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Carisoprodol, Aspirin and Codeine Phosphate
Overview
What is Carisoprodol, Aspirin and Codeine Phosphate?
Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP is a fixed-dose combination product containing the following three products:
It is available as a round, two-layered yellow and white tablet for oral administration.
Carisoprodol:
N
Aspirin:
Codeine Phosphate:
Each tablet, for oral administration, contains carisoprodol 200 mg, aspirin 325 mg, and codeine phosphate 16 mg. In addition, each tablet contains the following inactive ingredients: FD&C Yellow #5 Aluminum Lake, Corn starch, Hydroxypropyl Cellulose, Lactose Anhydrous, Microcrystalline Cellulose, Magnesium Stearate, Pregelatinized Starch, Sodium Starch Glycolate and Sodium Lauryl Sulfate.
What does Carisoprodol, Aspirin and Codeine Phosphate look like?
What are the available doses of Carisoprodol, Aspirin and Codeine Phosphate?
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What should I talk to my health care provider before I take Carisoprodol, Aspirin and Codeine Phosphate?
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How should I use Carisoprodol, Aspirin and Codeine Phosphate?
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
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 ).
Important Dosage and Administration Instructions
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals (see ).
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 ).
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.
Discontinuation of Carisoprodol, Aspirin and Codeine Phosphate Tablets
When a patient who has been taking Carisoprodol, Aspirin and Codeine Phosphate Tablets regularly and may be physically dependent no longer requires therapy with Carisoprodol, Aspirin and Codeine Phosphate Tablets, use a gradual downward titration of the dosage to prevent signs and symptoms of withdrawal. Do not stop Carisoprodol, Aspirin and Codeine Phosphate Tablets abruptly (see ).
What interacts with Carisoprodol, Aspirin and Codeine Phosphate?
- Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for:
- Carisoprodol, Aspirin and Codeine Phosphate Tablets are also contraindicated in patients with:
What are the warnings of Carisoprodol, Aspirin and Codeine Phosphate?
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against
may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of
, and surgical evaluation should be instituted as clinically indicated.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Carisoprodol, Aspirin, and Codeine Phosphate Tablets, and monitor all patients receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as Carisoprodol, Aspirin, and Codeine Phosphate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids and carisoprodol are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug (see ). Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Carisoprodol, Aspirin, and Codeine Phosphate Tablets.
To reduce the risk of respiratory depression, proper dosing and titration of Carisoprodol, Aspirin, and Codeine Phosphate Tablets are essential (see ).
Overestimating the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of Carisoprodol, Aspirin, and Codeine Phosphate Tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine and carisoprodol.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children less than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
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 ).
CYP2D6 Genetic Variability: Ultra-rapid metabolizer
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 ).
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.
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 ina 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 ).
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 ).
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 ).
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 ).
Alternatively, consider the use of non-opioid analgesics in these patients.
Interaction with Monoamine Oxidase Inhibitors
Adrenal Insufficiency
Severe Hypotension
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 ).
Withdrawal
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.
When discontinuing Carisoprodol, Aspirin, and Codeine Phosphate Tablets in a physicallydependent patient, gradually taper the dosage (see ). Do not abruptly discontinue Carisoprodol, Aspirin, and Codeine Phosphate Tablets in these patients (see ).
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 Abnoramlities 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.
Reye's Syndrome
Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye 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).
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- Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for all children younger than 12 years of age (see ).
- 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 ).
- 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, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
- As with adults, when prescribing codeine for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose (see ).
What are the precautions of Carisoprodol, Aspirin and Codeine Phosphate?
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Information for Patients
- 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 andpets, and unrecognizable to people who may intentionally go through the trash seekingdrugs).
- Place the mixture in a sealable bag, empty can, or other container to prevent the drug fromleaking or breaking out of a garbage bag, or to dispose of in accordance with the local stateguidelines and/or regulations.
