Zidovudine, ZDV
Ultracet Interactions
NOTE: This monograph discusses the use of this combination product for the management of pain. Clinicians may wish to consult the individual monographs for more information about the specific drug interactions of each agent.
Many prescription and non-prescription medicines contain acetaminophen. High dosages of acetaminophen on a chronic basis can cause depletion of glutathione stores, which can lead to a greater production of the hepatotoxic metabolite, NAPQI.[4925] To limit the hepatotoxic risk of acetaminophen overdosage, avoid concurrent use of products that contain acetaminophen, as the maximum daily dose (i.e., 4 g/day for adults) may be exceeded. Advise patients to carefully read the ingredients of any OTC or prescription products, or to ask their health care provider if they are not sure.[4925]
Enzyme-inducing anticonvulsant agents, such as carbamazepine, oxcarbazepine, barbiturates (e.g., phenobarbital, primidone), ethotoin, phenytoin, or fosphenytoin may induce cytochrome P450 isoenzymes.[4718] The analgesic activity of acetaminophen and tramadol may be reduced.[5043] Anticonvulsants may augment CNS depression seen with tramadol, and tramadol and may decrease the seizure threshold and thus, interfere with the ability of anticonvulsants to control seizures.[4754] Also, an increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1000 mg daily and phenobarbital 100 mg daily 107 and with acetaminophen 1300 - 6200 mg daily and phenytoin. In both cases, acetaminophen cessation led to serum transaminase normalization within 2 weeks.107 [4927] A reduced dose of acetaminophen; tramadol is recommended when used in patients without epilepsy who are receiving barbiturates, due to additive CNS depression. Concomitant usage of tramadol and carbamazepine is not recommended.
As cytochrome P450 isoenzyme inducers, rifampin, rifapentine, or rifabutin could induce the metabolism of acetaminophen; tramadol, altering the clinical response. For example, the analgesic activity of acetaminophen may be reduced. Also, an increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI.[4718] Hepatic failure and encephalopathy has been attributed to the combination of rifampin and acetaminophen. A 32 year-old female with normal prothrombin time and liver function developed a serum alanine transaminase concentration of 450 IU, an international normalized ratio of 5.2, confusion, and agitation 2 days after starting rifampicin 600 mg twice daily. She had been taking 2 - 4 grams of acetaminophen on a daily basis for several weeks. Her liver dysfunction resolved with rifampicin and acetaminophen withdrawal and vitamin K and N-acetylcysteine administration.[4929]
The combination of isoniazid, INH and acetaminophen has caused severe hepatotoxicity.[4930] [4931] Isoniazid, while present in the body, induces the hepatic cytochrome P450 isoenzyme 2E1.[3733] In slow N-acetylators, induction of 2E1 occurs for about 2 weeks after INH clearance by the body. Induction of 2E1 activity may potentially increase the risk for acetaminophen-induced hepatotoxicity via enhanced generation of acetaminophen’s hepatotoxic metabolite, NAPQI.[3733] Concomitant use of INH and acetaminophen when given at the same time resulted in a markedly decreased formation clearance for NAPQI in patients who received INH daily for 6 months. However, decreased formation clearance for NAPQI only persisted in slow acetylators when acetaminophen was administered 12 hours after INH administration. Rapid acetylators had enhanced formation of NAPQI.[4932] Thus, the timing of acetaminophen administration and whether a person is a fast or slow acetylator appears to affect the likelihood of acetaminophen hepatotoxicity..
As the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 may affect the analgesic effect of tramadol. Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor.[5043] Agents that inhibit CPY2D6 include amiodarone [4718], chloroquine[4718], haloperidol [4718], imatinib, STI-571 [4718], gefitinib [5012], ritonavir [4718], terbinafine [4718], propoxyphene [4718], quinacrine [4718], quinine [4718], quinidine [4718], and propafenone [4718]. The list of drugs that inhibit CYP2D6 is not all inclusive. Reduced analgesic effects of tramadol are possible when a concurrent CYP2D6 inhibitor is used.
Administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold. Tricyclic antidepressants and other tricyclic compounds (e.g., cyclobenzaprine) that decrease the seizure threshold have been associated with increased risk of seizures when given concurrently with tramadol.[2543] Other agents that may decrease the seizure threshold include neuroleptics (e.g., phenothiazines), amoxapine, maprotiline, bupropion, clozapine, meperidine, and cocaine. Additive CNS depression and respiratory depression may also occur when some of these agents are given concurrently with acetaminophen; tramadol.[5043] A reduced dose of acetaminophen; tramadol is recommended when used in patients who take a phenothiazine. Also, as the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 by amitriptyline or bupropion may affect the analgesic effect of tramadol.[4718] Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor.[5043]
Use acetaminophen; tramadol extremely cautiously, if at all, in patients also receiving monoamine oxidase inhibitors (MAOIs), including drugs with MAOI activity (e.g., furazolidone, linezolid and procarbazine). Concomitant usage of acetaminophen; tramadol and MAOIs is associated with an increased risk of seizures or serotonin syndrome.[5043] International recommendations contraindicate the concurrent use of tramadol and MAOIs or the use of tramadol within 14 days of discontinuing MAOI therapy.
Tramadol may cause additive CNS and/or respiratory depression when used with other agents that produce these effects, such as opiate agonists. Concomitant use of tramadol and other opiate agonists may increase the risk of seizures; avoid concurrent use whenever possible.[5043] If co-administered, use extreme caution; a reduced acetaminophen; tramadol dose is recommended.
Acetaminophen; tramadol can cause additive CNS depression and respiratory depression when used with other agents that are CNS depressants. A reduced dose of acetaminophen; tramadol is recommended when used in patients who use general anesthetics or anxiolytics, sedatives, and hypnotics. Other agents that may contribute to CNS depression when used with tramadol include mixed opiate agonists/antagonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine), droperidol, dronabinol, THC, entacapone, sedating H1-blockers, molindone, olanzapine, quetiapine, pimozide, risperidone, pramipexole, ropinirole, skeletal muscle relaxants, trazodone, and tolcapone. In addition, chlorpheniramine and diphenhydramine inhibit CYP2D6, an enzyme responsible for the metabolism of tramadol.[4718] Close monitoring for side effects in patients receiving tramadol-containing products and chlorpheniramine or diphenhydramine is recommended. Extreme caution is needed during concomitant use of any CNS-depressant drugs and acetaminophen; tramadol.
The risk of seizures and serotonin syndrome may be enhanced by concurrent use of tramadol and selective serotonin reuptake inhibitors(SSRIs).[5043] Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures.[2543] Several cases of serotonin syndrome have been reported following the administration of tramadol with a SSRI.[5933] [6683] [6684] Citalopram [4718], escitalopram [4718], fluoxetine [5043], paroxetine [5043], and sertraline [4718] inhibit the formation of the active M1 metabolite of tramadol by inhibiting cytochrome P450 2D6. The inhibition of M1 formation may decrease the analgesic effectiveness of tramadol but increase the serum concentration of the parent compound.
Medications that decrease the reuptake of serotonin, such as serotonin norepinephrine reuptake inhibitors (e.g., duloxetine or venlafaxine), or nefazodone may cause serotonin syndrome in patients taking tramadol.[5043] Also, additive CNS depression may occur when tramadol is used with a mirtazapine or nefazodone. The addition of tramadol to extended-release venlafaxine 300 mg/day and mirtazapine 30 mg/day likely caused serotonin syndrome. A patient developed agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever within 7 weeks of taking tramadol 400 mg daily. He had taken 300 mg tramadol without difficulty. Discontinuation of the 3 drugs and rehydration led to symptom resolution over 36 hours. Reinstitution of the antidepressants 3 days after patient presentation was uneventful.[6687]
Medications that decrease the reuptake of serotonin, such as St. John’s wort, Hypericum perforatum, may cause serotonin syndrome in patients taking tramadol.[5043] Also about 10 - 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 (major pathway), 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).[2678] Thus, theoretically St. John’s wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.[4935]
The risk of developing hepatotoxicity and dangerous CNS or respiratory depression from acetaminophen; tramadol appears to be increased in patients who consume ethanol. Chronic ethanol use can increase acetaminophen-induced hepatotoxicity by inducing cytochrome P450 (CYP) 2E1, which leads to an increased formation of the hepatotoxic metabolite.583 Also, chronic ethanol use depletes liver glutathione stores.[4934] Furthermore, alcohol withdrawal is associated with a seizure risk, and tramadol appears to increase the risk of seizure development.[5043] Ethanol should not be consumed while taking acetaminophen; tramadol, and acute intoxication with alcohol is a contraindication for acetaminophen; tramadol usage.
