Endocet (oxycodone HCl/acetaminophen)

It isessential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

To minimize risk of overdosage, recommended age-appropriate daily dosages of acetaminophen should not be exceeded.

Dosage of oxycodone hydrochloride is expressed in terms of the salt; dosage of oxycodone myristate is expressed in terms of oxycodone base.

Oxycodone should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient. Reduced dosage is indicated in debilitated patients and in very young or very old patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used. Some manufacturers recommend that initial dosages of 33-50% of the usual dosage be employed when therapy with oxycodone hydrochloride extended-release tablets is initiated in patients receiving other CNS depressants. When therapy with extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen is initiated in patients receiving other CNS depressants, the manufacturer states that the initial oxycodone hydrochloride dosage should be reduced by 50% (i.e., to 7.5 mg twice daily).

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days). When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 33 mg or more of oxycodone hydrochloride daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily (approximately 60 mg or more of oxycodone hydrochloride daily) or carefully justify their decision to titrate the dosage to such levels. Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.

Patients receiving long-term, daily, around-the-clock opiate analgesia should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for manifestations of opiate withdrawal and for the development of addiction, abuse, or misuse. To reduce the risk of respiratory depression, appropriate dosage selection and titration are essential. The initial dosage of oxycodone must be individualized, taking into account the patient's severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse. Because there is substantial interpatient variability in the relative potency of opiate analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opiate requirements and provide ''rescue'' therapy with an immediate-release opiate analgesic than to overestimate the requirements and manage an adverse reaction. Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.

In patients requiring long-term around-the-clock opiate analgesia, dosage of oxycodone should be titrated to a level that provides adequate analgesia and minimizes adverse effects. Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period. Patients who experience breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., ''rescue'' therapy with an immediate-release analgesic). If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the oxycodone dosage. During long-term therapy, the continued need for opiate analgesics should be continually reevaluated. If discontinuance of opiate therapy is required, the dosage should be tapered gradually to avoid manifestations of abrupt withdrawal.

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Oxycodone/acetaminophen should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals.

Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available.

Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with oxycodone/acetaminophen. Consider this risk when selecting an initial dose and when making dose adjustments.

Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with oxycodone/acetaminophen, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose.

Dosage of oxycodone/acetaminophen tablets: Initiate treatment using oxycodone hydrochloride and acetaminophen 2.5 mg/325 mg tablets in a dosing range of 1 to 2 tablets every 6 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose. The total daily dose of acetaminophen should not exceed 4 grams. When using the fixed combination of 2.5 mg/325 mg, the usual adult dosage is 1 or 2 tablets every 6 hours as needed for pain (maximum daily dose of 12 tablets). When using the fixed combination of 5 mg/325 mg, the usual adult dosage is 1 tablet every 6 hours as needed for pain (maximum daily dose of 12 tablets). When using the fixed combination of 7.5 mg/325 mg, the usual adult dosage is 1 tablet every 6 hours as needed for pain (maximum daily dose of 8 tablets). When using the fixed combination of 10 mg/325 mg, the usual adult dosage is 1 tablet every 6 hours as needed for pain (maximum daily dose of 6 tablets).

Dosage of oxycodone/acetaminophen oral solution: Initiate treatment with oxycodone hydrochloride and acetaminophen oral solution at a dose of 5 mL (one teaspoonful) every 6 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose. The total daily dose of acetaminophen should not exceed 4 grams. Maximum daily dose is 12 teaspoonfuls or 60 mL.

Conversion from oxycodone/acetaminophen to extended-release oxycodone: The relative bioavailability of oxycodone/acetaminophen tablets or oral solution compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to an increased risk of excessive sedation and respiratory depression.

Adjust the dosage of oxycodone/acetaminophen to obtain an appropriate balance between management of pain and opioid-related adverse reactions.

Do not rapidly reduce or abruptly discontinue oxycodone/acetaminophen in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.

In patients with impaired hepatic function, initial oxycodone dosages should be conservative and adjusted according to the clinical situation. The manufacturers recommend that therapy with oxycodone hydrochloride extended-release tablets or oxycodone myristate extended-release capsules be initiated at 33-50% of the usual dosage and titrated carefully. When extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are used for the management of acute pain in patients with hepatic impairment, the manufacturer recommends an initial oxycodone hydrochloride dose of 7.5 mg (given in fixed combination with 325 mg of acetaminophen); dosage should be adjusted as needed with close monitoring for respiratory depression.

