Version May 2024
The FDA has issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use. The required safety labeling changes include stating:
the risk of overdose increases as the dosage increases for all opioid pain medicines;
IR opioids should not be used for an extended period of time unless a patient's pain remains severe enough to require them and alternative treatment options continue to be inadequate;
many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine;
it is recommended to reserve ER/LA opioid pain medicines for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate; and
a warning about opioid-induced hyperalgesia (OIH), including information on differentiating OIH symptoms from those of opioid tolerance and withdrawal.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use.
Use 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 monitor all patients regularly for the development of these behaviors and conditions.
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 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 health care providers. Health care 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.
Serious, life-threatening, or fatal respiratory depression may occur with use. Monitor for respiratory depression, especially during initiation of therapy or following a dose increase.
Accidental ingestion, especially by children, can result in a fatal overdose of dihydrocodeine.
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 cytochrome P450 (CYP-450) 2D6 polymorphism. Acetaminophen/caffeine/dihydrocodeine is contraindicated in pediatric patients <12 years of age and in pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of acetaminophen/caffeine/dihydrocodeine in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.
Prolonged use of opioids 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.
The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with acetaminophen/caffeine/dihydrocodeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at dosages that exceed 4 g/day, and often involve more than 1 acetaminophen-containing product.
Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of acetaminophen/caffeine/dihydrocodeine 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.
Pain management:
General dosing: Note: For acute non–cancer-related pain severe enough to require an opioid, utilize multimodal pain control, maximize nonopioid analgesics, and limit the quantity prescribed to the expected duration of pain severe enough to require opioids (Ref).
Capsule (acetaminophen 320.5 mg/caffeine 30 mg/dihydrocodeine bitartrate 16 mg): Oral: Two capsules every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 10 capsules [acetaminophen 3,205 mg/caffeine 300 mg/dihydrocodeine 160 mg] per 24 hours).
Tablet (acetaminophen 325 mg/caffeine 30 mg/dihydrocodeine bitartrate 16 mg): Oral: Two tablets every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 10 tablets [acetaminophen 3,250 mg/caffeine 300 mg/dihydrocodeine 160 mg] per 24 hours).
Tablet (acetaminophen 712.8 mg/caffeine 60 mg/dihydrocodeine bitartrate 32 mg): Oral: One tablet every 4 hours as needed; adjust dose based on severity of pain (maximum dose: 5 tablets [acetaminophen 3,564 mg/caffeine 300 mg/dihydrocodeine 160 mg] per 24 hours).
Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid’s pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no specific dosage adjustments provided in the manufacturer's labeling; use with caution and at a reduced dose.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution and monitor carefully.
Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).
Refer to adult dosing. Initiate therapy at low end of dosing range and use caution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined. Most common reactions with this combination include:
Central nervous system: Dizziness, drowsiness, sedation
Dermatologic: Dermatological reaction, pruritus
Gastrointestinal: Constipation, nausea, vomiting
Postmarketing and/or case reports: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023), hypogonadism (Brennan 2013; Debono 2011)
Hypersensitivity (eg, anaphylaxis) to acetaminophen, caffeine, dihydrocodeine, codeine, or any component of the formulation; pediatric patients <12 years of age; postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment; hypercapnia; GI obstruction, including paralytic ileus (known or suspected).
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Constipation: May cause constipation, which may be problematic in patients with unstable angina and patients post-myocardial infarction (MI). Consider preventive measures (eg, stool softener, increased fiber) to reduce the potential for constipation.
• Hepatotoxicity: Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at dosages that exceed 4 g/day, and often involve >1 acetaminophen-containing product. Risk is increased with alcohol use, preexisting liver disease, and intake of more than one source of acetaminophen-containing medications. Chronic daily dosing in adults has also resulted in liver damage in some patients.
• Hypersensitivity/anaphylactic reactions: Hypersensitivity and anaphylactic reactions have been reported with acetaminophen use; discontinue immediately if symptoms of allergic or hypersensitivity reactions occur.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute MI), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Use with caution in patients with circulatory shock.
• Phenanthrene hypersensitivity: Use opioids with caution in patients with hypersensitivity reactions to other phenanthrene-derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxymorphone).