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 whentaken as recommended, can result in addiction, abuse, and misuse, which can lead to overdoseand death (see ). Instruct patients not to share Carisoprodol, Aspirin, and CodeinePhosphate Tablets with others and to take steps to protect Carisoprodol, Aspirin, and CodeinePhosphate Tablets from theft or misuse.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information thatthe risk is greatest when starting Carisoprodol, Aspirin, and Codeine Phosphate Tablets or whenthe dosage is increased, and that it can occur even at recommended dosages (see ).Advise patients how to recognize respiratory depression and to seek medical attention ifbreathing difficulties develop.
Accidental Ingestation
Inform patients that accidental ingestion, especially by children, may result in respiratorydepression or death. Instruct patients to take steps to store Carisoprodol, Aspirin, and CodeinePhosphate Tablets securely and to properly dispose of unused Carisoprodol, Aspirin, andCodeine Phosphate Tablets in accordance with the local state guidelines and/or regulations.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening RespiratoryDepression in Children
Advise caregivers that Carisoprodol, Aspirin and Codeine Phosphate Tablets is contraindicatedin all children younger than 12 years of age and in children younger than 18 years of agefollowing tonsillectomy and/or adenoidectomy. Advise caregivers of children ages 12 to18 yearsof age receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets to monitor for signs ofrespiratory depression (see ).
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 ).
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition resultingfrom concomitant administration of serotonergic drugs. Warn patients of the symptoms ofserotonin syndrome and to seek medical attention right away if symptoms develop. Instructpatients to inform their healthcare providers if they are taking, or plan to take serotonergicmedications. (see ).
MAOI Interaction
Inform patients not to take Carisoprodol, Aspirin, and Codeine Phosphate Tablets while usingany drugs that inhibit monoamine oxidase. Patients should not start MAOIs while takingCarisoprodol, Aspirin, and Codeine Phosphate Tablets (see ).
Adrenal Insufficiency
Inform patients that opioids could cause adrenal insufficiency, a potentially life-threateningcondition. Adrenal insufficiency may present with non-specific symptoms and signs such asnausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advisepatients to seek medical attention if they experience a constellation of these symptoms (see).
Important Administration Instructions
Instruct patients how to properly take Carisoprodol, Aspirin, and Codeine Phosphate Tablets.(see ).
Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, andno more frequently than prescribed.
Hypotension
Inform patients that Carisoprodol, Aspirin, and Codeine Phosphate Tablets may cause orthostatichypotension and syncope. Instruct patients how to recognize symptoms of low blood pressureand how to reduce the risk of serious consequences should hypotension occur (e.g., sit or liedown, carefully rise from a sitting or lying position) (see ).
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 andwhen to seek medical attention (see ).
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Pregnancy
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Lactation
Advise women that breastfeeding is not recommended during treatment with Carisoprodol,Aspirin, and Codeine Phosphate Tablets (see ).
Infertility
Inform patients that chronic use of opioids may cause reduced fertility. It is not known whetherthese effects on fertility are reversible (see ).
Risk of Bleeding
Inform patients about the signs and symptoms of bleeding. Tell patients to notify their physicianif they are prescribed any drug which may increase risk of bleeding.
Counsel patients who consume three or more alcoholic drinks daily about the bleeding risksinvolved with chronic, heavy alcohol use while taking aspirin (see ).
Driving or Operating Heavy Machinery
Inform patients that Carisoprodol, Aspirin, and Codeine Phosphate Tablets may impair theability to perform potentially hazardous activities such as driving a car or operating heavymachinery. Advise patients not to perform such tasks until they know how they will react to themedication (see ).
Constipation
Advise patients of the potential for severe constipation, including management instructions andwhen to seek medical attention (see ).
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of Carisoprodol, Aspirin and Codeine PhosphateTablets with NSAIDs or other salicylates (e.g., diflunisal, salsalate) is not recommended due tothe increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see). Alert patients that NSAIDs may bepresent 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 PhosphateTablets Advise patients to throw the drug in the household trash following these steps.
Carisoprodol Should Only Be Used for Short-Term Treatment
Patients should be advised that treatment with carisoprodol should be limited to acute use (up totwo or three weeks) for the relief of acute, musculoskeletal discomfort. In the post-marketingexperience with carisoprodol, cases of dependence, withdrawal, and abuse have been reportedwith prolonged use. If musculoskeletal symptoms still persist, patients should contact theirhealthcare provider for further evaluation.
