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Guide
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.
SYNALGOS-DC (NDA-011483)
(ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/22/2025 (SUPPL-38)
5 Warnings and Precautions
5.1 Addiction, Abuse, and Misuse
Additions and/or revisions underlined:
. . .
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SYNALGOS-DC. 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)].
Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing SYNALGOS-DC, and reassess all patients receiving SYNALGOS-DC 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 SYNALGOS-DC, but use in such patients necessitates intensive counseling about the risks and proper use of SYNALGOS-DC along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
. . .
5.2 Life-Threatening Respiratory Depression
Additions and/or revisions underlined:
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient's clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
. . .
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 (5.1, 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 (5.1, 5.3), Overdosage (10)].
5.3 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 SYNALGOS-DC 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.
. . .
If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2) Overdosage (10)].
. . .
5.14 Risks of Gastrointestinal Complications Including Peptic Ulcer Disease
Subsection title revised.
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)].
. . .
5.16 Withdrawal
Additions and/or revisions underlined:
Do not rapidly reduce or abruptly discontinue SYNALGOS-DC in a patient physically dependent on opioids. When discontinuing SYNALGOS-DC in a physically dependent patient, gradually taper the dosage. Rapid tapering of SYNALGOS-DC 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
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 (5.14].
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 2006through 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 to 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 for Intervention section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2, 2.5), Warnings and Precautions (5.1, 5.2, 5.3)].
Additions and/or revisions underlined for Examples section of Benzodiazepines and Other Central Nervous System (CNS) Depressants of table; please refer to table for complete information:
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin) other opioids, alcohol.
Additions and/or revisions underlined for Intervention section of Muscle Relaxants of table; please refer to table for complete information:
Because respiratory depression may be greater than otherwise expected, decrease the dosage of SYNALGOS-DC and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2), Warnings and Precautions (5.2, 5.3)].
Newly added Examples section of Muscle Relaxants of table; please refer to table for complete information:
Cyclobenzaprine, metaxalone
8 Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
. . .
Clinical Considerations
. . .
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. SYNALGOS-DC is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including SYNALGOS-DC, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined:
Important information about SYNALGOS-DC:
- Get emergency help or call 911 right away if you take too much SYNALGOS-DC (overdose). When you first start taking SYNALGOS-DC, 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 SYNALGOS-DC 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.
. . .
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 SYNALGOS-DC is used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3), Drug Interactions (7)].
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.
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 (5.3)].
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 their 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.
. . .
11/21/2024 (SUPPL-37)
5 Warnings and Precautions
5.21 Serious Skin Reactions
Newly added subsection:
NSAIDs, including aspirin, a component of SYNALGOS-DC, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of SYNALGOS-DC at the first appearance of skin rash or any other sign of hypersensitivity. SYNALGOS-DC is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].
6 Adverse Reactions
Additions and/or revisions underlined:
The following serious adverse reactions are described, or described in greater detail, in other sections:
…
Serious Skin Reactions [see Warnings and Precautions (5.21)]
…
Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).
12/15/2023 (SUPPL-35)
Boxed Warning
(Additions and/or revisions underlined)
WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF SYNALGOS-DC
Addiction, Abuse, and Misuse
Because the use of SYNALGOS-DC exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1)].
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of SYNALGOS-DC, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of SYNALGOS-DC are essential [see Warnings and Precautions (5.2)].
Accidental Ingestion
Accidental ingestion of even one dose of SYNALGOS-DC, especially by children, can result in a fatal overdose of dihydrocodeine [see Warnings and Precautions (5.2)].
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of SYNALGOS-DC and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3), Drug Interactions (7)]
Neonatal Opioid Withdrawal Syndrome (NOWS)
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4)].
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS):
Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5)].
Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening: Respiratory Depression in Children Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism [see Warnings and Precautions (5.4)]. SYNALGOS-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Contraindications (4)]. Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine…
4 Contraindications
(Additions and/or revisions underlined)
SYNALGOS-DC is contraindicated for:
All children younger than 12 years of age [see Warnings and Precautions (5.6)]
Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy [see Warnings and Precautions (5.6)]
SYNALGOS-DC is also contraindicated in patients with:
Significant respiratory depression [see Warnings and Precautions (5.2)]
Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)]
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
[see Warnings and Precautions (5.10), Drug Interactions (7)]
Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)]
Hypersensitivity to dihydrocodeine, codeine, or aspirin, or NSAIDs [see Adverse Reactions (6)]
Hemophilia [see Warnings and Precautions (5.19)]
Reye’s Syndrome [see Warnings and Precautions (5.20)]
Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) [see Warnings and Precautions (5.22)]
5 Warnings and Precautions
5.1 Addiction, Abuse, and Misuse
(Additions and/or revisions underlined)
SYNALGOS-DC contains dihydrocodeine bitartrate, a Schedule III controlled substance. As an opioid, SYNALGOS-DC 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 SYNALGOS-DC. 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 SYNALGOS-DC, and reassess all patients receiving SYNALGOS-DC 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 SYNALGOS-DC, but use in such patients necessitates intensive counseling about the risks and proper use of SYNALGOS-DC 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 SYNALGOS-DC. 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 the proper disposal of unused drug…
5.2 Life-Threatening Respiratory Depression
(Additions and/or revisions underlined)
…
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.1, 5.3), Overdosage (10)].
5.3 Risks from Concomitant Use with Benzodiazepines or Other Depressants
(Newly added subsection)
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SYNALGOS-DC with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug- related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
Advise both patients and caregivers about the risks of respiratory depression and sedation when SYNALGOS-DC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7)].
5.4 Neonatal Opioid Withdrawal Syndrome
(Newly added subsection)
Use of SYNALGOS-DC 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 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)].
5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
(Newly added subsection)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
5.8 Opioid-Induced Hyperalgesia and Allodynia
(Newly added subsection)
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), Warnings and Precautions (5)].
6 Adverse Reactions
(Additions and/or revisions underlined)
The following serious adverse reactions are described, or described in greater detail, in other sections:
Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
Life-Threatening Respiratory Depression [see Warnings and Precautions (5.32)]
Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3)]
Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children [see Warnings and Precautions (5.6)]
Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4)]
Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8)]
Adrenal Insufficiency [see Warnings and Precautions (5.11)]
Severe Hypotension [see Warnings and Precautions (5.12)]
Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.14)]
Seizures [see Warnings and Precautions (5.15)]
Withdrawal [see Warnings and Precautions (5.16)]
Coagulation Abnormalities and Bleeding [see Warnings and Precautions (5.19)]
Reye’s Syndrome [see Warnings and Precautions (5.20)]
Allergy [see Warnings and Precautions (5.22)]
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.23)]
The following adverse reactions associated with the use of SYNALGOS-DC were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.
Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature [see Warnings and Precautions (5)].
…
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SYNALGOS-DC.
Androgen Deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time.
Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8)]
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
8 Use in Specific Populations
8.2 Lactation
(Additions and/or revisions underlined)
…
Nursing women are advised against aspirin use because of the possible development of Reye’s Syndrome in their babies. The risk of Reye’s Syndrome caused by salicylate in breast milk is unknown [see Warnings and Precautions (5.20)].
8.5 Geriatric Use
(Additions and/or revisions underlined)
Clinical studies of SYNALGOS-DC did not include sufficient numbers of subjects 65 years of age and older to determine whether elderly subjects respond differently from younger subjects.
Elderly patients (aged 65 years or older) may have increased sensitivity to dihydrocodeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
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 SYNALGOS-DC slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions underlined)
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 SYNALGOS-DC securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving SYNALGOS-DC unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1, 5.2), Drug Abuse and Dependence (9.2)].
Accidental Ingestion
Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].
Interactions with Benzodiazepines and Other CNS Depressants
Inform patients and caregivers that potentially fatal additive effects may occur if SYNALGOS-DC 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 (5.3), Drug Interactions (7)].
04/28/2021 (SUPPL-34)
5 Warnings and Precautions
5.1 Addiction, Abuse, and Misuse(Newly added information)
Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
(Newly added section)
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs, including SYNALGOS-DC, in pregnant women at about 30 weeks gestation and later. NSAIDs, including SYNALGOS-DC, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including SYNALGOS-DC, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit SYNALGOS-DC use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if SYNALGOS-DC treatment extends beyond 48 hours. Discontinue SYNALGOS-DC if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].