In patients with impaired renal function (creatinine clearance less than 60 mL/minute), initial oxycodone dosages should be conservative and adjusted according to the clinical situation. When extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are used for the management of acute pain in patients with renal impairment, the manufacturer recommends an initial oxycodone hydrochloride dose of 7.5 mg (given in fixed combination with 325 mg of acetaminophen); dosage should be adjusted as needed with close monitoring for respiratory depression.

If the required dose of oxycodone myristate extended-release capsules is less than 9 mg of oxycodone, an alternative analgesic should be selected.

Acetaminophen injection is administered by IV infusion over 15 minutes.

Acetaminophen is also commercially available in fixed-combination with ibuprofen (Combogesic(R)IV) for IV administration. See the full prescribing information for administration of this combination product.

Several commercially available fixed-combination prescription preparations containing acetaminophen are also available for oral use. See the full prescribing information for administration of these combination products.

Acetaminophen is commercially available in various oral and rectal over-the-counter (OTC) preparations as a single ingredient or in combination with other analgesics (e.g., ibuprofen), antihistamines, or decongestants. See the FDA Orange Book and the manufacturer's Drug Facts for further information.

Oxycodone is administered orally as the hydrochloride salt, often in combination with nonopiate analgesics (e.g., acetaminophen), or as the myristate salt.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Opioid Analgesics/Opioid Antagonists

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Naltrexone, nalmefene, and samidorphan are opioid antagonists and thus inhibit the effects of opioid analgesics.(1-3)

CLINICAL EFFECTS: Concurrent administration or the administration of naltrexone within 7-10 days of opioids may induce acute abstinence syndrome or exacerbate a pre-existing subclinical abstinence syndrome.(1,4) Patients taking naltrexone may not experience beneficial effects of opioid-containing medications.(4) Samidorphan can precipitate opioid withdrawal in patients who are dependent on opioids. In patients who use opioids, delay initiation of samidorphan for a minimum of 7 days after last use of short-acting opioids and 14 days after last use of long-acting opioids.(3) Concurrent use of nalmefene tablets with opioid agonists may prevent the beneficial effects of the opioid.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of naltrexone states that the administration of naltrexone concurrently with opioids or to patients dependent on opioids is contraindicated.(1,4) Patients previously dependent on short-acting opioids should be opioid-free for a minimum of seven to ten days before beginning naltrexone therapy. Patients previously on buprenorphine or methadone may be vulnerable to withdrawal symptoms for as long as 2 weeks.(1,4) The manufacturer of naltrexone states that the naloxone challenge test, described in the naltrexone prescribing information, can be administered to determine if patients are opioid free.(1) The manufacturer of samidorphan states the concurrent use of samidorphan in patients using opioids or undergoing acute opioid withdrawal is contraindicated. Prior to initiating samidorphan, there should be at least a 7-day opioid free interval from the last use of short-acting opioids, and at least a 14-day opioid free interval from the last use of long-acting opioids.(3) The UK manufacturer of nalmefene tablets (for reduction of alcohol consumption) states the concurrent use of opioid analgesics is contraindicated.(2) Suspend the use of nalmefene tablets for 7 days prior to the anticipated use of opioids (e.g., elective surgery).(2)

