Prescription Drug Information: TRAMADOL HYDROCHLORIDE (Page 10 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity assessment has been conducted in mice, rats and p53(+/-) heterozygous mice. 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). In a second rat study, no evidence of carcinogenicity was noted in rats at oral doses up to 75 mg/kg/day for males and 100 mg/kg/day for females (approximately 2-fold the maximum recommended human daily dose MRHD) for two years. However, the excessive decrease in body weight gain observed in the rat study might have reduced their sensitivity to any potential carcinogenic effect of the drug. No carcinogenic effect of tramadol was observed in p53(+/–)-heterozygous mice at oral doses up to 150 mg/kg/day for 26 weeks.

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

Clinical Trial Experience

Tramadol hydrochloride extended-release tablets were studied in patients with chronic, moderate to moderately severe pain due to osteoarthritis and/or low back pain in four 12-week, randomized, double-blind, placebo- controlled trials. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 to 100 mm visual analog scale (VAS). Adequate evidence of efficacy was demonstrated in the following two studies:

Study 1: Osteoarthritis of the Knee and/or Hip

In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment was initiated at 100 mg QD for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in the tramadol hydrochloride extended-release tablets treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the tramadol hydrochloride extended-release tablets 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with tramadol hydrochloride extended-release tablets 100 mg and 10% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 2).

Figure 2

image-4
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Study 2: Osteoarthritis of the Knee

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of tramadol hydrochloride extended-release tablets in patients with osteoarthritis of the knee, patients titrated to an average daily tramadol hydrochloride extended-release tablets dose of approximately 270 mg/day. Forty-nine percent of patients randomized to tramadol hydrochloride extended-release tablets completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the tramadol hydrochloride extended-release tablets treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of tramadol hydrochloride extended-release tablets-treated patients. The tramadol hydrochloride extended-release tablets group demonstrated a statistically significant decrease in the mean VAS score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving tramadol hydrochloride extended-release tablets and placebo (see Figure 3).

Figure 3

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16 HOW SUPPLIED/STORAGE AND HANDLING

Tramadol hydrochloride extended-release tablets USP are supplied in the following package and dose strength forms:

200 mg tablets (white to off-white circular, biconvex, beveled edge, coated) imprinted with ‘L011’ on one side and plain on the other side.

NDC: 70518-0886-00

NDC: 70518-0886-01

NDC: 70518-0886-02

PACKAGING: 30 in 1 BOTTLE PLASTIC

PACKAGING: 30 in 1 BLISTER PACK

PACKAGING: 90 in 1 BOTTLE PLASTIC

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Store tramadol hydrochloride extended release tablets securely and dispose of properly

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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 extended-release 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), Drug Abuse and Dependence ( 9)]. Inform patients that leaving tramadol hydrochloride extended-release 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 DEA-registered collectors are available, instruct patients to dispose of tramadol hydrochloride extended-release tablets by following these four steps:

  • Mix tramadol hydrochloride extended-release 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 extended-release 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 extended-release tablets with others and to take steps to protect tramadol hydrochloride extended-release 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 extended-release tablets or when the dosage is increased, and that it can occur even at recommended dosages . Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.3)] .

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with tramadol hydrochloride extended release tablets. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions ( 5.3)].

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [ see Overdosage ( 10) ].

If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose

• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

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 extended-release 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 12 to 18 years of age receiving tramadol hydrochloride extended-release 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 extended-release tablets are 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 ( 5.7), 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 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), Drug Interactions ( 7)] .

Seizures

Inform patients that tramadol hydrochloride extended-release 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 extended-release tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking tramadol hydrochloride extended-release 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 extended-release tablets, including the following:

  • Tramadol hydrochloride extended-release tablets are designed to work properly only if swallowed intact. Taking cut, broken, chewed, crushed, or dissolved tramadol hydrochloride extended-release tablets can result in a fatal overdose [see Dosage and Administration ( 2.1)].
  • 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, hepatic toxicity, and death. [see Dosage and Administration ( 2.1)].
  • Do not discontinue tramadol hydrochloride extended-release tablets without first discussing the need for a tapering regimen with the prescriber [see Dosage and Administration ( 2.5)] .

Important Discontinuation Instructions

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue tramadol hydrochloride extended-release tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.5)]

Hypotension

Inform patients that tramadol hydrochloride extended-release 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 extended-release 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 extended-release tablets during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.5), Use in Specific Populations ( 8.1)] .

Embryo-Fetal Toxicity

Inform female patients of reproductive potential that tramadol hydrochloride extended-release tablets can cause fetal harm and to inform their 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 tramadol hydrochloride extended-release tablets [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 [see Adverse Reactions ( 6.2), Use in Specific Populations ( 8.3)].

Driving or Operating Heavy Machinery

Inform patients that tramadol hydrochloride extended-release 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), Clinical Pharmacology ( 12.1)].

Repackaged By / Distributed By: RemedyRepack Inc.

625 Kolter Drive, Indiana, PA 15701

(724) 465-8762

Medication Guide

Tramadol Hydrochloride Extended-Release Tablets , CIV

(tram’ a dol hye” droe klor’ ide)

Tramadol hydrochloride extended-release tablets are:

  • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require daily around-the-clock, long-term treatment with an opioid, when other pain treatments such as non-opioid pain medicines or immediate-release opioid medicines do not treat your pain well enough or you cannot tolerate them.
  • A long-acting (extended-release) 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.
  • Not for use to treat pain that is not around-the-clock.

