codeine/aspirin/caffeine (Rx)

Brand and Other Names:Synalgos-DC
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

dihydrocodeine/aspirin/caffeine

capsule: Schedule V

  • 16mg/356.4mg/30mg

Moderate-to-Severe Pain

2 capsules PO q4hr prn

Limitations of use

  • Because of risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve therapy for use in patients for whom alternative treatment options [e.g., non-opioid analgesics], have not been tolerated, or are not expected to be tolerated, have not provided adequate analgesia, or are not expected to provide adequate analgesia

Dosing considerations

  • Initiate dosing regimen for each patient individually, taking into account patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse
  • Monitor patients closely for respiratory depression, especially within first 24-72 hours of initiating therapy and following dosage increases and adjust dosage accordingly
  • Administer therapy with food or a full glass of water to minimize GI distress

Safety and efficacy not established

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Adverse Effects

Frequency Not Defined

Dihydrocodeine

  • Light-headedness
  • Dizziness
  • Drowsiness
  • Headache
  • Fatigue
  • Sedation
  • Confusion

Aspirin

  • Stomach pain
  • Heartburn
  • Nausea
  • Vomiting
  • Dyspepsia
  • Tinnitus (high or chronic dose)
  • Rash

Caffeine

  • Insomnia
  • Restlessness
  • Nervousness
  • Tremor
  • Tinnitus
  • Irritability
  • Nausea
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Warnings

Black Box Warnings

Opioid analgesic risk evaluation and mitigation strategy (REMS)

  • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products; under 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
    • Consider other tools to improve patient, household, and community safety

Addiction, abuse, and misuse

  • Exposes patients and other users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death assess each patient's risk prior to prescribing therapy, and monitor all patients regularly for development of these behaviors and conditions

Life-threatening respiratory depression

  • Serious, life-threatening, or fatal respiratory depression may occur; monitor for respiratory depression, especially during initiation of therapy or following a dose increase

Accidental ingestion

  • Accidental ingestion of even one dose of drug, especially by children, can result in a fatal overdose

Neonatal opioid withdrawal syndrome

  • Prolonged use 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 patient of risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available

Postoperative pain in children

  • Deaths have occurred in children with obstructive sleep apnea who receive codeine for postoperative pain following tonsillectomy and/or adenoidectomy
  • Codeine is converted to morphine by the liver; these children had evidence of being ultra-rapid metabolizers (via CYP2D6) of codeine, which is an inherited (genetic) ability that causes codeine to be converted rapidly into life-threatening or fatal amounts of morphine (see Pharmacology)
  • Contraindicated in children <12 years and in children < 18 years following tonsillectomy and/or adenoidectomy; avoid use of capsules in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression; when prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of morphine overdose

Coadministration with benzodiazepines

  • 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 this drug combination and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to minimum required; follow patients for signs and symptoms of respiratory depression and sedation

Interactions with drugs affecting cytochrome P450 isoenzymes

  • 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 therapy requires careful consideration of effects on dihydrocodeine, and active metabolite, dihydromorphine

Contraindications

Hypersensitivity

Any situation where opioids are contraindicated including significant respiratory depression (in unmonitored settings or in the absence of resuscitation equipment), and acute or severe bronchial asthma or hypercapnia

Children <12 years

Postoperative management in children <18 years following tonsillectomy and/or adenoidectomy (see Black Box Warnings)

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days

Known or suspected gastrointestinal obstruction, including paralytic ileus

Hemophilia

Reye’s syndrome

Known allergy to nonsteroidal anti-inflammatory drugs (NSAIDs)

Syndrome of asthma, rhinitis, and nasal polyps

Cautions

May impair mental/physical abilities required for hazardous tasks (eg, driving, operating machinery)

May cause respiratory depression; risk is greatest during initiation of therapy or following a dosage increase; monitor patients closely for respiratory depression, especially within first 24-72 hours of initiating therapy and following dosage increases; to reduce risk, proper dosing and titration are essential; overestimating; dosage when converting patients from another opioid product can result in fatal overdose with first dose

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), therapy may reduce respiratory drive, and resultant CO2 retention can further increase intracranial pressure; monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy; opioids may also obscure clinical course in patient with head injury; avoid therapy in patients with impaired consciousness or coma

