ULTRACET (Page 11 of 12)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

A 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 [see Use in Specific Populations (8.3)].

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.

14 CLINICAL STUDIES

14.1 Single-Dose Studies for Treatment of Acute Pain

In single-dose studies in acute pain, two tablets of ULTRACET 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 ULTRACET was faster than tramadol alone. Onset of analgesia occurred in less than one hour. The duration of pain relief after ULTRACET was longer than acetaminophen alone. Analgesia was generally comparable to that of the comparator, ibuprofen.

16 HOW SUPPLIED/STORAGE AND HANDLING

ULTRACET (tramadol hydrochloride/acetaminophen) tablets containing 37.5 mg tramadol hydrochloride and 325 mg acetaminophen are light yellow, coated, capsule-shaped tablets debossed with “O-M” on one side and “650″ on the other and are available as follows:

100′s: NDC 50458-650-60 Bottles of 100 tablets
HUD 100′s: NDC 50458-650-10 Packages of 100 unit doses in blister packs, 10 cards of 10 tablets each

Dispense in a tight container. Store at 20 – 25°C (68 – 77°F); excursions permitted to 15 – 30°C (59 – 86°F). [see USP Controlled Room Temperature].

Store ULTRACET securely and dispose of properly [see Patient Counseling Information (17)].

17 PATIENT COUNSELING INFORMATION

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

Storage and Disposal

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ULTRACET securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions (5.1, 5.20), Drug Abuse and Dependence (9.2)]. Inform patients that leaving ULTRACET unsecured can pose a deadly risk to others in 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 ULTRACET by following these four steps:

  • Mix ULTRACET (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.

Inform patients that they can visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

Addiction, Abuse, and Misuse

Inform patients that the use of ULTRACET, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1)]. Instruct patients not to share ULTRACET with others and to take steps to protect ULTRACET from theft or misuse.

Life-Threatening Respiratory Depression

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ULTRACET or when the dosage is increased, and that it can occur even at recommended dosages [see Warnings and Precautions (5.3)]. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3)].

Ultra-Rapid Metabolism of Tramadol and Other Risk Factors for Life-threatening Respiratory Depression in Children

Advise caregivers that ULTRACET is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Advise caregivers of children 12 to 18 years of age receiving ULTRACET to monitor for signs of respiratory depression [see Warnings and Precautions (5.4)].

Interactions with Benzodiazepines or Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if ULTRACET is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.8), Drug Interactions (7)].

Serotonin Syndrome

Inform patients that tramadol could cause a rare but potentially life-threatening condition, particularly during concomitant use with serotonergic drugs. Warn patients of the symptoms and signs of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications [see Warnings and Precautions (5.9)].

MAOI Interaction

Inform patients not to take ULTRACET while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ULTRACET [see Drug Interactions (7)].

Seizures

Inform patients that ULTRACET may cause seizures with concomitant use of serotonergic agents (including SSRIs, SNRIs, and triptans) or drugs that significantly reduce the metabolic clearance of tramadol [see Warnings and Precautions (5.10)].

Adrenal Insufficiency

Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.12)].

Important Administration Instructions

Instruct patients how to properly take ULTRACET [see Dosage and Administration (2)].

  • Do not adjust the dose of ULTRACET without consulting with a physician or other healthcare provider.
  • Do not take more than 4000 milligrams of acetaminophen per day and to call their healthcare provider if they took more than the recommended dose.

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue ULTRACET without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.4)].

Hypotension

Inform patients that ULTRACET may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.14)].

Anaphylaxis

Inform patients that anaphylaxis have been reported with ingredients contained in ULTRACET. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4), Warnings and Precautions (5.18), Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that ULTRACET should not be used for more than 5 days and that prolonged use of opioids such as ULTRACET, during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that ULTRACET can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with ULTRACET [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [Use in Specific Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that ULTRACET may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.21)].

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6)].

