Ultracet

Ultracet

tramadol + paracetamol

Manufacturer:

Janssen-Cilag

Distributor:

DKSH
Full Prescribing Info
Contents
Tramadol HCl, paracetamol.
Description
Each tablet contains tramadol HCl 37.5 mg and paracetamol 325 mg. It also contains the following inactive ingredients: Powdered cellulose, pregelatinized starch, sodium starch glycolate, starch, purified water, magnesium stearate, Opadry Light Yellow and carnauba wax.
Tramadol HCl is (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.
Paracetamol is N-acetyl-p-aminophenol (4-hydroxyacetanilide).
Action
Pharmacology: Tramadol is a centrally acting analgesic compound. At least 2 complementary mechanisms appear applicable, binding of parent and M1 metabolite to mu-opioid receptors and weak inhibition of re-uptake of norepinephrine and serotonin.
Paracetamol is another centrally acting analgesic. The exact site and mechanism of its analgesic action is not clearly defined.
When evaluated in a standard animal model, the combination of tramadol and paracetamol exhibited a synergistic effect.
Pharmacokinetics: General: Tramadol is administered as a racemate and both the (-) and (+) forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and paracetamol following oral administration of 1 Ultracet tablet are shown in the table. Tramadol has a slower absorption and longer half-life when compared to paracetamol. (See table.)
After a single oral dose of 1 tramadol/paracetamol combination tablet (37.5 mg/325 mg), peak plasma concentrations of 64.3/55.5 ng/mL [(+)-tramadol/(-)-tramadol] and 4.2 mcg/mL (paracetamol) are reached after 1.8 hrs [(+)-tramadol/(-)-tramadol] and 0.9 hrs (paracetamol), respectively. Mean elimination half-lives (t1/2) are 5.1/4.7 hrs [(+)-tramadol/(-)-tramadol] and 2.5 hrs (paracetamol).
Single- and multiple-dose pharmacokinetic studies of Ultracet in volunteers showed no significant drug interactions between tramadol and paracetamol.

