Acetaminophen; Codeine Interactions
- Acetaminophen
- Amiodarone
- Amitriptyline
- Amoxapine
Antacids
Antidiarrheals
Antimuscarinics
Anxiolytics, Sedatives, and Hypnotics
Barbiturates
- Bupropion
- Carbamazepine
- Cimetidine
- Citalopram
- Clomipramine
- Clozapine
- Delavirdine
- Doxepin
- Dronabinol, THC
- Droperidol
- Echinacea
- Entacapone
- Escitalopram
- Ethanol
- Ethotoin
- Fluoxetine
- Fosphenytoin
- Gefitinib
General Anesthetics
- Haloperidol
- Imatinib, STI-571
- Imipramine
- Isoniazid, INH
- Maprotiline
- Mirtazapine
Mixed opiate agonists/antagonists
- Molindone
Monoamine oxidase inhibitors (MAOIs)
- Nabilone
- Nefazodone
- Nortriptyline
- Olanzapine
Opiate agonists
Opiate antagonists
- Paroxetine
Phenothiazines
- Phenytoin
- Pimozide
- Pramipexole
- Pregabalin
- Propafenone
- Quetiapine
- Quinidine
- Rifampin
- Risperidone
- Ritonavir
- Ropinirole
Sedating H1-blockers
- Sertraline
Skeletal Muscle Relaxants
- Tolcapone
- Tramadol
- Trazodone
- Warfarin
Acetaminophen; Codeine Interactions
NOTE: This monograph discusses interactions with a combination product. Clinicians may wish to consult the individual monographs for more information about each agent.
Many prescription and non-prescription medicines contain acetaminophen. Avoid concurrent use of products that contain acetaminophen as the maximum daily dose (i.e., 4 g/day for adults; 75 mg/kg/day for infants and children) may be exceeded leading to an increased risk of hepatotoxicity. Advise patients to carefully read the ingredients of any other medicines they are taking with acetaminophen and codeine products.
Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
The activity of acetaminophen and codeine combinations is influenced by concurrent administration of hepatic cytochrome P450 (CYP) enzyme inducers such as barbiturates, carbamazepine, and rifampin. Codeine has a low affinity for CYP2D6; therefore, its analgesic activity may vary greatly when it is combined with any other drugs that may induce CYP2D6, primarily rifampin. In vitro studies have shown no effect of carbamazepine or phenytoin on the conversion of codeine to morphine. N-demethylation of codeine to norcodeine via cytochrome P450 isoenzyme 3A4 (CYP3A4) is a main metabolic pathway. Barbiturates, carbamazepine, and phenytoin all induce CYP3A4. Additive CNS depression may occur when codeine is combined with barbiturates, carbamazepine, phenytoin, fosphenytoin or ethotoin. Drugs that are inducers of CYP2E1 or 1A2 may increase the risk of acetaminophen-induced hepatotoxicity. At least one case has been reported of phenobarbital enhancing acetaminophen hepatotoxicity. While chronic acetaminophen use should be discouraged during phenobarbital therapy, intermittent use of acetaminophen is probably safe. Hepatic failure and encephalopathy have been attributed to the combination of rifampin and acetaminophen in one report. Isoniazid, INH appears to induce the CYP2E1 isoenzyme; the combination of isoniazid, INH and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid, INH potentiates acetaminophen hepatotoxicity. Monitoring for excessive toxicity or decreased efficacy is recommended in patients receiving these drugs in combination with acetaminophen-codeine.
Patients receiving inhibitors of cytochrome P450 (CYP) 2D6 isoenzyme may have a reduction in the metabolic conversion of codeine to morphine and, therefore, may not experience an adequate analgesic response to acetaminophen; codeine combinations. Quinidine has been shown to interfere with the conversion of codeine to morphine; a corresponding decrease in codeine analgesia was seen. Other inhibitors of CYP2D6 may also decrease the analgesic effect of codeine; these include amiodarone, bupropion, cimetidine, delavirdine, gefitinib , haloperidol, imatinib, STI-571, propafenone, some SSRIs (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), and thioridazine. Additive sedation may occur initially with concurrent use of some of these agents with acetaminophen; codeine products.
Ritonavir may decrease the conversion of codeine to morphine by inhibiting cytochrome P450 (CYP) 2D6. The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. In addition, ritonavir may inhibit microsomal isoenzymes CYP 2E1 or 1A2, which may decrease the formation of toxic metabolites of acetaminophen.
Concurrent use of antidiarrheals and acetaminophen; codeine products can lead to severe constipation and possibly additive CNS depression. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use.
The combination of ethanol and acetaminophen-codeine may result in additive CNS depression. In addition, the risk of developing acetaminophen-induced hepatotoxicity appears to be increased in patients who regularly consume ethanol. In these patients, hepatotoxicity is possible even at normal, therapeutic dosages of acetaminophen. Administration of acetaminophen should be limited or avoided altogether in alcoholics or patients who consume more than 3 ethanol-containing beverages per day.
Clinicians should be alert for an increased INR if acetaminophen-codeine is administered daily in large doses for longer than 10 days in patients stabilized on warfarin. Acetaminophen has been shown to augment the hypoprothrombinemic response to warfarin in a dose-dependent manner. Both INR prolongation and clinical bleeding have been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen-codeine are probably safe in most patients taking warfarin.
Opiate antagonists, such as nalmefene, naloxone, and naltrexone, are pharmacologic opposites of codeine. These drugs can block the actions of codeine reducing the analgesic effect and, if administered to patients who have received chronic acetaminophen; codeine therapy, can produce acute withdrawal reactions.
Concomitant use of acetaminophen-codeine with other CNS depressants can potentiate the CNS effects (e.g., sedation) or respiratory depression effects of both of these agents. CNS depressants include amitriptyline, amoxapine, anxiolytics, sedatives, and hypnotics, clomipramine, clozapine, doxepin, dronabinol, THC, droperidol, entacapone, general anesthetics, sedating H1-blockers, haloperidol, imipramine, MAOIs, maprotiline, mirtazapine, molindone, nabilone, nefazodone, nortriptyline, other opiate agonists, olanzapine, phenothiazines, pimozide, pramipexole, pregabalin, quetiapine, risperidone, ropinirole, skeletal muscle relaxants, tolcapone, tramadol and trazodone.
Mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, or pentazocine) may partially block the analgesic, respiratory depressant and CNS depressant effects of pure opiate agonists. These agents may also be used concurrently with some opiate agonists and cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of pure opiate agonist used; antagonistic effects are more common at low to moderate doses of the pure opiate agonist. Due to their antagonistic properties, mixed opiate agonists/antagonists may cause withdrawal symptoms in patients receiving chronic opiate agonists.
Although rare, hepatotoxicity has been reported with echinacea use. A proposed mechanism for the hepatotoxicity associated with echinacea is that some species may contain pyrrolizidine alkaloids; pyrrolizidine alkaloids deplete glutathione, which may increase the risk of liver toxicity, especially when used in conjunction with acetaminophen. The significance of echinacea-induced hepatotoxicity has been challenged as echinacea does not contain the 1,2 unsaturated necrine ring system that is typically associated with pyrrolizidine alkaloid hepatotoxicity. The hepatoxicity could be derived from contaminants, rather than the herb itself. It is prudent to monitor for signs of hepatoxicity if these drugs are coadministered.
[ Last revised: 6/15/2006 1:07:00 PM ]
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