DISCUSSION: A double-blind, randomized, placebo-control study evaluated pain relief and side effects of 35 opioid-naive patients undergoing cesarean section. All patients received spinal anesthesia (bupivacaine and morphine) and were randomized to also receive placebo, naltrexone 3 mg, or naltrexone 6 mg. Patients treated with naltrexone experienced shorter duration of pain relief (not statistically significant), however incidence of opioid-induced side effects was reduced. Patients in the naltrexone 6 mg group had lower rates of pruritus, vomiting, and somnolence (all statistically significant) compared to the placebo group.(5) In a double-blind, randomized, placebo-control trial ten recreational opioid users were studied to determine the effects of hydromorphone (4 mg and 16 mg), tramadol (87.5 mg, 175 mg, and 350 mg), and placebo after pretreatment with naltrexone (50 mg) or placebo. Results show that lower doses of hydromorphone and tramadol acted similar to placebo. Hydromorphone 16 mg alone caused euphoria and miosis which were blocked by naltrexone. Tramadol 350 mg produced a lower magnitude of euphoria and miosis compared to hydromorphone. Naltrexone partially diminished the euphoria caused by tramadol, while it enhanced some of the unpleasant monoaminergic effects (flushing, malaise, vomiting).(6) A case report describes a 28 year-old ex-heroin addict who was stable on methadone 100 mg daily and simultaneously stopped using heroin and began drinking alcohol. He was admitted to the hospital for alcohol detoxification and, by mistake, was given naltrexone 100 mg instead of methadone 100 mg. The patient experienced withdrawal symptoms including chills, agitation, muscle and abdominal pain, generalized piloerection, and dilated pupils. Treatment of withdrawal was titrated to treat symptoms and required administration 78 mg of parenteral hydromorphone, after which the patient experienced relief for the following six hours.(8) Intentional administration of an opioid antagonist, naloxone, with opioid analgesics has been performed with close monitoring to lower required opioid dose by inducing withdrawal. Three case reports describe patients who had improved pain relief on significantly reduced doses of opioid analgesics.(8) In a double-blind controlled trial, 267 trauma patients were randomized to receive 0.05 mg/kg intravenous morphine either alone or in combination with 5 mg naltrexone oral suspension. Evaluated endpoints include reduction of pain and incidence of side effects. Results indicate that ultra-low dose naltrexone does not alter opioid requirements for pain control, but does lower incidence of nausea [2 (1.16%) vs 16 (11.6%), p<0.001].(9)

Selected Opioids/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil.(1)

CLINICAL EFFECTS: Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are particularly susceptible to significant toxicity, including profound sedation, respiratory depression, coma, and/or death.(1,2)

PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity.

PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with CYP3A4 substrates with a narrow therapeutic range, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil, is contraindicated.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) If concomitant use is unavoidable, monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.(1) Mifepristone is a time- and concentration-dependent CYP3A4 inhibitor. Single dose mifepristone 200 mg may have a lower risk of inhibiting the metabolism of CYP3A4 substrates, including selected opioids.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Acetaminophen/Sodium Fusidate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium fusidate and acetaminophen may inhibit the biotransformation of each other by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use may result in toxicity from sodium fusidate and acetaminophen.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian manufacturer of sodium fusidate states that concurrent use of sodium fusidate and CYP3A4 biotransformed drugs such as acetaminophen should be avoided.(1)

DISCUSSION: Although the specifics of sodium fusidate metabolic pathways are not known, an interaction between sodium fusidate and drugs that are biotransformed by CYP3A4 is suspected.(1)

Acetaminophen; Nsaids/Alprostadil

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Alprostadil is a prostaglandin E1 product used to maintain patency of a patent ductus arteriosus (PDA).(1) Acetaminophen and nonsteroidal anti-inflammatory (NSAID) agents inhibit prostaglandins and may be used for PDA closure in addition to pain/fever management.(2-4)

CLINICAL EFFECTS: Simultaneous administration of acetaminophen or NSAIDs may result in decreased clinical effects from alprostadil, including reduction in PDA.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of acetaminophen or NSAIDs in patients on alprostadil for maintaining patency of a patent ductus arteriosus (PDA).(1)

DISCUSSION: NSAIDs and acetaminophen are used as management for patent ductus arteriosus (PDA) closure.(2-4) Alprostadil is used to maintain patency of a PDA.(1) In a case report, a 37-week gestational age neonate with cardiac defects required alprostadil therapy for PDA patency. After multiple doses of acetaminophen for pain, an echocardiogram showed reduction of the PDA requiring increased doses of alprostadil. Additional acetaminophen was discontinued. Follow up echocardiogram showed successful reversal of PDA reduction and alprostadil dose was reduced.(5)

Agents That May Cause Respiratory Depression/Sodium Oxybate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Anticholinergics; Opioids/Eluxadoline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eluxadoline is a mixed mu-opioid and kappa-opioid agonist and delta-opioid antagonist and may alter or slow down gastrointestinal transit.(1)