(Newly added section)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as SYNALGOS-DC. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue SYNALGOS-DC and evaluate the patient immediately.
(Newly added information)
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 Patient Counseling Information (17)].
Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose
Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with SYNALGOS-DC. 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). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].
Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone [see Warnings and Precautions (5.1, 5.7), Patient Counseling Information (17)].
(Newly added information)
If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions underlined)
Risk Summary
Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5)]. Use of NSAIDs, including aspirin, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SYNALGOSDC use between about 20 and 30 weeks of gestation, and avoid SYNALGOS-DC use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).
Premature Closure of Fetal Ductus Arteriosus
Use of NSAIDs, including aspirin, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as aspirin, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) 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.
Premature Closure of Fetal Ductus Arteriosus:
Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SYNALGOS-DC, can cause premature closure of the fetal ductus arteriosus (see Data).
Oligohydramnios/Neonatal Renal Impairment:
If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If SYNALGOS-DC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SYNALGOS-DC and follow up according to clinical practice (see Data).
Data
Human Data
Premature Closure of Fetal Ductus Arteriosus
Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Additions and/or revisions underlined)
Get emergency help or call 911 right away if you take too much SYNALGOS-DC (overdose). When you first start
taking SYNALGOS-DC, 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.
Before taking SYNALGOS-DC, tell your healthcare provider if you have a history of. . .
• abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems
Taking NSAID-containing
products like SYNALGOS-DC at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take
NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to
monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of
pregnancy.
• breastfeeding. Not recommended; may harm your baby.
• develop any type of rash or fever. Contact your healthcare provider as soon as possible and stop taking SYNALGOS-DC.
• living in a household where there are small children or someone who has abused street or prescription drugs.
The possible side effects of SYNALGOS-DC:
• bleeding, constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain, rash, or fever. 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.
(Newly added information)
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 SYNALGOS-DC. 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.
Serious Skin Reactions, including DRESS
Advise patients to stop taking SYNALGOS-DC immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.20)].
If treatment with SYNALGOS-DC is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.16) and Use in Specific Populations (8.1)].
10/07/2019 (SUPPL-33)
5 Warnings and Precautions
Additions and/or revisions underlined:
5.3 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression
Newly added information to the end of this subsection:
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep- related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.
Additions and/or revisions underlined:
5.15 Withdrawal
Do not abruptly discontinue SYNALGOS DC Tablets in a patient physically dependent on opioids. When discontinuing SYNALGOS DC Tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of methadone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain. Additionally, avoid the use of mixed agonist/antagonist …
7 Drug Interactions
Table 1: Clinically Significant Drug Interactions with SYNALGOS DC
Serotonergic Drugs
Additions and/or revisions underlined:
Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
09/18/2018 (SUPPL-32)
Boxed Warning
In the boxed warning title, the following underlined language was added after “ADDICTION, ABUSE, AND MISUSE”: RISK EVALUATION AND MITIGATION STRATEGY (REMS)
Addition of the following information:
Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to
- complete a REMS-compliant education program,
- counsel patients and/or their caregivers, with every prescription, on safe use, serious risks, storage, and disposal of these products,
- emphasize to patients and their caregivers the importance of reading the Medication Guide every time it is provided by their pharmacist, and
- consider other tools to improve patient, household, and community safety.
5 Warnings and Precautions
Addition of the following subsection after the warning regarding addiction, abuse and misuse:
5.2 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)
To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:
Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.
Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.
Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.
Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.
To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503- 0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.
08/29/2017 (SUPPL-30)
Boxed Warning
(additions/revisions underlined)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE- THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
…
Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. SYNALGOS-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. (4) Avoid the use of SYNALGOS- DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.
...
4 Contraindications
(additions underlined)
SYNALGOS-DC is contraindicated for:
All children younger than 12 years of age
Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy
SYNALGOS-DC is also contraindicated in patients with:
Significant respiratory depression
…
5 Warnings and Precautions
5.3 Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children(subsection revised)
Because of comparable metabolic pathways for codeine and dihydrocodeine and similar potencies for codeine and dihydrocodeine and morphine and dihydromorphine, the risks associated with ultra-rapid metabolism of codeine are present for dihydrocodeine.
