Ultracet Contraindications/Precautions

abrupt discontinuation
acetaminophen hypersensitivity
ethanol intoxication
opiate agonist hypersensitivity
alcoholism
anemia
asthma
bone marrow suppression
breast-feeding
children
driving or operating machinery
elderly
G6PD deficiency
GI disease
head trauma
hepatic disease
hepatitis
immunosuppression
increased intracranial pressure
infection
labor
neutropenia
obstetric delivery
pregnancy
renal failure
renal impairment
respiratory depression
salicylate hypersensitivity
seizure disorder
seizures
substance abuse

Ultracet Contraindications/Precautions

NOTE: This monograph discusses the use of the acetaminophen; tramadol combination product for the management of pain. Clinicians may wish to consult the individual monographs for more information about the specific precautions and contraindications of each agent.

Acetaminophen; tramadol combinations should not be used in a patient with a known acetaminophen hypersensitivity. Acetaminophen hypersensitivity reactions are rare, but severe sensitivity reactions are possible. Patients who have demonstrated a prior opiate agonist hypersensitivity reaction to codeine or other opiate agonists should not receive tramadol because there is an increased risk of developing anaphylactoid reactions to tramadol. Postmarketing surveillance has revealed reports of anaphylactoid reactions following the initial tramadol dose, particularly in patients with a history of codeine hypersensitivity. Any patient who is hypersensitive to tramadol, acetaminophen or any of the components in the commercial formulation should not receive acetaminophen; tramadol.

Normal and excessive doses of tramadol have been associated with seizure activity. Additionally, tramadol should be used with caution in patients who are at risk of seizures including those who have a pre-existing seizure disorder, are receiving medications which reduce the seizure threshold, who have certain medical conditions (i.e., increased intracranial pressure, CNS infection, head trauma), or who are experiencing ethanol or illicit drug withdrawal. In tramadol overdose, naloxone administration may increase the risk of seizure. In addition, administration of tramadol to patients with increased intracranial pressure or head trauma may obscure the existence, extent, or course of intracranial pathology because tramadol induces pupillary changes (miosis).

Acetaminophen; tramadol is contraindicated for use in patients with hepatic disease, hepatitis or alcoholism as both agents are extensively metabolized in the liver. The use of acetaminophen; tramadol is contraindicated in cases of acute ethanol intoxication and intoxication with other agents such as opiate agonists, hypnotics, centrally acting analgesics, or psychotropic drugs. Acetaminophen; tramadol should not be used with alcohol. Alcoholic patients are at risk for acetaminophen-induced hepatotoxicity as well as increased seizure activity with tramadol. Acetaminophen-induced hepatotoxicity should be suspected in alcoholic patients with aminotransferase levels > 1000 U/L and acetaminophen blood levels should be checked in these patients. Patients using acetaminophen; tramadol should be warned not to consume additional OTC acetaminophen or prescription tramadol due to the potential for overdose.

Acetaminophen should be used cautiously in patients with asthma who also have salicylate hypersensitivity. Of 50 patients with aspirin-sensitive asthma, 17 had either a naso-ocular or bronchospastic reaction after ingestion of either 1000 mg or 1500 mg of acetaminophen. The magnitude of FEV1 decline after a mean aspirin dose of 47 mg was similar to the decline seen after a mean acetaminophen dose of 1227 mg. The lower the aspirin provocative dose, the more likely patients were to cross-react to acetaminophen. For example, 5 of 6 patients with aspirin-induced bronchospasm after a dose of 30 mg or less had cross-reactivity to acetaminophen whereas no patients had cross-reactivity when the provocative aspirin dose was at least 150 mg. The acetaminophen challenges were performed before any aspirin challenges and all patients had a measured FEV1 of at least 70% of predicted or best previously recorded value, an absolute value greater than 1.5 liters, and a fall of less than 15% in FEV1 from morning baseline during placebo challenges._[1112]

Administer acetaminophen; tramadol with caution to patients at risk for respiratory depression. Alternative non-opioid analgesics should be considered. Respiratory depression is possible with large doses of tramadol, especially when given concurrently with ethanol, anesthetic agents or other respiratory depressants. If respiratory depression occurs, treat as an overdose; however, administer naloxone cautiously in these situations due to an increased risk of seizures.

Tramadol should be used with caution in patients with GI disease. It may be difficult to assess the condition of patients with acute abdominal conditions if they are taking tramadol.

Acetaminophen; tramadol should not be used in patients with a current or previous opioid substance abuse problem. The risk for dependence is not limited to patients with a previous opioid abuse history. Tramadol has been shown to reinitiate physical dependence in some patients. Patients who have recently taken substantial amounts of opiate agonists may experience withdrawal symptoms after treatment with tramadol. Psychologic dependence similar to that of codeine or dextropropoxyphene is possible with tramadol.

