Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

QDOLO (NDA-214044)

(TRAMADOL HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/22/2025 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Addiction, Abuse, Misuse

Additions and/or revisions underlined:

. . .

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed QDOLO. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2)].

. . .

5.3 Life-Threatening Respiratory Depression

Additions and/or revisions underlined:

. . .

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.2, 5.3)].

Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.

Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3), Overdosage (10)].

5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of QDOLO with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

. . .

5.11 Increased Risk of Seizures

Additions and/or revisions underlined:

. . .

Risk of seizure may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections). In tramadol overdose, administration of an opioid overdose reversal agent (e.g., naloxone, nalmefene) may increase the risk of seizure [see Overdosage (10)].

5.17 Risks of Gastrointestinal Complications

Additions and/or revisions underlined:

. . .

Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2)].

5.19 Withdrawal

Additions and/or revisions underlined:

Do not rapidly reduce or abruptly discontinue QDOLO in a patient physically dependent on opioids. When discontinuing QDOLO in a physically dependent patient, gradually taper the dosage. Rapid tapering of tramadol in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].

. . .

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

. . .

Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.17)].

Adverse Reactions from Observational Studies

A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months.

Over 12 months:

approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and

approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument.

A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in

patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up.

Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were

fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates.

The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

7 Drug Interactions

Additions and/or revisions underlined:

. . .

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin and pregabalin), other opioids, and alcohol.

. . .

Muscle Relaxants

. . .

cyclobenzaprine, metaxalone

. . .

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

. . .

Labor or Delivery

Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Interactions with Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if QDOLO is used with benzodiazepines, CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), or some illicit drugs and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4), Drug Interactions (7)].

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.4)].

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

Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene 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 an opioid overdose reversal agent is administered [see Overdosage (10)].

Advise patients and caregivers:

how to treat with the overdose reversal agent in the event of an opioid overdose.
to tell family and friends about the opioid overdose reversal agent 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 opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

. . .

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Get emergency help or call 911 right away if you take too much QDOLO (overdose). When you first start taking QDOLO, 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. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.
Taking QDOLO with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.

12/15/2023 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risk of Accidental Overdose and Death due to Medication Errors

Additions and/or revisions underlined:

Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL when prescribing, dispensing, and administering QDOLO. Ensure that the dose is communicated clearly and dispensed accurately.

Instruct patients and caregivers on how to measure and take or administer the correct dose of QDOLO and to use extreme caution when measuring the dose. Strongly advise patients and caregivers to always use a graduated device that can measure and deliver the prescribed dose accurately, and to never use household teaspoons or tablespoons to measure a dose because these are not adequate measuring devices.

5.2 Addiction, Abuse, and Misuse

Additions and/or revisions underlined:
QDOLO contains tramadol, a Schedule IV controlled substance. As an opioid, QDOLO exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed QDOLO. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing QDOLO, and reassess all patients receiving QDOLO for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as QDOLO, but use in such patients necessitates intensive counseling about the risks and proper use of QDOLO along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing QDOLO. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug . Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.5 Neonatal Opioid Withdrawal Syndrome

Additions and/or revisions underlined:
Use of QDOLO for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)].

5.8 Risks of Interactions with Drugs Affecting Cytochrome P450 Isoenzyme

Additions and/or revisions underlined:
…

Evaluate patients receiving QDOLO and any CYP2D6 inhibitor at frequent intervals for the risk of serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity, and opioid withdrawal when QDOLO is used in conjunction with inhibitors of CYP2D6 [see Drug Interactions (7)].
…

Evaluate patients receiving QDOLO and any CYP3A4 inhibitor or inducer at frequent intervals for the risk for serious adverse events including seizures and serotonin syndrome, signs and symptoms that may reflect opioid toxicity and opioid withdrawal when QDOLO is used in conjunction with inhibitors and inducers of CYP3A4 [see Drug Interactions (7)].

5.9 Opioid-Induced Hyperalgesia and Allodynia

Newly added subsection:

Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5), Warnings and Precautions (5.19)]

5.10 Serotonin Syndrome Risk

Additions and/or revisions underlined:
Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol products, including QDOLO, particularly during concomitant use with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use but may occur later than that. Discontinue QDOLO if serotonin syndrome is suspected.

5.13 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

Additions and/or revisions underlined:

…

Elderly, Cachectic, or Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3)].

Regularly evaluate patients closely, particularly when initiating and titrating QDOLO and when QDOLO is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3, 5.4), Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

5.17 Risks of Use in Patients with Gastrointestinal Conditions

Additions and/or revisions underlined:

QDOLO is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus [see Contraindications (4)].

The tramadol in QDOLO may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.9)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology (12.2)].