Life-threatening respiratory depression and death have occurred in children who received codeine. Codeine is subject to variability in metabolism based upon CYP2D6 genotype (described below), which can lead to an increased exposure to the active metabolite morphine. Based upon postmarketing reports, children younger than 12 years old appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of
being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with opioids for post- tonsillectomy and/or adenoidectomy pain may be particularly sensitive to their respiratory depressant effect. Because of the risk of life-threatening respiratory depression and death:
SYNALGOS-DC is contraindicated for all children younger than 12 years of age.
SYNALGOS-DC is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
As with adults, when prescribing opioids for adolescents, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of opioid overdose.
Nursing Mothers
At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with SYNALGOS-DC.
CYP2D6 Genetic Variability: Ultra-rapid metabolizer
Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 1 to 10% for Whites (European, North American), 3 to 4% for Blacks (African Americans), 1 to 2% for East Asians (Chinese, Japanese, Korean), and may be greater than 10% in certain racial/ethnic groups (i.e., Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). Data are not available for other ethnic groups. These individuals convert dihydrocodeine into its active metabolite, dihydromorphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum dihydromorphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). Therefore, individuals who are ultra-rapid metabolizers should not use SYNALGOS-DC.
6 Adverse Reactions
(addition underlined)
The following serious adverse reactions are described, or described in greater detail, in other sections:
Addiction, Abuse, and Misuse
Life-Threatening Respiratory Depression
Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children
…
8 Use in Specific Populations
8.2 Lactation(additions/revisions underlined)
Risk Summary
SYNALGOS-DC is not recommended for use in nursing women.
Dihydrocodeine. Dihydrocodeine and its active metabolite, dihydromorphine, are present in human milk. There are published studies and cases that have reported excessive sedation, respiratory depression, and death in infants exposed to codeine via breast milk. Women who are ultra-rapid metabolizers of codeine achieve higher than expected serum levels of morphine, potentially leading to higher levels of morphine in breast milk that can be dangerous in their breastfed infants; this would be expected to occur with dihydrocodeine as well. In women with normal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent.
There is no information on the effects of the dihydrocodeine on milk production. Because of the potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SYNALGOS-DC.
…
(additions underlined)
Preparations containing aspirin should be kept out of the reach of children. Reye’s Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. The safety and effectiveness of SYNALGOS-DC in pediatric patients below 12 years of age have not been established.
Life-threatening respiratory depression and death have occurred in children who received codeine. In most of the reported cases, these events followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Children with sleep apnea may be particularly sensitive to the respiratory depressant effects ofopioids. Because of the risk of life-threatening respiratory depression and death:
SYNALGOS-DC is contraindicated for all children younger than 12 years of age
SYNALGOS-DC is contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.
Avoid the use of SYNALGOS-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as post-operative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(additions underlined)
…
Other Risk Factors for Life-Threatening Respiratory Depression in Children Advise caregivers that SYNALGOS-DC is contraindicated in all 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 SYNALGOS-DC to monitor for signs of respiratory depression.
…
12/16/2016 (SUPPL-29)
Boxed Warning
(Extensive additions)
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; DEATH RELATED TO ULTRA- RAPID METABOLISM OF DIHYDROCODEINE TO DIHYDROMORPHINE; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS
Addiction, Abuse, and Misuse
SYNALGOS-DC exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing SYNALGOS-DC, and monitor all patients regularly for the development of these behaviors and conditions.
Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of SYNALGOS-DC. Monitor for respiratory depression, especially during initiation of SYNALGOS-DC or following a dose increase.
Accidental Ingestion
Accidental ingestion of even one dose of SYNALGOS-DC, especially by children, can result in a fatal overdose of SYNALGOS-DC.
Neonatal Opioid Withdrawal Syndrome
Prolonged use of SYNALGOS-DC during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life- threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Death Related to Ultra-Rapid Metabolism of Dihydrocodeine to Dihydromorphine
Respiratory depression and death have occurred in children who received dihydrocodeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of dihydrocodeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high dihydromorphine concentrations).