CLINICAL EFFECTS: Constipation related adverse events that sometimes required hospitalization have been reported, including the development of intestinal obstruction, intestinal perforation, and fecal impaction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use with other drugs that may cause constipation. If concurrent use is necessary, evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(1) Instruct patients to stop eluxadoline and immediately contact their healthcare provider if they experience severe constipation. Loperamide may be used occasionally for acute management of severe diarrhea, but must be discontinued if constipation develops.(1)

DISCUSSION: In phase 3 clinical trials, constipation was the most commonly reported adverse reaction (8%). Approximately 50% of constipation events occurred within the first 2 weeks of treatment while the majority occurred within the first 3 months of therapy. Rates of severe constipation were less than 1% in patients receiving eluxadoline doses of 75 mg and 100 mg.(1)

Selected Opioids/Ceritinib; Crizotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ceritinib(1) and crizotinib(2) inhibit CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme, including alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil.

CLINICAL EFFECTS: Concurrent use of ceritinib(1) or crizotinib(2) with alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil may lead to elevated drug levels and increased side effects of the opioid, including profound sedation, respiratory depression, coma, and/or death.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid coadministration of sensitive or narrow therapeutic window CYP3A4 substrates such as alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, or sufentanil with ceritinib and crizotinib. If concomitant use is unavoidable, dosage adjustments of the opioid should be considered when initiating or discontinuing ceritinib(1) or crizotinib.(2) Patients maintained on ceritinib or crizotinib may need lower initial doses of opioid medications. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for adverse affects, including unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(6)

DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Crizotinib (250 mg twice daily for 28 days) increased the AUC of oral midazolam by 3.7-fold.(2) Thus, ceritinib(1) and crizotinib(2) are expected to increase levels of opioids metabolized by CYP3A4.

Selected Opioids/Selected Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil.(6) Benzhydrocodone is a prodrug of hydrocodone.(3)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil,(6) including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: Heat.

PATIENT MANAGEMENT: Monitor patients receiving potent or moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of itraconazole states that concomitant administration of fentanyl is not recommended during and 2 weeks after itraconazole treatment.(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(6) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9)

