to pregnant rats during pregnancy and for 25 days after delivery increased neonatal mortality at birth. This dose is 1.6 times the maximum recommended human dose of 180 mg/day on a body surface area comparison.

Nursing Mothers

Risk Summary

Codeine and its active metabolite, morphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death (one case) in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. There is no information on the effects of the codeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with Carisoprodol, Aspirin and Codeine Phosphate Tablets (see WARNINGS ).

The aspirin in Carisoprodol, Aspirin and Codeine Phosphate Tablets are also excreted in breast milk in small amounts. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Furthermore, nursing women are advised against aspirin use because of the possible development of Reye's Syndrome in their babies.

Very limited data in humans show that carisoprodol is present in breast milk and may reach concentrations two to four times the maternal plasma concentrations. In one case report, a breast-fed infant received about 4 to 6% of the maternal daily dose through breast milk and experienced no adverse effects. However, milk production was inadequate and the baby was supplemented with formula. In lactation studies in mice, female pup survival and pup weight at weaning were decreased. This information suggests that maternal use of carisoprodol may lead to reduced or less effective infant feeding (due to sedation) and/or decreased milk production. Caution should be exercised when carisoprodol is administered to a nursing woman.

Clinical Consideration

If infants are exposed to Carisoprodol, Aspirin and Codeine Phosphate Tablets through breast milk, they should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Females and Males of Reproductive Potential

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible (see  ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, PRECAUTIONS; Carcinogenesis, Mutagenesis, Impairment of Fertility ).

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including aspirin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including aspirin, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Preparations containing aspirin should be kept out of the reach of children. Reye’s Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. The efficacy and safety of Carisoprodol, Aspirin and Codeine Phosphate Tablets in pediatric patients less than 18 years of age have not been established.

Life-threatening respiratory depression and death have occurred in children who received codeine (see  WARNINGS ). In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects of codeine.

Because of the risk of life-threatening respiratory depression and death:

• Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for all children younger than 12 years of age (see  CONTRAINDICATIONS ).
• Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for post-operative management in pediatric patients 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 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 (see  WARNINGS ).

Geriatric Use

Clinical studies of Carisoprodol, Aspirin, and Codeine Phosphate Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients (aged 65 years or older) may have increased sensitivity to Carisoprodol, Aspirin, and Codeine Phosphate Tablets. 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 Carisoprodol, Aspirin, and Codeine Phosphate Tablets slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see  WARNINGS ).

Components of this product are 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 monitor renal function.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and monitor patients for adverse effects (see  WARNINGS ).

Hepatic Impairment

No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of aspirin, codeine and in this patient population are unknown. Start these patients cautiously with lower doses of Carisoprodol, Aspirin, and Codeine Phosphate Tablets or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In patients with severe hepatic disease, monitor effects of therapy with serial liver function tests

Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired hepatic function. Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis.

Renal Impairment

Carisoprodol, Aspirin, and Codeine Phosphate Tablets contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).

Codeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of Carisoprodol, Aspirin, and Codeine Phosphate Tablets or with longer dosing intervals and titrate slowly while carefully monitoring for side effects. In patients with renal disease, monitor effects of therapy with serial renal function tests.

Since carisoprodol is excreted by the kidney and is metabolized in the liver, caution should be exercised if carisoprodol is administered to patients with impaired renal function.

Carisoprodol is dialyzable by hemodialysis and peritoneal dialysis.