…

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

7 Drug Interactions

Changes to table 2; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome[see Warnings and Precautions (5.5)]. Available data with QDOLO in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported with fetal exposure to opioid analgesics (see Clinical Considerations).

In animal reproduction studies, tramadol administration during organogenesis decreased fetal weights and reduced ossification in mice, rats, and rabbits at 1.4, 0.6, and 3.6 times the maximum recommended human daily dosage (MRHD). In a pre- and post-natal development study, tramadol decreased pup body weight and increased pup mortality at 1.2 and 1.9 times the MRHD. In a published study, tramadol caused structural abnormalities in the brains of fetuses when administered to female Sprague Dawley rats from Gestation Days 10-21 at a dose comparable to the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

…

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2)].

Published studies in adult male rodents report that tramadol, at clinically relevant doses, can produce adverse effects on male reproductive hormones and tissues [See Nonclinical Toxicology (13.1)].

8.5 Geriatric Use

Additions and/or revisions underlined:

A total of 455 elderly (65 years of age or older) subjects were exposed to tramadol hydrochloride in controlled clinical trials. Of those, 145 subjects were 75 years of age and older.

In studies including geriatric patients, treatment-limiting adverse events were higher in subjects over 75 years of age compared to those under 65 years of age. Specifically, 30% of those over 75 years of age had gastrointestinal treatment-limiting adverse events compared to 17% of those under 65 years of age. Constipation resulted in discontinuation of treatment in 10% of those over 75.

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of QDOLO slowly in geriatric patients starting at the low end of the dosing range and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.13)].

Tramadol is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Tell your healthcare provider if you are:

noticing your pain getting worse. If your pain gets worse after you take QDOLO, do not take more of QDOLO without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking QDOLO.
pregnant or planning to become pregnant. Use of QDOLO for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.
breastfeeding. Not recommended during treatment with QDOLO; it may harm your baby.
taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking QDOLO with certain other medicines can cause serious side effects that could lead to death.

When taking QDOLO:

Do not change your dose. Take QDOLO exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.
For acute (short-term) pain, you may only need to take QDOLO for a few days. You may have some QDOLO left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused QDOLO.

…

Dispose of expired, unwanted, or unused QDOLO 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 QDOLO by mixing QDOLO with dirt, cat litter, or used coffee grounds; placing the mixture in a container such as a sealed plastic bag; and throwing the container in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

…

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 QDOLO. Call your healthcare provider 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.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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 QDOLO by following these four steps:

· Mix QDOLO 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;

· Remove 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. Medication Errors

Strongly advise patients and caregivers to always use a graduated oral syringe or measuring cup, with metric units of measurements (i.e., mL), to correctly measure the prescribed amount of medication.

Inform patients that oral dosing devices may be obtained from their pharmacy and to never use household teaspoons or tablespoons to measure QDOLO [see Dosage and Administration (2.1), Warnings and Precautions (5.1)].

…

Hyperalgesia and Allodynia

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

…

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that use of QDOLO for an extended period of time 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 Specific Populations (8.1)].

…

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

09/10/2021 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.20 Hyponatremia

(Newly Added Subsection)

Hyponatremia (serum sodium < 135 mmol/L) has been reported with the use of tramadol, and many cases are severe (sodium level < 120 mmol/L). Most cases of hyponatremia occurred in females over the age of 65 and within the first week of therapy. In some reports, hyponatremia resulted from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Monitor for signs and symptoms of hyponatremia (e.g., confusion, disorientation), during treatment with QDOLO, especially during initiation of therapy. If signs and symptoms of hyponatremia are present, initiate appropriate treatment (e.g., fluid restriction) and discontinue QDOLO [see Dosage and Administration: Safe Reduction or Discontinuation of QDOLO (2.5)].

5.21 Hypoglycemia

(Newly Added Subsection)

Cases of tramadol-associated hypoglycemia have been reported, some resulting in hospitalization. In most cases, patients had predisposing risk factors (e.g. diabetes). If hypoglycemia is suspected, monitor blood glucose levels and consider drug discontinuation as appropriate [see Dosage and Administration: Safe Reduction or Discontinuation of QDOLO (2.5)].

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post-approval use of tramadol hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

QT prolongation/torsade de pointes: Cases of QT prolongation and/or torsade de pointes have been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g., hypokalemia), or in the overdose setting.

Eye disorders – mydriasis

Metabolism and nutrition disorders

Hyponatremia: Cases of severe hyponatremia and/or SIADH have been reported in patients taking tramadol, most often in females over the age of 65, and within the first week of therapy [see Warnings and Precautions (5.20)].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients [see Warnings and Precautions (5.21)].

Nervous system disorders – movement disorder, speech disorder

Psychiatric disorders – delirium