DISCUSSION: A nested-case control study of patients who were prescribed fentanyl patches, hydromorphone, or oxycodone and were hospitalized for opioid toxicity found that, among 70 cases and 120 control patients, CYP3A4-inhibiting macrolides (erythromycin and clarithromycin) were associated with a higher risk of opioid toxicity (aOR 3.80, 95% CI: 1.36-11.56 with fentanyl; aOR 3.38, 95% CI: 1.28-8.97 with hydromorphone; aOR 3.11, 95% CI: 1.05-9.51 with oxycodone).(10) In a randomized, placebo-controlled trial in 20 healthy subjects, clarithromycin (500 mg twice daily) increased the area-under-curve (AUC) of a single oral dose of oxycodone (10 mg) by 2-fold and 2.3-fold in young and elderly subjects, respectively.(11) In a controlled cross-over study in 6 subjects, 7 days of pretreatment with erythromycin decreased the clearance of alfentanil by 25%. Alfentanil half-life increased by 56%.(12) Erythromycin has been shown to inhibit fentanyl metabolism in vitro.(13) In a randomized, double-blind, placebo-controlled crossover study in 9 subjects, single doses of intravenous fluconazole (400 mg) and oral fluconazole (400 mg) decreased the clearance of a single dose of alfentanil (20 mcg/kg) by 58% and 55%, respectively. Alfentanil half-life almost doubled after both intravenous and oral fluconazole. Both intravenous and oral fluconazole increased subjective effects of alfentanil and increased alfentanil-induced respiratory depression.(14) In a cross-over study, pretreatment with itraconazole (200 mg daily for 4 days) had no effect on a single dose of intravenous fentanyl (3 mcg/kg).(15) In a cross-over study in 12 healthy subjects, itraconazole (200 mg daily for 5 days) increased the AUC and Cmax of a single oral dose of oxycodone (10 mg) by 144% and 45%, respectively. The AUC of noroxycodone decreased 49% and the AUC of oxymorphone increased 359% with concurrent itraconazole and oral oxycodone. Itraconazole increased the AUC of a single intravenous dose of oxycodone (0.1 mg/kg) by 51%.(16) In a randomized cross-over study in 12 healthy subjects, ketoconazole increased the AUC of oxycodone by 2-fold to 3-fold and also increased oxycodone-related nausea, drowsiness, and pruritus.(17) In a randomized cross-over study in 10 healthy subjects, ketoconazole increased the AUC of oxymorphone by 3-fold following a single dose of oxycodone (0.2 mg/kg). Increased side effects were also noted.(18,19) Ketoconazole has been shown to inhibit the metabolism of alfentanil,(20) fentanyl,(13) and oxycodone(21) in vitro. In a study of 11 subjects, ritonavir reduced the clearance of fentanyl 67% and increased the AUC 174%. Eight subjects reported nausea during the study.(22) In a randomized cross-over study in 16 healthy subjects, ritonavir (300 mg twice daily for 4 days) and lopinavir/ritonavir (400/100 mg twice daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg) by 3.0-fold and 2.6-fold, respectively. Oxycodone half-life increased 55% and 58%, respectively, with concurrent ritonavir or lopinavir/ritonavir. Both regimens also increased self-reported oxycodone effects.(23) The Australian manufacturer of ritonavir states that the AUC of fentanyl may be potentially increased 3-fold with concurrent ritonavir.(24) In a randomized cross-over study in 11 healthy subjects, telithromycin (800 mg daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg immediate-release) by 80%. The AUC of noroxycodone was decreased by 46%. There was a modest increase in the pharmacodynamic effects of oxycodone.(25) In a randomized cross-over study in 10 healthy subjects, troleandomycin increased the AUC of alfentanil by 135%.(26) In a randomized cross-over study in 12 healthy subjects, troleandomycin increased the AUC of a single dose of fentanyl (oral transmucosal, 10 mcg/kg) by 76%.(27) Troleandomycin has been shown to inhibit alfentanil(19) and fentanyl(28) metabolism in vitro. In a randomized, cross-over study in 12 healthy subjects, concurrent use of voriconazole and alfentanil increased the AUC of alfentanil 6-fold and decreased its clearance by 85%.(25,29) In a randomized, cross-over study in 12 healthy subjects, voriconazole (400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400 mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(30) In a randomized cross-over study in 12 healthy subjects, pretreatment with voriconazole for 4 days increased the AUC, Cmax, and half-life of a single dose of oxycodone (10 mg) by 3.6-fold, 1.7-fold, 2.0-fold, respectively.(31) There are case reports of interactions between alfentanil and erythromycin,(32) fentanyl and clarithromycin,(33) fentanyl and fluconazole,(34) fentanyl and itraconazole,(35) and oxycodone and voriconazole.(36) In the case report with fentanyl and fluconazole, the patient died of respiratory depression.(34) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(2) In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(6) Strong CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone or would be expected to interact with these agents include: boceprevir, clarithromycin, cobicistat, elvitegravir, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, voriconazole.(37) Moderate CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone include: erythromycin and fluconazole.(37)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Acetaminophen/Busulfan

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Busulfan is eliminated from the body via glutathione conjugation. Acetaminophen reduces glutathione levels in the blood and tissues and therefore could decrease the elimination rate of busulfan.(1,2)

CLINICAL EFFECTS: Concurrent use of acetaminophen may result in elevated levels of, prolonged exposure to, and toxicity from busulfan, including myelosuppression, granulocytopenia, thrombocytopenia, anemia, seizures, hepatic veno-occlusive disease, cardiac tamponade, bronchopulmonary dysplasia, or cellular dysplasia.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use acetaminophen concurrent with busulfan with caution.(1) Consider withholding acetaminophen for 72 hours before and during busulfan therapy. If concurrent use cannot be avoided, monitor patients for busulfan toxicity.

DISCUSSION: Although a small population study in adult patients found no effect of acetaminophen on busulfan clearance,(3) caution is still warranted.(1)

Acetaminophen/Isoniazid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Isoniazid may induce the metabolism of acetaminophen to its toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite by CYP2E1.(1)

CLINICAL EFFECTS: Concurrent isoniazid and acetaminophen may result in hepatotoxicity.(1) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: The interaction may be more severe in fast acetylators.

