HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use -----------------------DOSAGE AND ADMINISTRATION----------------------- SYNALGOS®-DC safely and effectively. See full prescribing information for • Use the lowest effective dose for the shortest duration consistent with SYNALGOS®-DC. individual patient treatment goals. (2.1) • Individualize dosing based on the severity of pain, patient response, prior SYNALGOS®-DC (aspirin, caffeine, and dihydrocodeine bitartrate) capsules, analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) for oral use, CIII • Initiate treatment with two capsules orally every 4 hours as needed for pain. Initial U.S. Approval: 1958 (2.2) • Administer SYNALGOS-DC with food or a full glass of water to minimize WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE­ gastrointestinal (GI) distress. (2.1) THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL • Do not stop SYNALGOS-DC abruptly in a physically dependent patient. INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE (2.4) AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS Capsules: 16 mg dihydrocodeine bitartrate, 356.4 mg aspirin, and 30 mg caffeine AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM (3) CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS ------------------------------CONTRAINDICATIONS------------------------------­ • Children younger than 12 years of age (4) See full prescribing information for complete boxed warning. • Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy (4) • SYNALGOS-DC exposes users to risks of addiction, abuse, and misuse, • Significant respiratory depression (4) which can lead to overdose and death. Assess patient's risk before • Acute or severe bronchial asthma in an unmonitored setting or in absence of prescribing and monitor regularly for these behaviors and conditions. resuscitative equipment (4) (5.1) • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs • Serious, life-threatening, or fatal respiratory depression may occur. within the last 14 days (4) Monitor closely, especially upon initiation or following a dose increase. • Known or suspected gastrointestinal obstruction, including paralytic ileus (4) (5.2) • Hypersensitivity to dihydrocodeine, codeine, or aspirin (4) • Accidental ingestion of SYNALGOS-DC, especially by children, can • Hemophilia (4) result in a fatal overdose of dihydrocodeine. (5.2) • Reye’s Syndrome (4) • Life-threatening respiratory depression and death have occurred in • Known allergy to NSAIDs (4) children who received codeine; most cases followed tonsillectomy • Syndrome of asthma, rhinitis, and nasal polyps (4) and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. ------------------------WARNINGS AND PRECAUTIONS----------------------­ (5.3) SYNALGOS-DC is contraindicated in children younger than 12 • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary years of age and in children younger than 18 years of age following Disease or in Elderly, Cachectic, or Debilitated Patients: Monitor closely, tonsillectomy and/or adenoidectomy. (4) Avoid the use of SYNALGOS­ particularly during initiation and titration. (5.7) DC in adolescents 12 to 18 years of age who have other risk factors that • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of may increase their sensitivity to the respiratory depressant effects of corticosteroids, and wean patient off of the opioid. (5.9) dihydrocodeine. • Severe Hypotension: Monitor during dosage initiation and titration. Avoid • Prolonged use of SYNALGOS-DC during pregnancy can result in use of SYNALGOS-DC in patients with circulatory shock. (5.10) neonatal opioid withdrawal syndrome, which may be life-threatening if • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, not recognized and treated. If prolonged opioid use is required in a Head Injury, or Impaired Consciousness: Monitor for sedation and pregnant woman, advise the patient of the risk of neonatal opioid respiratory depression. Avoid use of SYNALGOS-DC in patients with withdrawal syndrome and ensure that appropriate treatment will be impaired consciousness or coma. (5.11) available. (5.4) • Risks of Use in Patients with Gastrointestinal Conditions Including Peptic • The effects of concomitant use or discontinuation of cytochrome P450 Ulcer Disease: Aspirin can cause an increased risk of serious gastrointestinal 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with dihydrocodeine (GI) adverse events including bleeding, ulceration, and perforation of the are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or stomach or intestines, which can be fatal. These events can occur at any time 2D6 inhibitors with SYNALGOS-DC requires careful consideration of during use and without warning symptoms. Elderly patients and patients the effects on the parent drug, dihydrocodeine, and the active with a prior history of peptic ulcer disease and/or GI bleeding are at greater metabolite, dihydromorphine. (5.5), (7) risk for serious GI events. (5.12) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in -------------------------------ADVERSE REACTIONS-----------------------------­ profound sedation, respiratory depression, coma, and death. Reserve Most common adverse reactions were lightheadedness, dizziness, drowsiness, concomitant prescribing for use in patients for whom alternative sedation, nausea, vomiting, constipation, pruritus, and skin reactions. (6) treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of To report SUSPECTED ADVERSE REACTIONS, contact Sun respiratory depression and sedation. (5.6), (7) Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------------------------RECENT MAJOR CHANGES--------------------------­ Boxed Warning 08/2017 -------------------------------DRUG INTERACTIONS-----------------------------­ Indications and Usage (1) 12/2016 • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Dosage and Administration (2) 08/2017 Discontinue SYNALGOS-DC if serotonin syndrome is suspected. (7) Contraindications (4) 08/2017 • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use Warnings and Precautions (5) 08/2017 with SYNALGOS-DC because they may reduce analgesic effect of SYNALGOS-DC or precipitate withdrawal symptoms. (7) ----------------------------INDICATIONS AND USAGE--------------------------­ SYNALGOS-DC is a combination of dihydrocodeine, an opioid agonist, aspirin, a ------------------------USE IN SPECIFIC POPULATIONS----------------------­ nonsteroidal anti-inflammatory drug, and caffeine, a methylxanthine, and is • Pregnancy: May cause fetal harm. Use of aspirin, including SYNALGOS­ indicated for the management of pain severe enough to require an opioid analgesic DC, during the third trimester of pregnancy increases the risk of premature and for which alternative treatments are inadequate. (1) closure of the fetal ductus arteriosus. (8.1) • Lactation: Breastfeeding not recommended. (8.2) Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, even at See 17 for PATIENT COUNSELING INFORMATION and Medication recommended doses, reserve SYNALGOS-DC for use in patients for whom Guide. alternative treatment options (e.g., non-opioid analgesics): Revised: 8/2017 • Have not been tolerated, or are not expected to be tolerated, • Have not provided adequate analgesia, or are not expected to provide adequate analgesia Reference ID: 4145172 FULL PRESCRIBING INFORMATION: CONTENTS* 5.13 Increased Risk of Seizures in Patients with Convulsive or Seizure Disorders WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING 5.14 Withdrawal RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA­ 5.15 Risks of Driving and Operating Machinery RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK 5.16 Coagulation Abnormalities and Bleeding Risks FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN 5.17 Reye’s Syndrome CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; 5.18 Allergy INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 5.19 Renal Toxicity and Hyperkalemia ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH 5.20 Premature Closure of Fetal Ductus Arteriosus BENZODIAZEPINES OR OTHER CNS DEPRESSANTS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS 2 DOSAGE AND ADMINISTRATION 8.1 Pregnancy 2.1 Important Dosage and Administration Instructions 8.2 Lactation 2.2 Initial Dosage 8.3 Females and Males of Reproductive Potential 2.3 Titration and Maintenance of Therapy 8.4 Pediatric Use 2.4 Discontinuation of SYNALGOS-DC 8.5 Geriatric Use 3 DOSAGE FORMS AND STRENGTHS 8.6 Hepatic Impairment 4 CONTRAINDICATIONS 8.7 Renal Impairment 5 WARNINGS AND PRECAUTIONS 9 DRUG ABUSE AND DEPENDENCE 5.1 Addiction, Abuse, and Misuse 9.1 Controlled Substance 5.2 Life-Threatening Respiratory Depression 9.2 Abuse 5.3 Ultra-Rapid Metabolism of Dihydrocodeine and Other Risk Factors for 9.3 Dependence Life-Threatening Respiratory Depression in Children