Drug Interactions
Table 1 includes clinically significant drug interactions with Carisoprodol, Aspirin and CodeinePhosphate Tablets.
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 ).
Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see ).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.
| Inhibitors of CYP3A4 | |
| Clinical Impact: | The concomitant use of Carisoprodol, Aspirin, and Codeine PhosphateTablets with CYP3A4 inhibitors may result in an increase in codeineplasma concentrations with subsequently greater metabolism bycytochrome CYP2D6, resulting in greater morphine levels, which couldincrease or prolong adverse reactions and may cause potentially fatalrespiratory depression, particularly when an inhibitor is added after astable dose of Carisoprodol, Aspirin, and Codeine Phosphate Tablets isachieved (see ).After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline,it may result in lower codeine levels, greater norcodeine levels, and lessmetabolism via 2D6 with resultant lower morphine levels (see ), resulting in decreased opioidefficacy or a withdrawal syndrome in patients who had developedphysical dependence to codeine. |
| Intervention: | If concomitant use with CYP3A4 inhibitor is necessary, consider dosagereduction of Carisoprodol, Aspirin, and Codeine Phosphate Tablets untilstable drug effects are achieved. Monitor patients for respiratorydepression and sedation at frequent intervals.If a CYP3A4 inhibitor is discontinued, consider increasing theCarisoprodol, Aspirin, and Codeine Phosphate Tablets dosage until stabledrug 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 PhosphateTablets and CYP3A4 inducers can result in lower codeine levels, greaternorcodeine levels, and less metabolism via 2D6 with resultant lowermorphine levels (see ), resulting in decreased efficacy or onset of awithdrawal syndrome in patients who have developed physicaldependence (see ).After stopping a CYP3A4 inducer, as the effects of the inducer decline,the codeine plasma concentration may increase with subsequently greatermetabolism by cytochrome CYP2D6, resulting in greater morphine levels(see ), which couldincrease 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 patientfor reduced efficacy and signs of opioid withdrawal and considerincreasing the Carisoprodol, Aspirin, and Codeine Phosphate Tabletsdosage as needed.If a CYP3A4 inducer is discontinued, consider Carisoprodol, Aspirin,and Codeine Phosphate Tablets dosage reduction, and monitor for signsof 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 ).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 ). |
| 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 ). |
| 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 theserotonergic 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 serotoninsyndrome is suspected. |
| Examples: | Selective serotonin reuptake inhibitors (SSRIs), serotonin andnorepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants(TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect theserotonin neurotransmitter system (e.g., mirtazapine, trazodone,tramadol), monoamine oxidase (MAO) inhibitors (those intended to treatpsychiatric disorders and also others, such as linezolid and intravenousmethylene blue). | Monoamine Oxidase Inhibitors (MAOIs) |
| Clinical Impact: | MAOI interactions with opioids may manifest as serotonin syndrome oropioid toxicity (e.g., respiratory depression, coma) (see ). |
| Intervention: | Do not use Carisoprodol, Aspirin, and Codeine Phosphate Tablets inpatients taking MAOIs or within 14 days of stopping such treatment.If urgent use of an opioid is necessary, use test doses and frequenttitration 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 CodeinePhosphate 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/Laboratory Test Interactions
Aspirin:
Codeine:
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF
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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 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 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 strains with or without metabolizing enzymes, and was not clastogenic in an 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
- Codeine
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 showed behavioral alterations that persisted into adulthood. For children exposed to meprobamate , 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 ).
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.
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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
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 ).
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 ).
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
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 ). 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:
GERIATRIC USE
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 ).
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 ).
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.
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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
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What are the side effects of Carisoprodol, Aspirin and Codeine Phosphate?
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What should I look out for while using Carisoprodol, Aspirin and Codeine Phosphate?
Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for:
Carisoprodol, Aspirin and Codeine Phosphate Tablets are also contraindicated in patients with:
Addiction, Abuse, and Misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Carisoprodol, Aspirin, and Codeine Phosphate Tablets, and monitor all patients receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as Carisoprodol, Aspirin, and Codeine Phosphate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids and carisoprodol are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug (see ). Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory Depression
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Carisoprodol, Aspirin, and Codeine Phosphate Tablets.
To reduce the risk of respiratory depression, proper dosing and titration of Carisoprodol, Aspirin, and Codeine Phosphate Tablets are essential (see ).
Overestimating the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of Carisoprodol, Aspirin, and Codeine Phosphate Tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine and carisoprodol.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children less than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
What might happen if I take too much Carisoprodol, Aspirin and Codeine Phosphate?
Clinical Presentation
Acute overdose with Carisoprodol, Aspirin and Codeine Phosphate Tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see ].
Carisoprodol:
Aspirin:
Symptoms and signs of severe salicylate poisoning, associated with plasma salicylic concentrations greater than 400 mcg/mL, include hyperthermia, dehydration, delirium, GI hemorrhage, pulmonary edema, and CNS depression (e.g., coma). Death is usually due to respiratory failure or cardiovascular collapse.
Overdose of aspirin in pediatric patients:
Codeine Phosphate:
Treatment of Overdosage
In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support techniques.
The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to codeine phosphate overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to codeine overdose.
Because the duration of opioid reversal is expected to be less than the duration of action of codeine in Carisoprodol, Aspirin and Codeine Phosphate Tablets, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.
Carisoprodol:
Aspirin:
Additional treatment of aspirin overdose in pediatric patients:
Exchange transfusion may be indicated in infants and young children.
How should I store and handle Carisoprodol, Aspirin and Codeine Phosphate?
Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature]. Protect from light. Keep bottles tightly closed to protect from moisture.Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018Carisoprodol, Aspirin and Codeine Phosphate Tablets, USP are supplied as:Yellow and white color, round unscored convex, two layered tablets debossed on yellow layer with “CL” over “024” and plain on the white layer.The tablets are available in bottles of 100, NDC 64980-176-01.StorageStore at 20° to 25°C (68° to 77°F) (See USP Controlled Room Temperature). Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).Manufactured for:Rising Pharmaceuticals, Inc.Allendale, NJ 07401 USAManufactured by:5508 Rev.01/2018
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Carisoprodol:
Aspirin:
Codeine Phosphate:
Non-Clinical Toxicology
Carisoprodol, Aspirin and Codeine Phosphate Tablets are contraindicated for:Carisoprodol, Aspirin and Codeine Phosphate Tablets are also contraindicated in patients with:
Addiction, Abuse, and Misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Addiction can occur at recommended dosages and if the drug is misused or abused.
Assess each patient’s risk for addiction, abuse, or misuse prior to prescribing Carisoprodol, Aspirin, and Codeine Phosphate Tablets, and monitor all patients receiving Carisoprodol, Aspirin, and Codeine Phosphate Tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient.
Patients at increased risk may be prescribed opioids such as Carisoprodol, Aspirin, and Codeine Phosphate Tablets, but use in such patients necessitates intensive counseling about the risks and proper use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids and carisoprodol are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing Carisoprodol, Aspirin, and Codeine Phosphate Tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug (see ). Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory Depression
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Carisoprodol, Aspirin, and Codeine Phosphate Tablets, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of Carisoprodol, Aspirin, and Codeine Phosphate Tablets.
To reduce the risk of respiratory depression, proper dosing and titration of Carisoprodol, Aspirin, and Codeine Phosphate Tablets are essential (see ).
Overestimating the Carisoprodol, Aspirin, and Codeine Phosphate Tablets dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of Carisoprodol, Aspirin, and Codeine Phosphate Tablets, especially by children, can result in respiratory depression and death due to an overdose of codeine and carisoprodol.
Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-threatening Respiratory Depression in Children
Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon post-marketing reports, children less than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
Table 1 includes clinically significant drug interactions with Carisoprodol, Aspirin and CodeinePhosphate Tablets.
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 ).
Carisoprodol is metabolized in the liver by CYP2C19 to form meprobamate (see ).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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Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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