PATIENT MANAGEMENT: Concurrent use of acetaminophen in patients treated with isoniazid should be approached with caution. Consider an alternative analgesic agent. If concurrent therapy is warranted, advise patients not to exceed the maximum recommended daily dose of acetaminophen and to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Isoniazid has been shown to induce, after initially inhibiting, the metabolism of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxicity. Normally, NAPQI is rapidly converted to non-toxic metabolites by glutathione; however, high levels of NAPQI can overwhelm this system.(2-4) In a case report, a patient receiving isoniazid developed severe acetaminophen toxicity following a suicide attempt, despite only having ingested a maximum of 11.5 grams of acetaminophen and having a blood acetaminophen level of 15 mmol/L 13 hours later. Toxicity is usually seen with levels greater than 26 mmol/L.(5) In a retrospective review of 20 deaths in patients taking isoniazid alone or with ethambutol during a 13 year period, two deaths involved patients receiving concurrent isoniazid and acetaminophen.(6,7)

Acetaminophen/Selected Anticoagulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Acetaminophen may reduce levels of functional Factor VI, thereby increasing the International Normalized Ratio (INR).(1) In one trial factors II and VII levels were also reduced, thereby increasing the INR. (2)

CLINICAL EFFECTS: Concurrent use of routine acetaminophen, especially at dosages greater than 2 grams/day, and coumarin anticoagulants may result in elevated anticoagulant effects.

PREDISPOSING FACTORS: Routine use of acetaminophen at dosages greater than 2 grams/day may increase the risk of the interaction.

PATIENT MANAGEMENT: Patients receiving routine acetaminophen at dosages greater than 2 grams/day with coumarin anticoagulants should be closely monitored for changes in anticoagulant effects. The dosage of the anticoagulant may need to be adjusted. Patients receiving coumarin anticoagulants should be counseled on the use of acetaminophen.

DISCUSSION: A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 4 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and non-NSAID analgesics (OR=2.12; 95% CI 1.65-2.73). Increased bleeding risk was also seen in subgroup analyses with acetaminophen (OR=2.32; 95% CI 1.22-4.44).(3) In a study in 11 patients maintained on warfarin, use of acetaminophen (4 grams daily for 14 days) increased INR values by an average of 1.04.(4) In a study in 36 patients maintained on warfarin, the addition of acetaminophen (2 grams/day or 4 grams/day) increased INR values.(5) In a study in 20 patients maintained on warfarin, the addition of acetaminophen (4 grams/day for 14 days) increased average INR values by 1.20 (from 2.6 to 3.45).(6) In a study, 12 patients maintained on various anticoagulants (anisindione, dicoumarol, phenprocoumon, and warfarin) who received 4 weeks of acetaminophen (2.6 grams/day) were compared to 50 subjects maintained on various anticoagulants who did not receive acetaminophen. By the third week of concurrent acetaminophen, prothrombin times increased from 23 seconds to 28.4 seconds. The average warfarin-equivalent dose decreased by 5.8 mg to 4.4 mg. In another phase, 50 subjects maintained on various anticoagulants received acetaminophen (2.6 grams/day for 14 days). The mean prothrombin increase was 3.6 seconds.(7) There have been case reports of increased INRs following concurrent acetaminophen in patients maintained on warfarin(8-11) and acenocoumarol.(12) In contrast to the above reports, other studies have found no effects on acenocoumarol,(14) phenprocoumon,(13-15) or warfarin(16,17) by acetaminophen. In a study in 45 patients maintained on warfarin, the addition of acetaminophen (2 or 3 grams/day for 10 days) increased average INR by 0.7 and 0.67 with 2 grams/day and 3 grams/day, respectively. This increase was apparent by day 3, and a decrease in factor II and VII was observed.(2) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and acetaminophen resulted in a ratio of rate ratios (95% CI) of 1.28 (1.18-1.38).(18) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Agents With Hyponatremia Risk/Desmopressin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Opioids (Immediate Release)/Benzodiazepines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and benzodiazepines may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as benzodiazepines, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(5) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(6) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(7) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(8) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(9) A study of 315,428 privately insured patients who filled at least one prescription for an opioid from 2001 to 2013 were enrolled in a retrospective study. Concurrent use of a benzodiazepine was recorded as having at least one day of overlap in a given calendar year. Baseline characteristics among opioid users with concurrent use of a benzodiazepine were older (44.5 v. 42.4, p<0.001), less likely to be men (35% v. 43%, p<0.001), and had a higher prevalence rate of every comorbidity examined (p<0.001). The proportion of opioid users with concurrent benzodiazepine use nearly doubled from 9% in 2001 to 17% in 2013. The primary outcome was an emergency room visit or inpatient admission for opioid overdose within a calendar year. Among all opioid users, the annual adjusted incidence for the primary outcome was 1.16% without concurrent benzodiazepine use compared to 2.42% with concurrent benzodiazepine use (OR 2.14; 95% CI 2.05-2.24; p<0.001). Intermittent opioid users (1.45% v. 1.02%; OR 1.42; 95% CI 1.33-1.51; p<0.001) and chronic opioid users (5.36% v. 3.13%; OR 1.81; 95% CI 1.67-1.96; p<0.001) also experienced a higher adjusted incidence of the primary outcome with concurrent benzodiazepine use compared to without concurrent benzodiazepine use, respectively.(10) In a nested case-control study of adults with a new opioid dispensing between 2010-2018, patients with concurrent use of an opioid with a benzodiazepine were significantly more likely to have opioid-related overdose compared to patients receiving opioids, benzodiazepines, or neither (OR 9.28; 95% CI 7.87, 10.93). Longer concurrent use of 1-7, 8-30, and 31-90 days was associated with 4.6, 12.1, and 26.7-fold higher likelihood of opioid-related overdose (p<0.01). Patients with overlapping prescriptions during previous 0-30, 31-60, and 61-90 days were 13.2, 6.0, and 3.2-times more likely to experience an overdose (p<0.01).(11)