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 for signs of hypotension after initiating or titrating dosage; in patients with circulatory shock, therapy may cause vasodilation that can further reduce cardiac output and blood pressure; avoid use in patients with circulatory shock

Adrenal insufficiency have been reported with opioid use, more often following greater than one month of use; if adrenal insufficiency is suspected, confirm the diagnosis and if diagnosed, treat with physiologic replacement doses of corticosteroids; wean the patient off of 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; information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency

Contains dihydrocodeine bitartrate, a Schedule III controlled substance; as an opioid, the drug exposes users to risks of addiction, abuse, and misuse; assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing the drug, and monitor all patients for development of addiction behaviors and conditions; reduce risks by prescribing drug in smallest appropriate quantity and advising patient on proper disposal of unused drug

Caution in elderly or debilitated patients, or in patients with following conditions: adrenocortical insufficiency (Addison disease), asthma, central nervous system depression or coma, chronic obstructive pulmonary disease, decreased respiratory reserve (including emphysema, severe obesity, cor pulmonale, or kyphoscoliosis), delirium tremens, head injury, hypotension, increased intracranial pressure, myxedema or hypothyroidism, prostatic hypertrophy or urethral stricture, and toxic psychosis

Life-threatening respiratory depression and death have occurred in children who received codeine; codeine is subject to variability in metabolism based upon CYP2D6 genotype, which can lead to an increased exposure to active metabolite morphine; children < 12 years appear to be more susceptible to respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression; many reported cases of death occurred in postoperative period following tonsillectomy and/or adenoidectomy, and many of children had evidence of being ultra-rapid metabolizers of codeine

Avoid use in adolescents 12-18 years of age who have other risk factors that may increase sensitivity to respiratory depressant effects of codeine unless benefits outweigh risks; risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression; when prescribing codeine for adolescents, healthcare providers should choose lowest effective dose for shortest period of time and inform patients and caregivers about risks and the signs of morphine overdose

Use opioids with caution with MAOIs

Gastrointestinal bleeding; particular caution in patients with history of GI bleed, alcoholism, or bleeding disorders

Even low doses of aspirin can inhibit platelet function leading to 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

Aspirin may cause premature closure of the fetal ductus arteriosus; avoid use in pregnant women starting at 30 weeks of gestation (third trimester)

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury; correct volume status in dehydrated or hypovolemic patients prior to initiating therapy; monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during therapy; avoid use of drug in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function; if used in patients with advanced renal disease, monitor patients for signs of worsening renal function Avoid in severe hepatic impairment

Caffeine may produce CNS/CV stimulation and GI irritation

Aspirin should not be used in children or teenagers for viral infections, with or without fever, because of risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses

Opioid analgesic risk evaluation and mitigation strategy (REMS)

  • To ensure that benefits of opioid analgesics outweigh risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products
  • 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; use the following link to obtain the Patient Counseling Guide (PCG): 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 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
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Pregnancy & Lactation

Pregnancy Category: D; avoid aspirin during pregnancy, particularly in third trimester because of risk for premature closure of the ductus arteriosus

Pregnancy

Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome; available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage

Labor and delivery

  • Use of codeine during labor may lead to respiratory depression in the neonate; opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates; an opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate; use is not recommended in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate; opioid analgesics, 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 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

Lactation

Codeine and its active metabolite, morphine, 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; in women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent

There is no information on effects of codeine milk production; because of potential for serious adverse reactions, including excess sedation, respiratory depression, and death in a breastfed infant, breastfeeding is not recommended during treatment

Lactation: Distributed in breast milk in small amounts, caution advised

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Dihydrocodeine: Semisynthetic opioid agonist analgesic related to codeine

Aspirin: Acts on hypothalamus to produce antipyresis; anti-inflammatory properties attributed to prostaglandin synthetase inhibition resulting in decreased formation of thromboxane A2

Caffeine: Vasoconstrictive properties may be helpful when treating vascular headaches

Pharmacogenomics

10% of codeine is metabolized to morphine by CYP2D6; the active morphine metabolite has a higher affinity for opioid receptors

CYP2D6 poor metabolizers may not achieve adequate analgesia

Ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion

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Formulary

FormularyPatient Discounts

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Tier Description
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.