Interactions with Drugs Affecting Cytochrome P450 Isoenzymes
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with dihydrocodeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SYNALGOS-DC requires careful consideration of the effects on dihydrocodeine, and the active metabolite, dihydromorphine.
Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.
• Reserve concomitant prescribing of SYNALGOS-DC and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dosages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation.
4 Contraindications
(additions underlined)
SYNALGOS-DC is contraindicated in patients with:
• Significant respiratory depression
• Postoperative pain management in children who have under-gone tonsillectomy and/or adenoidectomy
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity to dihydrocodeine, codeine, or aspirin, or NSAIDs
• Hemophilia
• Reye’s Syndrome
• Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs)
• Syndrome of asthma, rhinitis, and nasal polyps
5 Warnings and Precautions
5.1 Addiction, Abuse, and Misuse(subsection added)
SYNALGOS-DC contains dihydrocodeine bitartrate, a Schedule III controlled substance. As an opioid, SYNALGOS-DC exposes users to the risks of addiction, abuse, and misuse.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed SYNALGOS-DC. 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 SYNALGOS-DC, and monitor all patients receiving SYNALGOS-DC 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 SYNALGOS-DC, but use in such patients necessitates intensive counseling about the risks and proper use of SYNALGOS-DC along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing SYNALGOS-DC. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the 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.
(subsection added)
SYNALGOS-DC may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) .Monitor these patients for signs of hypotension after initiating or titrating the dosage of SYNALGOS-DC. In patients with circulatory shock, SYNALGOS-DC may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of SYNALGOS-DC in patients with circulatory shock.
(subsection added)
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), SYNALGOS-DC may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with SYNALGOS-DC.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of SYNALGOS-DC in patients with impaired consciousness or coma.
(subsection added)
SYNALGOS-DC is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
The dihydrocodeine in SYNALGOS-DC may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms.
Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation and bleeding.
Gastrointestinal Bleeding, Ulceration, and Perforation: The aspirin in SYNALGOS-DC can cause GI side effects including stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated patients:
• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such high risk patients, as well as those with active GI bleeding, consider alternate therapies other than SYNALGOS-DC.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SYNALGOS-DC until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients
(subsection added)
The dihydrocodeine in SYNALGOS-DC may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during SYNALGOS-DC therapy.
(subsection added)
Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including SYNALGOS-DC. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
When discontinuing SYNALGOS-DC, gradually taper the dosage. Do not abruptly discontinue
SYNALGOS-DC more closely for evidence of GI bleeding.
(additions underlined)
SYNALGOS-DC may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of SYNALGOS-DC and know how they will react to the medication.
(subsection added)
Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (i.e. hemophilia) or acquired (i.e. liver disease or vitamin K deficiency) bleeding disorders. Aspirin is contraindicated in patients with hemophilia.
Aspirin administered pre-operatively may prolong the bleeding time.
Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.
(subsection added)
Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses.
(subsection added)
Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma).
(subsection added)
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of SYNALGOS-DC in patients with advanced renal disease. The renal effects of SYNALGOS-DC may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating SYNALGOS-DC. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of SYNALGOS-DC. Avoid the use of SYNALGOS-DC in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If SYNALGOS-DC is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic- hypoaldosteronism state.
(subsection added)
Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of SYNALGOS-DC, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of SYNALGOS-DC.
To reduce the risk of respiratory depression, proper dosing and titration of SYNALGOS-DC are essential. Overestimating the SYNALGOS-DC dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.
Accidental ingestion of even one dose of SYNALGOS-DC, especially by children, can result in respiratory depression and death due to an overdose of dihydrocodeine.
(subsection added)
Aspirin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including SYNALGOS-DC, in pregnant women starting at 30 weeks of gestation (third trimester)
(subsection added)
Prolonged use of SYNALGOS-DC 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 a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
(additions underlined)
Because of comparable metabolic pathways for codeine and dihydrocodeine and similar potencies for codeine and dihydrocodeine and morphine and dihydromorhine, the risks associated with ultra-rapid metabolism of codeine are present for dihyrodcodeine.
(subsection added)
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with dihydrocodeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with SYNALGOS-DC requires careful consideration of the effects on dihydrocodeine and the active metabolite, dihydromorphine.