Naloxone should be used cautiously in situations of acetaminophen; tramadol overdose. Naloxone administration may increase the risk of seizures in patients receiving tramadol.[5043] Naloxone will reverse some but not all symptoms caused by tramadol overdosage.
An increased incidence of digoxin toxicity has been reported during post-marketing reports with the concurrent use of tramadol and digoxin.[5043] If concurrently used, monitor serum digoxin concentrations, especially after the initiation and cessation of acetaminophen; tramadol.
Significant drug interactions may occur between acetaminophen; tramadol and warfarin. Acetaminophen has been shown to augment the hypoprothrombinemic response to warfarin in a dose-dependent manner when given in large doses for an extended period of time.[1628] [2678] Both INR prolongation and clinical bleeding have been reported during acetaminophen therapy. Also, elevation of prothrombin times during concurrent tramadol and warfarin usage has been reported rarely during the post-marketing period.[5043] Increased INRs have been reported in patients previously stabilized on warfarin who start taking tramadol.[6685] [6686] The mechanism of the interaction is unknown; tramadol is not highly protein bound and is not known to affect enzymes associated with the metabolism of warfarin. Careful monitoring of a patient’s INR is recommended after initiation and cessation of acetaminophen; tramadol. Another alternative analgesic agent may be warranted in patients receiving warfarin.
Sulfinpyrazone can induce hepatic microsomal enzymes that metabolize acetaminophen. Sulfinpyrazone has been shown to increase acetaminophen clearance by roughly 23%.[4939] The risk for acetaminophen hepatotoxicity may be increased due to the formation of higher amounts of toxic acetaminophen metabolites. The risk of acetaminophen hepatotoxicity in patients taking sulfinpyrazone increases with larger acetaminophen doses, particularly overdoses.
Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. In a case-controlled study of patients with early renal failure, the regular use of aspirin and acetaminophen was associated with an odds ratio of 2.2 (95% confidence interval 1.4 to 3.5) when regular aspirin users were the reference group.[4064] The trend toward greater risk with an increasing cumulative life-time dose of acetaminophen was statistically significant with a risk that was 2.4-times as high for subjects who had consumed a total > 500 g of acetaminophen in combination with aspirin than for those who had used aspirin alone. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy, such as may occur with acetaminophen; tramadol.
Use of acetaminophen prior to (<72 hours) or concurrently with busulfan may result in decreased clearance of busulfan due to acetaminophen-induced decreases in glutathione levels.[4749] Busulfan is metabolized in the liver through conjugation with glutathione, which is catalyzed by glutathione S-transferase. During high-dose busulfan treatment, glutathione hepatocellular concentrations may be depleted. As the hepatotoxic metabolite of acetaminophen, NAPQI, is inactivated by conjugation with glutathione, the risk of acetaminophen-related hepatotoxicity may be increased.[4943]
Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.[5099]
Patients treated with prilocaine who are receiving acetaminophen concurrently are at greater risk for developing methemoglobinemia.[5799]
The o-toluidine metabolite of prilocaine can cause the formation of methemoglobin, which can lead to methemoglobinemia. Also, acetaminophen can cause methemoglobinemia. Patients treated concurrently with prilocaine and acetaminophen; tramadol need to be monitored for the development of hemolytic anemia.
Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. Data suggest that acetaminophen glucuronidation is competitively inhibited by zidovudine, whereas zidovudine glucuronidation is only slightly inhibited by acetaminophen. As more acetaminophen is oxidized, glutathione reserves are needed to detoxify the hepatotoxic intermediate, NAPQI. Thus, the interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism. Also, patients taking an inducer of 2E1 or 1A2 with zidovudine and acetaminophen will have greater production of NAPQI and thus, a greater likelihood of hepatotoxicity.[4928]
Tobacco smoking induces the cytochrome P450 isoenzyme CYP1A2 [4718] and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen’s hepatotoxic metabolite, NAPQI. In one study, current tobacco smoking was found to be very frequent in patients admitted with acetaminophen poisoning. Tobacco smoking appears to be an independent risk factor of severe hepatotoxicity, acute liver failure and death following acetaminophen overdose.[4940]
Excessive sedation and other central nervous system depressant effects may occur with concomitant valerian and acetaminophen; tramadol use. The valerian derivative, dihydrovaltrate binds at barbiturate binding sites. Also, valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain, and the non-volatile monoterpenes (valepotriates) have sedative activity.[4933]
[ Last revised: 12/6/2004 2:09:00 PM ]
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