TRAMADOL HYDROCHLORIDE (Page 10 of 11)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 (0.36 times the 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, 0.73 times the MRHD.

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.

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 1.2 and 1.8 times the maximum recommended human daily dose based on body surface area, respectively.

14 CLINICAL STUDIES

Tramadol hydrochloride has been given in single oral doses of 50 mg, 75 mg and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).

In single-dose models of pain following oral surgery, pain relief was demonstrated in some patients at doses of 50 mg and 75 mg. A dose of 100 mg tramadol hydrochloride tended to provide analgesia superior to codeine sulfate 60 mg, but it was not as effective as the combination of aspirin 650 mg with codeine phosphate 60 mg.

Tramadol hydrochloride has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol hydrochloride. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration. Average daily doses of approximately 250 mg of tramadol hydrochloride in divided doses were generally comparable to five doses of acetaminophen 300 mg with codeine phosphate 30 mg (TYLENOL with Codeine #3) daily, five doses of aspirin 325 mg with codeine phosphate 30 mg daily, or two to three doses of acetaminophen 500 mg with oxycodone hydrochloride 5 mg (TYLOX) daily.

Titration Trials

In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily tramadol hydrochloride dose of 200 mg (50 mg four times per day), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration.

16 HOW SUPPLIED/STORAGE AND HANDLING

Bottles of 100 tablets with child-resistant closure: NDC 69543-136-10

Bottles of 500 tablets: NDC 69543-136-50

Bottles of 1000 tablets: NDC 69543-136-11

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

Store tramadol hydrochloride tablets 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 tramadol hydrochloride tablets 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, 5.17), Drug Abuse and Dependence (9.2)]. Inform patients that leaving tramadol hydrochloride tablets 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 tramadol hydrochloride tablets by following these four steps:

•

Mix tramadol hydrochloride tablets (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 tramadol hydrochloride tablets, 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 tramadol hydrochloride tablets with others and to take steps to protect tramadol hydrochloride tablets 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 tramadol hydrochloride tablets 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 tramadol hydrochloride tablets are 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 ages 12 to 18 years of age receiving tramadol hydrochloride tablets to monitor for signs of respiratory depression [see Warnings and Precautions (5.4)].

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if tramadol hydrochloride tablets are used with benzodiazepines, CNS depressants, including alcohol, or some illicit drugs and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.7); Drug Interactions (7)].

Serotonin Syndrome

Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms 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 (5.8)].

Seizures

Inform patients that tramadol hydrochloride tablets 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 (5.9)].

MAOI Interaction

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

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 (5.11)].

Important Administration Instructions

•

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

•

Advise patients not to adjust the dose of tramadol hydrochloride tablets without consulting with a physician or other healthcare professional.

Important Discontinuation Instructions

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

Hypotension

Inform patients that tramadol hydrochloride tablets 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 (5.13)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in tramadol hydrochloride tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4); Warnings and Precautions (5.16); Adverse Reactions (6)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of tramadol hydrochloride tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated and that the patient should inform their healthcare provider if they have used opioids at any time during their pregnancy, especially near the time of birth. [see Warnings and Precautions (5.5); Use in Special Populations (8.1)].

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that tramadol hydrochloride tablets may cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Special Populations (8.1)].

Lactation

Advise women that breastfeeding is not recommended during treatment with tramadol hydrochloride tablets [see Warnings and Precautions (5.4); Use in Special 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 [see Use in Special Populations (8.3)].

Driving or Operating Heavy Machinery

Inform patients that tramadol hydrochloride tablets 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 (5.18)].

Constipation

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

Maximum single-dose and 24-hour dose

Advise patients not to exceed the single-dose and 24-hour dose limit and the time interval between doses, since exceeding these recommendations can result in respiratory depression, seizures and death [see Dosage and Administration (2); Warnings and Precautions (5.3)].

All Product/Brand names are the trademarks of their respective owners.

Distributed by:
Virtus Pharmaceuticals, LLC
Langhorne, PA 19047 USA
1-888-848-3593
vpi-rv-102019
Manufactured by:
CSPC Ouyi Pharmaceutical Co., Ltd. Shijiazhuang, China, 052160

Medication Guide Tramadol Hydrochloride Tablets, USP (tram’ a dol hye” droe klor’ ide) CIV
Tramadol hydrochloride tablets are: • A strong prescription pain medicine that contains an opioid (narcotic) that is used for the management pain in adults, 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 tramadol hydrochloride tablets: • Get emergency help right away if you take too much tramadol hydrochloride tablets (overdose). When you first start taking tramadol hydrochloride tablets, 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. • Taking tramadol hydrochloride tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Never give anyone else your tramadol hydrochloride tablets. They could die from taking it. Selling or giving away tramadol hydrochloride tablets are against the law. • Store tramadol hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.
Important Information Guiding Use in Pediatric Patients: • Do not give tramadol hydrochloride tablets to a child younger than 12 years of age. • Do not give tramadol hydrochloride tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids. • Avoid giving tramadol hydrochloride tablets 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 tramadol hydrochloride tablets 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 tramadol. • Taken a Monoamine Oxidase Inhibitor, MAOI, (medicine used for depression) within the last 14 days.
Before taking tramadol hydrochloride tablets, 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 tramadol hydrochloride tablets 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 tramadol hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death.
When taking tramadol hydrochloride tablets: • Do not change your dose. Take tramadol hydrochloride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. • Take your prescribed dose as indicated by your healthcare provider. The maximum dosage is 1 or 2 tablets every 4 to 6 hours, as needed for pain relief. 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 tramadol hydrochloride tablets regularly, do not stop taking tramadol hydrochloride tablets without talking to your healthcare provider. • Dispose of expired, unwanted, or unused tramadol hydrochloride tablets 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 tramadol hydrochloride tablets 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 tramadol hydrochloride tablets DO NOT: • Drive or operate heavy machinery, until you know how tramadol hydrochloride tablets affect you. Tramadol hydrochloride tablets 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 tramadol hydrochloride tablets may cause you to overdose and die.
The possible side effects of tramadol hydrochloride tablets: • 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 tramadol hydrochloride tablets. 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.

Distributed by:
Virtus Pharmaceuticals, LLC
Langhorne, PA 19047 USA
1-888-848-3593
Manufactured by:
CSPC Ouyi Pharmaceutical Co., Ltd.
Shijiazhuang, China, 052160
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Rev. 10/2019