• Respiratory depression: Fatal respiratory depression may occur. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.
• Skin reactions: Serious and potentially fatal skin reactions, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have occurred rarely with acetaminophen use. Discontinue therapy at the first appearance of skin rash or any other sign of hypersensitivity.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenocortical insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• CNS depression/coma: Use with caution in patients with CNS depression or coma as these patients are susceptible to intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens
• Ethanol use: Use with caution in patients with alcoholic liver disease; consuming ≥3 alcoholic drinks/day may increase the risk of liver damage.
• G6PD deficiency: Use acetaminophen with caution in patients with known G6PD deficiency.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Renal impairment: Use with caution and at a reduced dose in patients with renal impairment.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale and those having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or preexisting respiratory depression, particularly when initiating therapy and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Seizure disorder: Use with caution in patients with a history of seizure disorder; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Benzodiazepines and other CNS depressants: Concomitant use may result in respiratory depression and sedation, which may be fatal. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.
• Cytochrome P450 interactions: The effects of concomitant use or discontinuation of cytochrome P450 (CYP-450) 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with codeine are complex. Use of CYP-450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with acetaminophen/caffeine/dihydrocodeine requires careful consideration of the effects on the parent drug, codeine, and the active metabolite, morphine.
Special populations:
• CYP2D6 "ultra-rapid metabolizers": Use caution in patients with ≥2 copies of the variant CYP2D6*2 allele; may have extensive conversion to morphine and thus increased opioid-mediated effects. The occurrence of this phenotype is seen in 0.5% to 1% of Chinese and Japanese patients, 0.5% to 1% of Hispanic patients, 1% to 10% of Caucasian patients, 3% of Black patients, and 16% to 28% of North African, Ethiopian, and Arab patients. There are no published recommendations for CYP2D6 genetic testing prior to dihydrocodeine use and no guidelines addressing dosing adjustments specific to CYP2D6 phenotype or genotype.
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.
• Neonates: Neonatal withdrawal syndrome: Prolonged use during pregnancy can cause neonatal withdrawal syndrome, which may be life-threatening if not recognized and treated 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. Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
• Pediatric: 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 ultra-rapid metabolizers of codeine due to a CYP-450 2D6 polymorphism. Acetaminophen/caffeine/dihydrocodeine is contraindicated in pediatric patients <12 years of age and in pediatric patients <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of acetaminophen/caffeine/dihydrocodeine in pediatric patients 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine. 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. Deaths have also occurred in nursing infants after being exposed to high concentrations of morphine because the mothers were ultra-rapid metabolizers. Use the lowest effective dose for the shortest period of time to reduce the risk of high concentrations of dihydromorphine.
Other warnings/precautions:
• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial agonist analgesics (eg, buprenorphine) may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.
• Abuse/misuse/diversion: Use exposes patients and other users to the risks of opioid use disorder, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing acetaminophen/caffeine/dihydrocodeine, and monitor all patients regularly for the development of these behaviors or conditions. Use with caution in patients with a history of substance use disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).
• Accidental ingestion: Accidental ingestion, especially in children, can result in a fatal overdose of dihydrocodeine.
• Appropriate use: Outpatient setting: Opioids should not be used as first-line therapy for acute (<1 month duration), subacute (1 to 3 month duration), or chronic pain (>3 month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications and antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and non-opioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]).
• Caffeine: May cause CNS and cardiovascular stimulation, as well as GI irritation in high doses.
• Dosage limit: Limit acetaminophen dose from all sources (prescription and OTC) to <4 g/day in adults. Do not use acetaminophen/caffeine/dihydrocodeine concomitantly with other acetaminophen-containing products.
• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help (FDA 2020).
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based on the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.
• Risk Evaluation and Mitigation Strategy (REMS): To ensure that the benefits of opioid analgesics outweigh the risks of substance use disorder, abuse, and misuse, the FDA has required a 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 health care providers. Health care 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.
• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in postoperative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Trezix: Acetaminophen 320.5 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg [contains fd&c red #40 (allura red ac dye)]
Generic: Acetaminophen 320.5 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg
Tablet, Oral:
Dvorah: Acetaminophen 325 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg [DSC]
Generic: Acetaminophen 325 mg, caffeine 30 mg, and dihydrocodeine bitartrate 16 mg [DSC]
Yes
Capsules (APAP-Caff-Dihydrocodeine Oral)
320.5-30-16 mg (per each): $3.89
Capsules (Trezix Oral)
320.5-30-16 mg (per each): $5.89
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
C-III
Pain management: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
Limitations of use: Reserve for use in patients for whom alternative treatment options (eg, nonopioid analgesics) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.
Panlor may be confused with Pamelor
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Duplicate therapy issues: This product contains acetaminophen, which may be a component of other combination products. Do not exceed the maximum recommended daily dose of acetaminophen.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acebrophylline: May enhance the stimulatory effect of CNS Stimulants. Risk X: Avoid combination
Adenosine: Caffeine and Caffeine Containing Products may diminish the therapeutic effect of Adenosine. Management: Monitor for decreased effect of adenosine if patient is receiving caffeine; significantly higher adenosine doses or alternative agents may be required. Discontinue caffeine 24 hours in advance of scheduled diagnostic use of adenosine if possible. Risk D: Consider therapy modification
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Busulfan: Acetaminophen may increase the serum concentration of Busulfan. Risk C: Monitor therapy
Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy
CarBAMazepine: May increase the metabolism of Acetaminophen. This may 1) diminish the effect of acetaminophen; and 2) increase the risk of liver damage. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Risk D: Consider therapy modification
CYP1A2 Inducers (Moderate): May decrease the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Dapsone (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Dasatinib: Acetaminophen may enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and dasatinib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider therapy modification
Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
Doxofylline: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Doxofylline. Risk X: Avoid combination
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Flucloxacillin: May enhance the adverse/toxic effect of Acetaminophen. Specifically, the risk for high anion gap metabolic acidosis may be increased. Risk C: Monitor therapy
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Formoterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Formoterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Formoterol. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: May decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity). Risk C: Monitor therapy
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Imatinib: Acetaminophen may enhance the hepatotoxic effect of Imatinib. Risk C: Monitor therapy
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Acetaminophen may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Indacaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Indacaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Indacaterol. Risk C: Monitor therapy
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Isoniazid: May enhance the hepatotoxic effect of Acetaminophen. Isoniazid may increase the metabolism of Acetaminophen. Specifically, formation of the hepatotoxic NAPQI metabolite may be increased. Risk C: Monitor therapy
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Kratom: May enhance the adverse/toxic effect of Sympathomimetics. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Levothyroxine: May enhance the adverse/toxic effect of Sympathomimetics. Specifically, the risk of coronary insufficiency may be increased in patients with coronary artery disease. Levothyroxine may enhance the therapeutic effect of Sympathomimetics. Sympathomimetics may enhance the therapeutic effect of Levothyroxine. Risk C: Monitor therapy
Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Consider initial dose reductions of sympathomimetic agents, and closely monitor for enhanced blood pressure elevations, in patients receiving linezolid. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lithium: Caffeine and Caffeine Containing Products may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Local Anesthetics: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Local Anesthetics. Specifically, the risk for methemoglobinemia may be increased. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lorlatinib: May decrease the serum concentration of Acetaminophen. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyraPONE: May increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk X: Avoid combination
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
MigALAstat: Caffeine and Caffeine Containing Products may decrease the serum concentration of MigALAstat. Risk X: Avoid combination
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Mipomersen: Acetaminophen may enhance the hepatotoxic effect of Mipomersen. Risk C: Monitor therapy
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: Dihydrocodeine may enhance the adverse/toxic effect of Monoamine Oxidase Inhibitors. Management: Consider avoiding use of dihydrocodeine while the patient is taking monoamine oxidase inhibitors (MAOIs) and for 2 weeks after MAOI discontinuation. Risk D: Consider therapy modification