Maximum Daily Acetaminophen Use

Advise patients not to take more than 4,000 milligrams of acetaminophen per day and call their doctor if they have taken more than the recommended dose [see Warnings and Precautions (5.7, 5.19)].

Use with Other Acetaminophen-Containing Products

Advise patients not to take ULTRACET in combination with other tramadol or acetaminophen-containing products, including over-the-counter preparations [see Warnings and Precautions (5.7, 5.19)].

Manufactured by:
Janssen Ortho LLC
Gurabo, Puerto Rico 00778

Manufactured for:
Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560

© Janssen Pharmaceuticals, Inc. 2003

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 10/2019
Medication Guide ULTRACET® [UHL-truh-set](tramadol hydrochloride/acetaminophen)Tablets, CIV
ULTRACET is:
  • A strong prescription pain medicine that contains an opioid (narcotic) that is used for the short-term (five days or less) management of acute pain, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.
  • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.
Important information about ULTRACET:
  • Get emergency help right away if you take too much ULTRACET (overdose). When you first start taking ULTRACET, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur.
  • ULTRACET can cause severe drowsiness, breathing problems (respiratory depression), coma and death when taken with benzodiazepines or other medicines that depress consciousness.
  • Never give anyone else your ULTRACET. They could die from taking it. Selling or giving away ULTRACET is against the law.
  • Store ULTRACET securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.
  • Get emergency help right away if you take more than 4,000 mg of acetaminophen in 1 day. Taking ULTRACET with other products that contain acetaminophen can lead to serious liver problems and death.
Important Information Guiding Use in Pediatric Patients:
  • Do not give ULTRACET to a child younger than 12 years of age.
  • Do not give ULTRACET to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids.
  • Avoid giving ULTRACET to children between 12 to 18 years of age who have risk factors for breathing problems such as obstructive sleep apnea, obesity, or underlying lung problems.
Do not take ULTRACET if you have:
  • Severe asthma, trouble breathing, or other lung problems.
  • A bowel blockage or have narrowing of the stomach or intestines.
  • An allergy to any of its ingredients (e.g., tramadol hydrochloride or acetaminophen).
  • Taken a Monoamine Oxidase Inhibitor, MAOI, (medicine used for depression) within the last 14 days.
Before taking ULTRACET, tell your healthcare provider if you have a history of:
  • head injury, seizures
  • problems urinating
  • liver, kidney, thyroid problems
  • pancreas or gallbladder problems
  • abuse of street or prescription drugs, alcohol addiction, or mental health problems.
Tell your healthcare provider if you are:
  • pregnant or planning to become pregnant. Prolonged use of ULTRACET during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
  • breastfeeding. Not recommended; it may harm your baby.
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking ULTRACET with certain other medicines can cause serious side effects that could lead to death.
When taking ULTRACET:
  • Do not change your dose. Take ULTRACET exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose: 2 tablets every 4 to 6 hours as needed for pain relief for a maximum of 5 days. Do not take more than your prescribed dose and do not take more than 8 tablets per day. If you miss a dose, take your next dose at your usual time.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • If you have been taking ULTRACET regularly, do not stop taking ULTRACET without talking to your healthcare provider.
  • Dispose of expired, unwanted, or unused ULTRACET by taking your drug to an authorized Drug Enforcement Administration (DEA)-registered collector or drug take-back program. If one is not available, you can dispose of ULTRACET by mixing the product with dirt, cat litter, or coffee grounds; placing the mixture in a sealed plastic bag and throwing the bag in your trash.
While taking ULTRACET DO NOT:
  • Drive or operate heavy machinery, until you know how ULTRACET affects you. ULTRACET can make you sleepy, dizzy, or lightheaded.
  • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ULTRACET may cause you to overdose and die.
The possible side effects of ULTRACET:
  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.
Get emergency medical help if you have:
  • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.
These are not all the possible side effects of ULTRACET. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured by: Janssen Ortho LLC, Gurabo, Puerto Rico 00778. Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, New Jersey 08560, 1-800-526-7736.

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