Important information about tramadol hydrochloride extended-release tablets:

  • Get emergency help or call 911 right away if you take too much tramadol hydrochloride extended-release tablets (overdose). When you first start taking tramadol hydrochloride extended-release 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. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose.
  • Taking tramadol hydrochloride extended-release 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 extended-release tablets. They could die from taking it. Selling or giving away tramadol hydrochloride extended-release tablets is against the law.
  • Store tramadol hydrochloride extended-release 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 extended-release tablets to a child younger than 12 years of age.
  • Do not give tramadol hydrochloride extended-release tablets to a child younger than 18 years of age after surgery to remove the tonsils and/or adenoids.
  • Avoid giving tramadol hydrochloride extended-release 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 extended-release tablets if you have:

  • severe asthma, trouble breathing, or other lung problems.
  • a bowel blockage or have narrowing of the stomach or intestines.

Before taking tramadol hydrochloride extended-release tablets, tell your healthcare provider if you have a history of:

  • head injury, seizures
  • problems urinating
  • abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.
  • liver, kidney, thyroid problems
  • pancreas or gallbladder problems

Tell your healthcare provider if you are:

  • pregnant or planning to become pregnant. Prolonged use of tramadol hydrochloride extended-release 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.
  • living in a household where there are small children or someone who has abused street or prescription drugs
  • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking tramadol hydrochloride extended-release tablets with certain other medicines can cause serious side effects that could lead to death.

When taking tramadol hydrochloride extended-release tablets:

  • Do not change your dose. Take tramadol hydrochloride extended-release tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
  • Take your prescribed dose once a day at the same time every day. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.
  • Swallow tramadol hydrochloride extended-release tablets whole. Do not cut, break, chew, crush, dissolve, snort, or inject tramadol hydrochloride extended-release tablets because this may cause you to overdose and die.
  • Call your healthcare provider if the dose you are taking does not control your pain.
  • Do not stop taking tramadol hydrochloride extended-release tablets without talking to your healthcare provider.
  • Dispose of expired, unwanted, or unused tramadol hydrochloride extended-release tablets by taking your drug to an authorized DEA-registered collector or drug take-back program. If one is not available, you can dispose of tramadol hydrochloride extended-release 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 extended-release tablets DO NOT:

  • Drive or operate heavy machinery, until you know how tramadol hydrochloride extended-release tablet affects you. Tramadol hydrochloride extended-release 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 extended-release tablets may cause you to overdose and die.

The possible side effects of tramadol hydrochloride extended-release tablets:

  • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, seizure. Call your healthcare provider if you have any of these symptoms and they are severe.

Get emergency medical help or call 911 right away 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 extended-release 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 or www.lupinpharmaceuticals.com or call Lupin Pharmaceuticals, Inc. at 1-800-399-2561.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Repackaged By / Distributed By: RemedyRepack Inc.

625 Kolter Drive, Indiana, PA 15701

(724) 465-8762

DRUG: TRAMADOL HYDROCHLORIDE

GENERIC: TRAMADOL HYDROCHLORIDE

DOSAGE: TABLET, EXTENDED RELEASE

ADMINSTRATION: ORAL

NDC: 70518-0886-0

NDC: 70518-0886-1

NDC: 70518-0886-2

COLOR: white

SHAPE: ROUND

SCORE: No score

SIZE: 9 mm

IMPRINT: L011

PACKAGING: 30 in 1 BOTTLE, PLASTIC

PACKAGING: 30 in 1 BLISTER PACK

PACKAGING: 90 in 1 BOTTLE PLASTIC

ACTIVE INGREDIENT(S):

  • TRAMADOL HYDROCHLORIDE 200mg in 1

INACTIVE INGREDIENT(S):

  • CELLULOSE, MICROCRYSTALLINE
  • DIBUTYL SEBACATE
  • ETHYLCELLULOSES
  • FERROSOFERRIC OXIDE
  • POVIDONE
  • PROPYLENE GLYCOL
  • SHELLAC
  • SILICON DIOXIDE
  • SODIUM STEARYL FUMARATE
Remedy_Label
(click image for full-size original)
MM2
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MM3
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TRAMADOL HYDROCHLORIDE tramadol hydrochloride tablet, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70518-0886(NDC:68180-698)
Route of Administration ORAL DEA Schedule CIV
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TRAMADOL HYDROCHLORIDE (TRAMADOL) TRAMADOL HYDROCHLORIDE 200 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE
DIBUTYL SEBACATE
ETHYLCELLULOSES
FERROSOFERRIC OXIDE
POVIDONE
PROPYLENE GLYCOL
SHELLAC
SILICON DIOXIDE
SODIUM STEARYL FUMARATE
Product Characteristics
Color white (white to off-white) Score no score
Shape ROUND (biconvex) Size 9mm
Flavor Imprint Code L011
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:70518-0886-0 30 TABLET, EXTENDED RELEASE in 1 BOTTLE, PLASTIC None
2 NDC:70518-0886-1 30 TABLET, EXTENDED RELEASE in 1 BLISTER PACK None
3 NDC:70518-0886-2 90 TABLET, EXTENDED RELEASE in 1 BOTTLE, PLASTIC None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200503 12/04/2017
Labeler — REMEDYREPACK INC. (829572556)

Revised: 01/2021 REMEDYREPACK INC.

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