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy
Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification
Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Nefazodone: Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Risk C: Monitor therapy
Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Norfloxacin: May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Olodaterol: Caffeine and Caffeine Containing Products may enhance the adverse/toxic effect of Olodaterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Olodaterol. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Risk C: Monitor therapy
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Phenylephrine (Systemic): Acetaminophen may increase the serum concentration of Phenylephrine (Systemic). Risk C: Monitor therapy
Pipemidic Acid: May increase the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Acetaminophen. Probenecid may also limit the formation of at least one major non-toxic metabolite, possibly increasing the potential for formation of the toxic NAPQI metabolite. Management: Consider limiting acetaminophen use in combination with probenecid. Probenecid may reduce clearance of acetaminophen to one of its non-toxic metabolities, increasing the risk for acetaminophen toxicity, even a lower doses. Risk D: Consider therapy modification
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
QuiNIDine: May diminish the analgesic effect of Dihydrocodeine. Specifically, quinidine may prevent the metabolic conversion of dihydrocodeine to its active metabolite Risk C: Monitor therapy
Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Regadenoson: Caffeine and Caffeine Containing Products may diminish the vasodilatory effect of Regadenoson. Management: Avoiding using caffeine or other methylxanthine containing products (e.g., theophylline) for at least 12 hours prior to the administration of regadenoson. Risk D: Consider therapy modification
RifAMPin: May enhance the hepatotoxic effect of Acetaminophen. RifAMPin may decrease the serum concentration of Acetaminophen. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for decreased therapeutic response (eg, analgesia) and opioid withdrawal when coadministered with SSRIs that strongly inhibit CYP2D6. Additionally, monitor for serotonin syndrome/serotonin toxicity if these drugs are combined. Risk C: Monitor therapy
Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Risk C: Monitor therapy
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Solriamfetol: CNS Stimulants may enhance the hypertensive effect of Solriamfetol. CNS Stimulants may enhance the tachycardic effect of Solriamfetol. Risk C: Monitor therapy
Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy
SORAfenib: Acetaminophen may enhance the hepatotoxic effect of SORAfenib. SORAfenib may increase the serum concentration of Acetaminophen. Management: Avoid coadministration of acetaminophen and sorafenib if possible. If coadministration is unavoidable, monitor for signs/symptoms of hepatotoxicity, particularly in patients with greater acetaminophen exposure. Risk D: Consider therapy modification
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Tobacco (Smoked): May decrease the serum concentration of Caffeine and Caffeine Containing Products. Risk C: Monitor therapy
Vaccines: Acetaminophen may diminish the therapeutic effect of Vaccines. Management: Consider avoiding routine prophylactic use of acetaminophen before or during vaccine administration when possible. Acetaminophen is still recommended to treat fevers and/or pain that occurs after vaccination. Risk D: Consider therapy modification
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Acetaminophen may enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Risk C: Monitor therapy
Warfarin: Caffeine and Caffeine Containing Products may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Long-term opioid use may cause secondary hypogonadism, which may lead to sexual dysfunction and infertility (Brennan 2013).
[US Boxed Warning]: Prolonged use 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.
Dihydrocodeine is a semisynthetic analogue of codeine; it has been shown to cause respiratory depression in the fetus when administered to women during labor (Leppert 2010; Myers 1958; Sliom 1970). Also refer to the Acetaminophen and Caffeine individual monographs for additional information.
Acetaminophen, caffeine, and dihydrocodeine are present in breast milk.
Concentrations of dihydrocodeine are dependent on the mother's CYP2D6 metabolism. In women with normal CYPD2D6 metabolism, the amount detected in breast milk is expected to be dose-dependent; women who are ultrarapid metabolizers may have higher than expected milk concentrations, which may lead to serious adverse reactions in a breastfeeding infant. Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer.
Also refer to the Acetaminophen and Caffeine individual monographs for additional information.
Pain relief, respiratory and mental status, blood pressure, heart rate; bowel function; signs/symptoms of misuse, abuse, and substance use disorder; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).
Alternate recommendations: Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2022]).
Acetaminophen: Although not fully elucidated, the analgesic effects are believed to be due to activation of descending serotonergic inhibitory pathways in the CNS. Interactions with other nociceptive systems may be involved as well (Smith 2009). Antipyresis is produced from inhibition of the hypothalamic heat-regulating center.
Caffeine: CNS stimulant; use with acetaminophen and dihydrocodeine increases the level of analgesia provided by each agent.
Dihydrocodeine: Binds to opiate receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; produces generalized CNS depression.
See individual agents.
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