· Cytochrome P450 3A4 Interaction
The concomitant use of SYNALGOS-DC with all cytochrome P450 3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a cytochrome P450 3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in dihydrocodeine plasma concentrations with subsequently greater metabolism by cytochrome P450 2D6, resulting in greater dihydromorphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
The concomitant use of SYNALGOS-DC with all cytochrome P450 3A4 inducers or discontinuation of a cytochrome P450 3A4 inhibitor may result in lower dihydrocodeine levels, greater dihydronorcodeine levels, and less metabolism via 2D6 with resultant lower dihydromorphine levels. This may be associated with a decrease in efficacy, and in some patients, may result in signs and symptoms of opioid withdrawal. Follow patients receiving SYNALGOS-DC and any CYP3A4 inhibitor or inducer for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when SYNALGOS-DC is used in conjunction with inhibitors and inducers of CYP3A4.
If concomitant use of a CYP3A4 inhibitor is necessary or if a CYP3A4 inducer is discontinued, consider dosage reduction of SYNALGOS-DC until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.
If concomitant use of a CYP3A4 inducer is necessary or if a CYP3A4 inhibitor is discontinued, consider increasing the SYNALGOS-DC dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
· Risks of Concomitant Use or Discontinuation of Cytochrome P450 2D6 Inhibitors
The concomitant use of SYNALGOS-DC with all cytochrome P450 2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in dihydrocodeine plasma concentrations and a decrease in active metabolite dihydromorphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.
Discontinuation of a concomitantly used cytochrome P450 2D6 inhibitor may result in a decrease in dihydrocodeine plasma concentration and an increase in active metabolite dihydromorphine plasma concentration which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.
Follow patients receiving SYNALGOS-DC and any CYP2D6 inhibitor for signs and symptoms that may reflect opioid toxicity and opioid withdrawal when SYNALGOS-DC is used in conjunction with inhibitors of CYP2D6.
If concomitant use with a CYP2D6 inhibitor is necessary, follow the patient for signs of reduced efficacy or opioid withdrawal and consider increasing the SYNALGOS-DC dosage. After stopping use of a CYP2D6 inhibitor, consider reducing the SYNALGOS-DC dosage and follow the patient for signs and symptoms of respiratory depression or sedation.
(subsection added)
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of SYNALGOS-DC with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug- related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.
Advise both patients and caregivers about the risks of respiratory depression and sedation when SYNALGOS-DC is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.
(subsection added)
The use of SYNALGOS-DC in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: SYNALGOS-DC-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of SYNALGOS-DC.
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.
Monitor such patients closely, particularly when initiating and titrating SYNALGOS-DC and when SYNALGOS-DC is given concomitantly with other drugs that depress respiration.Alternatively, consider the use of non- opioid analgesics in these patients.
(subsection added)
Monoamine oxidase inhibitors (MAOIs) may potentiate the effects of dihydromorphine, dihydrocodeine’s active metabolite, including respiratory depression, coma, and confusion. SYNALGOS-DC should not be used in patients taking MAOIs or within 14 days of stopping such treatment.
(subsection added)
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
6 Adverse Reactions
(additions underlined)
The following serious adverse reactions are described, or described in greater detail, in other sections:
• Addiction, Abuse, and Misuse
• Life-Threatening Respiratory Depression
• Neonatal Opioid Withdrawal Syndrome
• Death Related to Ultra-Rapid Metabolism of Dihydrocodeine to Dihydromorphine
• Interactions with Benzodiazepines or Other CNS Depressants
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Seizures
• Withdrawal
• Coagulation Abnormalities and Bleeding
• Reye’s Syndrome
• Allergy
• Renal Toxicity and Hyperkalemia
• Premature Closure of Fetal Ductus Arteriosus
The following adverse reactions associated with the use of SYNALGOS-DC were identified in clinical studies or postmarketing reports. Because some of these reactions were 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.
Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse reactions that have been reported in the literature.
Body as a Whole: Fever, hypothermia, thirst.
Cardiovascular: Dysrhythmias, hypotension, tachycardia.
Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache, subdural or intracranial hemorrhage, lethargy, seizures.
Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis.
Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting, transient elevations of hepatic enzymes, hepatitis, Reye's syndrome, pancreatitis.
Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia.
Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema, urticaria.
Musculoskeletal: Rhabdomyolysis.
Metabolism: Hypoglycemia (in children), hyperglycemia.
Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding.
Respiratory: Hyperpnea, pulmonary edema, tachypnea.
Special Senses: Hearing loss, tinnitus. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism.
Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure.
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
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in SYNALGOS-DC.
Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids
7 Drug Interactions
(Extensive additions, please refer to table 1 in label)
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion, please refer to label)
(PLLR conversion, additions underlined)
Risk Summary
SYNALGOS-DC is not recommended for use in nursing women.
Dihydrocodeine bitartrate is secreted into human milk. In women with normal dihydrocodeine metabolism (normal CYP2D6 activity), the amount of dihydrocodeine secreted into human milk is low and dose-dependent. However, some women are ultra- rapid metabolizers of dihydrocodeine. These women achieve higher-than-expected serum levels of dihydrocodeine’s active metabolite, dihydromorphine, leading to higher-than-expected levels of dihydromorphine in breast milk and potentially dangerously high serum dihydromorphine levels in their breastfed infants. Therefore, maternal use of dihydrocodeine can potentially lead to serious adverse reactions, including death, in nursing infants.
Aspirin and caffeine are also excreted in breast milk in small amounts. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk. Use of high doses of aspirin may lead to rashes, platelet abnormalities, and bleeding in nursing infants.
Nursing women are advised against aspirin use because of the possible development of Reye’s Syndrome in their babies. The risk of Reye’s Syndrome caused by salicylate in breast milk is unknown.
Because of the potential for serious adverse reactions, including excess sedation and respiratory depression, rashes, platelet abnormalities, bleeding, and the possibility of Reye Syndrome in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with SYNALGOS-DC.
Clinical Considerations
Infants exposed to SYNALGOS-DC through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast- feeding is stopped.
Aspirin and caffeine are also excreted in breast milk in small amounts. Adverse effects on platelet function in the nursing infant exposed to aspirin in breast milk may be a potential risk.
(PLLR conversion)
Infertility
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including aspirin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including aspirin, in women who have difficulties conceiving or who are undergoing investigation of infertility.
(additions underlined)
Preparations containing aspirin should be kept out of the reach of children. Reye’s Syndrome is a rare condition that affects the brain and liver and is most often observed in children given aspirin during a viral illness. SYNALGOS-DC is not recommended for patients 12 years of age and under. Since there is no experience in children who have received SYNALGOS-DC, safety and efficacy in children have not been established.
(Additions underlined)
Clinical studies of Synalgos-DC did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects.
Elderly patients (aged 65 years or older) may have increased sensitivity to dihydrocodeine. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
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 SYNALGOS-DC slowly in geriatric patients and follow closely for signs of central nervous system and respiratory depression.
Component of this drug product are 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 monitor renal function.
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, dose selection should start at the low end of the dosing range, and follow patients for adverse effects.
(additions underlined)
SYNALGOS-DC contains aspirin, which should be avoided in patients with severe hepatic impairment..
No formal studies have been conducted in patients with hepatic impairment so the pharmacokinetics of dihydrocodeine in this patient population is unknown. Start these patients cautiously with lower doses of SYNALGOS-DC or with longer dosing intervals and titrate slowly while carefully following for side effects. In patients with severe hepatic disease, follow effects of therapy with serial liver function tests.
(additions underlined)
SYNALGOS-DC contains aspirin, which should be avoided in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).
Dihydrocodeine pharmacokinetics may be altered in patients with renal failure. Clearance may be decreased and the metabolites may accumulate to much higher plasma levels in patients with renal failure as compared to patients with normal renal function. Start these patients cautiously with lower doses of SYNALGOS-DC or with longer dosing intervals and titrate slowly while carefully following for side effects. In patients with renal disease, follow effects of therapy with serial renal function tests.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Extensive additions, please refer to label)
(Newly added, please refer to label)
Other
(PLR conversion and revisions to the Package Insert to incorporate the opioid analgesic template language)