Click on icon to see table/diagram/image

Absorption: Tramadol HCl has a mean absolute bioavailability of approximately 75% following administration of a single 100-mg oral dose of tramadol tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of 2 Ultracet tablets occurs at approximately 2 and 3 hrs, respectively, postdose in healthy adults.
Oral absorption of paracetamol following administration of Ultracet is rapid and almost complete and occurs primarily in the small intestine. Peak plasma concentrations of paracetamol occur within 1 hr and are not affected by co-administration with tramadol.
Food Effects: The oral administration of Ultracet with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol, so that Ultracet can be taken independently of meal times.
Distribution: The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100-mg IV dose. The binding of tramadol to human plasma proteins is approximately 20%.
Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg.
A relative small portion (~20%) of paracetamol is bound to plasma protein.
Metabolism: Plasma concentration profiles for tramadol and its M1 metabolite measured following dosing of Ultracet in volunteers showed no significant change compared to dosing with tramadol alone.
Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Tramadol is extensively metabolized by a number of pathways, including CYP2D6.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves 3 principle separate pathways: Conjugation with glucuronide; conjugation with sulfate; and oxidation via cytochrome P-450 enzyme pathway.
Elimination: Tramadol and its metabolites are eliminated primarily by the kidney. The plasma elimination half-lives of racemic tramadol and M1 are approximately 6 and 7 hrs, respectively. The plasma elimination half-life of racemic tramadol increased from approximately 6-7 hrs upon multiple dosing of Ultracet.
The half-life of paracetamol is about 2-3 hrs in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.
Toxicology: Preclinical Safety Data: Tramadol/Paracetamol Combination: There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis or impairment of fertility.
No drug-related teratogenic effects were observed in the progeny of rats treated orally with the combination of tramadol and paracetamol. The tramadol/paracetamol combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose (50/434 mg/kg tramadol/paracetamol) 8.3 times the maximum human dose but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Lower and less severe maternally toxic dosages (10/87 and 25/217 mg/kg tramadol/paracetamol) did not produce embryo or fetal toxicity.
Carcinogenicity/Mutagenicity: Tramadol HCl: A slight but statistically significant increase in 2 common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30 mg/kg for approximately 2 years, although the study was not done with the maximum tolerated dose). This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters.
Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
Impairment of Fertility/Effect on Reproduction: No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.
Tramadol was evaluated in peri- and postnatal studies in rats. Progeny of dams receiving oral (gavage) dose levels of ≥50 mg/kg had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6-10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol in this study, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.
Indications/Uses
Management of moderate to severe pain.
Dosage/Direction for Use
Unless otherwise prescribed, Ultracet should be administered as follows:
Adults and Children >16 years: The maximum single dose is 1-2 tabs every 4-6 hrs as needed for pain relief up to a maximum of 8 tabs/day.
Ultracet can be administered without regard to food.
Elderly: No overall differences with regard to safety or pharmacokinetics were noted between subjects ≥65 years and younger subjects.
Overdosage
Ultracet is a combination product. The clinical presentation of overdose may include the signs and symptoms of tramadol toxicity, paracetamol toxicity or both. The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. The initial symptoms seen within the first 24 hrs following a paracetamol overdose may include: Gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor and diaphoresis.
Human Experience: Tramadol: Serious potential consequences of overdosage of the tramadol component are respiratory depression, lethargy, coma, seizure, cardiac arrest and death.
Paracetamol: In massive overdosage, paracetamol may cause hepatic toxicity in some patients. Early symptoms following a potentially hepatotoxic overdosage may include: Gastrointestinal irritability, anorexia, nausea, vomiting, malaise, pallor and diaphoresis. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48-72 hrs post-ingestion.
Treatment: A single or multiple overdose with Ultracet may be a potentially lethal polydrug overdose, and appropriate expert consultation, if available, is recommended.
While naloxone will reverse some, but not all, symptoms caused by overdose with tramadol, the risk of seizures is also increased with naloxone administration. Based on experience with tramadol, hemodialysis is not expected to be helpful in an overdose because it removes <7% of the administered dose in a 4-hr dialysis period.
In treating an overdosage of Ultracet, primary attention should be given to maintaining adequate ventilation along with general supportive treatment. Measures should be taken to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The 1st dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic in etiology and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endotracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration.
In adult and pediatric patients, any individual presenting with an unknown amount of paracetamol ingested or with a questionable or unreliable history about the time of ingestion should have a plasma paracetamol level drawn and be treated with acetylcysteine. If an assay cannot be obtained and the estimated paracetamol ingestion exceeds 7.5-10 g for adults and adolescents or 150 mg/kg for children, dosing with N-acetylcysteine should be initiated and continued for a full course of therapy.
Contraindications
Patients who have previously demonstrated hypersensitivity to tramadol, paracetamol or any other component of Ultracet or opioids. In cases of acute intoxication with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs.
