TAP 325

In moderate to severe pain

Children younger than 12 years of age

Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Significant respiratory depression.

Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment.

Known or suspected gastrointestinal obstruction, including paralytic ileus.

Previous hypersensitivity to tramadol hydrochloride, acetaminophen, any other component of this product, or opioids.

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

Tramadol Hydrochloride IP: Tramadol is an opioid analgesic that works by binding to mu-opioid receptors in the central nervous system. It also inhibits the reuptake of serotonin and norepinephrine, which contributes to its analgesic effects. Tramadol's pain-relieving properties make it useful for managing moderate to moderately severe pain.

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Acetaminophen (Paracetamol) IP: The exact mechanism of action of acetaminophen is not fully understood. It is believed to inhibit an enzyme in the brain called cyclooxygenase (COX). Unlike nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, acetaminophen has minimal antiinflammatory effects. It is primarily used for its analgesic (pain-relieving) and antipyretic (fever-reducing) properties.

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• Serotonin Syndrome:May be life-threatening. Can occur with use of tramadol alone, with concomitant use of serotonergic drugs, with drugs that impair metabolism of serotonin or tramadol.
• Risk of Seizure: Can occur at the recommended dose of tramadol. Concomitant use with other drugs may increase seizure risk. Risk may increase in patients with epilepsy, a history of seizures, and in patients with a recognized risk for seizures.
• Risk of Suicide:Do not prescribe for suicidal or addiction-prone patients.
• Adrenal Insufficiency:If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid.
• Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients:Monitor closely, particularly during initiation and titration.
• Severe Hypotension: Monitor during dosage initiation and titration. Avoid use of TAP 325 in patients with circulatory shock.
• Risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness: Monitor for sedation and respiratory depression. Avoid use of TAP 325 in patients with impaired consciousness or coma.

Analgesic

• Benzodiazepines and Other Central Nervous System (CNS) Depressants:

  Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

• Serotonergic Drugs:

  The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

• Monoamine Oxidase Inhibitors (MAOIs):

  MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma)

• Muscle Relaxants:

  Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

• Diuretics:

  Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

• Anticholinergic Drugs:

  The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

The most common incidence of treatment-emergent adverse events in patients from clinical trials were constipation, diarrhoea, nausea, somnolence, anorexia, dizziness, and sweating increased.

OD, BID & SOS

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store TAP 325 securely, out of sight and reach of children, and in a location not accessible by others.

There are no animal or laboratory studies on the combination product (tramadol and acetaminophen) to evaluate carcinogenesis, mutagenesis, or impairment of fertility. Data on the individual components are described below.

Carcinogenesis

slight but statistically significant increase in two common murine tumors, pulmonary and hepatic, was observed in an NMRI mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg in the drinking water (0.5 times the maximum recommended daily human dosage or MRHD) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No evidence of carcinogenicity was noted in a rat 2-year carcinogenicity study testing oral doses of up to 30 mg/kg in the drinking water (1 times the MRHD).

Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen. In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 1.2 times the maximum human daily dose (MHDD) of 2.6 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats (1.1 times) or mice (1.9-2.2 times the MHDD, based on a body surface area comparison).

Mutagenesis

Tramadol was mutagenic in the presence of metabolic activation in the mouse lymphoma assay. Tramadol was not mutagenic in the in vitro bacterial reverse mutation assay using Salmonella and E. coli (Ames), the mouse lymphoma assay in the absence of metabolic activation, the in vitro chromosomal aberration assay, or the in vivo micronucleus assay in bone marrow.

Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test). In contrast, acetaminophen tested positive for induction of sister chromatid exchanges and chromosomal aberrations in in vitro assays using Chinese hamster ovary cells. In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (2.8-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.

Impairment of Fertility

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. These dosages are 1.6 and 2.4 times the MRHD.

In studies of acetaminophen conducted by the National Toxicology Program, fertility assessments have been completed in Swiss mice via a continuous breeding study. There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, there was a significant increase in the percentage of abnormal sperm in mice consuming 1.7 times the MHDD (based on a body surface area comparison) and there was a reduction in the number of mating pairs producing a fifth litter at this dose, suggesting the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical significance of these findings is not known.

Single-Dose Studies for Treatment of Acute Pain

In single-dose studies in acute pain, two tablets of TAP 325 administered to patients with pain following oral surgical procedures provided greater relief than placebo or either of the individual components given at the same dose. The onset of pain relief after TAP 325 was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after TAP 325 was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen

Advise the patient to read the FDA-approved patient labelling (Medication Guide).

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store TAP 325 securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Inform patients that medicine take-back options are the preferred way to safely dispose of most types of unneeded medicines. If no take back programs or Drug Enforcement Administration (DEA)-registered collectors are available, instruct patients to dispose of TAP 325 by following these four steps:

• Mix TAP 325 (do not crush) with an unpalatable substance such as dirt, cat litter, or used coffee grounds;
• Place the mixture in a container such as a sealed plastic bag;
• Throw the container in the household trash;
• Delete all personal information on the prescription label of the empty bottle.

• Abbreviations:

  MRHD – Maximum Recommended Human Dose
• MHDD - Maximum Human Daily Dose