To prevent withdrawal symptoms, avoid abrupt discontinuation of tramadol. Withdrawal symptoms may include anxiety, sweating, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, panic attacks, severe anxiety, paresthesias, and hallucinations (rarely). Clinical experience suggests that withdrawal symptoms may be relieved by tapering the dosage of tramadol.

Tramadol should be administered with caution to patients with renal impairment or renal failure. Impaired renal function affects the rate and extent of excretion for both tramadol and its active metabolite M1. Dosage reductions are recommended if creatinine clearance falls below 30 ml/min. It may take several days for elevated plasma concentrations and toxicity to develop.

Acetaminophen; tramadol is classified as FDA pregnancy risk category C. Studies have not assessed tramadol use during human pregnancy; it should only be given if the need clearly outweighs the risk. Tramadol crosses the placenta and the effects on postnatal growth, development and functional maturation of the fetus are unknown. Neonatal seizures, neonatal withdrawal syndrome, fetal death, and still birth have been reported with chronic use of tramadol during pregnancy. High dosage levels in animal studies show tramadol as embryotoxic and fetotoxic but not teratogenic. Tramadol should not be given to women prior to labor, or during obstetric delivery unless the benefits outweigh the risk. Tramadol has been used outside the U.S. for the management of pain associated with labor. The effect of tramadol on respiratory depression in the neonate has been studied and was not significantly different from that following the administration of morphine or meperidine._[902] No overall increase in fetal mortality, as determined by pregnancy outcomes of mothers that overdosed on various amounts of acetaminophen, was apparent amongst 300 women._[4441] Treatment with acetylcysteine or methionine did not appear to affect fetal or neonatal toxicity. Of 235 infants exposed to an overdose of only acetaminophen, 168 were normal, 8 had malformations, 16 were spontaneously aborted, and 43 were electively terminated. Of 67 infants exposed to an overdose of a combination acetaminophen product, 51 were normal, 3 had malformations, 2 were spontaneously aborted (late fetal deaths), and 11 were electively terminated. None of the infants with malformations were exposed during the first trimester, but all of the spontaneous abortions and one of the late fetal deaths were subsequent to first trimester exposure.

Tramadol and its metabolites are excreted into human milk in small amounts. Acetaminophen also crosses into breast milk, with a concentration ranging from 0.1-1.85% of the maternal dose. According to the American Academy of Pediatrics (AAP), acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast-feeding._[4201] The AAP regards acetaminophen as a maternal medicine that is usually compatible with breast-feeding. No recommendations are available from AAP for tramadol. Because of the potential for serious adverse reactions in breast-fed infants, including respiratory depression, alternative analgesics to acetaminophen; tramadol should be considered for a woman who is breast-feeding her infant.

In studies looking at the single agent tramadol, elderly patients > 75 years experienced slightly elevated serum concentrations and a prolonged elimination half-life. In elderly patients >= 65 years of age, the pharmacokinetics of acetaminophen; tramadol were not altered. In general, elderly patients will vary in their tolerance of acetaminophen; tramadol. Although specific guidelines are not available, a lower starting dose, slower dose titration, and a lower maximum daily dose may be prudent in these patients.

In the US, the safety and efficacy of tramadol in children < 16 years of age have not been established. Acetaminophen in appropriate dosages is safe for use in children. The manufacturers of acetaminophen; tramadol recommend that it only be used in adult patients.

Patients should be warned against driving or operating machinery until they know how acetaminophen; tramadol may affect them. Tramadol may affect the ability to safely perform hazardous tasks.

Overdose with acetaminophen may lead to hepatic necrosis, hepatic failure and death. Emergency help should be sought immediately for suspected acetaminophen overdose. Patients with G6PD deficiency who overdose with acetaminophen may be at increased risk for drug-induced hemolysis. During acetaminophen overdose, cyanosis may not be apparent in patients with pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin.

Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen in patients with bone marrow suppression, especially neutropenia or immunosuppression.

Acetaminophen may interfere with some home blood glucose monitoring systems resulting in decreases of > 20% in mean glucose values. This effect seems to be drug, concentration and system dependent.
[ Last revised: 7/23/2004 3:39:00 PM ]

References
₉₀₂. Prasetsawat PO, Herbabutya Y, Chaturachinda K. Obstetric analgesia: comparison of tramadol, morphine, and pethidine. Curr Ther Res 1986;40:1022 - 8.
₁₁₁₂. Settipane RA et al. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol 1995;96:480 - 5.
₄₂₀₁. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776 - 89.
₄₄₄₁. McElhatton PR, Sullivan FM, Volans GN. Paracetamol overdose in pregnancy. Analysis of the outcomes of 300 cases referred to the teratology information service. Reproductive Toxicol 1997;11:85 - 94.

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