Special Precautions
Seizures: Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking: Selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), tricyclic antidepressants (TCAs) and other tricyclic compounds (eg, cyclobenzaprine, promethazine, etc) or opioids.
Administration of tramadol may enhance the seizure risk in patients taking: MAO inhibitors, neuroleptics or other drugs that reduce the seizure threshold.
Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (eg, head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, naloxone administration may increase the risk of seizure.
Anaphylactoid Reactions: Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Ultracet.
Respiratory Depression: Administer Ultracet cautiously in patients at risk for respiratory depression. When large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Treat such cases as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.
Use with CNS Depressants: Ultracet should be used with caution and in reduced dosages when administered to patients receiving CNS depressants eg, alcohol, opioids, anesthetic agents, phenothiazines, tranquilizers or sedative hypnotics.
Increased Intracranial Pressure or Head Trauma: Ultracet should be used with caution in patients with increased intracranial pressure or head injury.
Use in Opioid-Dependent Patients: Ultracet should not be used in opioid-dependent patients. Tramadol has been shown to reinitiate physical dependence in some patients that have been previously dependent on other opioids.
Use with Alcohol: Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive paracetamol use.
Withdrawal: Withdrawal symptoms may occur if Ultracet is discontinued abruptly. Panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms have also been very rarely reported with abrupt discontinuation of tramadol HCl. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication.
Use with MAO Inhibitors and Serotonin Reuptake Inhibitors: Use Ultracet with great caution in patients taking MAO inhibitors. Concomitant use of tramadol with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.
Use in Renal Disease: Ultracet has not been studied in patients with impaired renal function. In patients with creatinine clearances of <30 mL/min, it is recommended that the dosing interval be increased not to exceed 2 tablets every 12 hrs.
Use in Hepatic Disease: The use in patients with severe hepatic impairment is not recommended.
General Precautions: The recommended dose of Ultracet should not be exceeded.
Ultracet should not be co-administered with other tramadol- or paracetamol-containing products.
Effects on the Ability to Drive or Operate Machinery: Ultracet may impair mental or physical abilities required for the performance of potentially hazardous tasks eg, driving a car or operating machinery.
Use in children: The safety and effectiveness of Ultracet has not been established in the pediatric population (children <16 years).
Use In Pregnancy & Lactation
Tramadol has been shown to cross the placenta. There are no adequate and well-controlled studies in pregnant women.
Safe use in pregnancy has not been established. Ultracet is not recommended for nursing mothers because its safety in infants and newborns has not been studied.
Adverse Reactions
The most frequently reported events were in the central nervous system and gastrointestinal system.
The most common reported events were nausea, dizziness and somnolence.
In addition, the following effects have been frequently observed, though the frequency is generally lower:
Body as a Whole: Asthenia, fatigue, hot flushes.
Central and Peripheral Nervous System: Headache, tremor.
Gastrointestinal System: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, vomiting.
Psychiatric Disorders: Anorexia, anxiety, confusion, euphoria, insomnia, nervousness.
Skin and Appendages: Pruritus, rash, increased sweating.
Uncommon reported clinically significant adverse experiences with at least a possible causal link to Ultracet include:
Body as a Whole: Chest pain, rigors, syncope, withdrawal syndrome.
Cardiovascular Disorders: Hypertension, aggravated hypertension, hypotension.
Central and Peripheral Nervous System: Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paraesthesia, stupor, vertigo.
Gastrointestinal System: Dysphagia, melena, tongue edema.
Hearing and Vestibular Disorders: Tinnitus.
Heart Rate and Rhythm Disorders: Arrhythmia, palpitation, tachycardia.
Liver and Biliary System: Liver test abnormalities.
Metabolic and Nutritional Disorders: Decreased weight.
Psychiatric Disorders: Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, bad dreams, abnormal thinking.
Red Blood Cell Disorders: Anemia.
Respiratory System: Dyspnea.
Urinary System: Albuminuria, micturition disorder, oliguria, urinary retention.
Vision Disorders: Abnormal vision.
Other clinically significant adverse experiences previously reported in clinical trials or post-marketing reports with tramadol HCl: Other events which have been reported with the use of tramadol products include: Orthostatic hypotension, allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS), cognitive dysfunction, suicidal tendency and hepatitis. Reported laboratory abnormalities included elevated creatinine. Serotonin syndrome (whose symptoms may include fever, excitation, shivering and agitation) has been reported with tramadol when used concomitantly with other serotonergic agents eg, SSRIs and MAO inhibitors. Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
Other clinically significant adverse experiences previously reported in clinical trials or post-marketing reports with paracetamol: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to paracetamol are rare and generally controlled by discontinuation of the drug, and when necessary, symptomatic treatment. There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.
Drug Interactions
Management of moderate to severe pain.
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Store in the original package.
MIMS Class
ATC Classification
N02AJ13 - tramadol and paracetamol ; Belongs to the class of opioids in combination with other non-opioid analgesics. Used to relieve pain.
Presentation/Packing
Caplet (light yellow, film-coated, capsule-shaped, debossed with "J-C" on one side and "T/P" on the other) 3 x 10's.
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