Opioids (Immediate Release)/Cyclobenzaprine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and cyclobenzaprine may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as cyclobenzaprine, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Opioids (Immediate Release)/Muscle Relaxants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and muscle relaxants may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as muscle relaxants to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Opioids (Immediate Release)/Selected Stimulants

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS.

CLINICAL EFFECTS: Opposing CNS effects of opioids and stimulants may compromise the effectiveness of both agents and mask opioid overdose symptoms such as drowsiness and inability to focus.

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).

DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)

Opioids (Immediate Release)/Sleep Drugs

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and sleep drugs may result in additive CNS depression and sleep-related disorders.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1) Concurrent use of opioids with eszopiclone, zaleplon, or zolpidem may increase the risk of sleep-related disorders including central sleep apnea and sleep-related hypoxemia and complex sleep behaviors like sleepwalking, sleep driving, and other activities while not fully awake. Rarely, serious injuries or death have resulted from complex sleep behaviors.(2)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as sleep drugs to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who have had a previous episode of complex sleep behavior.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10) As of April 2019, the FDA had identified 66 cases of complex sleep behaviors with eszopiclone, zaleplon, or zolpidem, of which 20 cases resulted in death and the remainder resulted in serious injuries. It was not reported how many of the cases involved concomitant use of other CNS depressants.(2)

Opioids (Ir & Er)/Gabapentinoids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Opioid-induced reduction in GI motility may increase the absorption of gabapentin and pregabalin.(1) Gabapentin and pregabalin may reverse opioid-induced tolerance of respiratory depression.(2) Concurrent use may result in profound sedation, respiratory depression, coma, and/or death.(3)

CLINICAL EFFECTS: Concurrent use of opioids may result in elevated levels of and toxicity from gabapentin and pregabalin, including profound sedation, respiratory depression, coma, and/or death.(1-7)

PREDISPOSING FACTORS: Patients who are elderly, are taking other CNS depressants, have decreased renal function, and/or have conditions that reduce lung function (e.g. Chronic Obstructive Pulmonary Disease [COPD]) may be at a higher risk of this interaction.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics and gabapentinoids to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a gabapentinoid with an opioid analgesic, prescribe a lower initial dose of the gabapentinoid than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a gabapentinoid, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9)

DISCUSSION: In a study in 12 healthy males, administration of a single dose of morphine (60 mg sustained release) increased the area-under-curve (AUC) of a single dose of gabapentin (600 mg) by 44%.(1,3,4) There were no affects on the pharmacokinetics of morphine.(1,3,4) The combination of gabapentin plus morphine increased pain tolerance over the combination of morphine plus placebo. Side effects were not significantly different between morphine plus placebo and morphine plus gabapentin.(1) A retrospective, case-control study of opioid users in Ontario, Canada between August 1, 1997 and December 31, 2013 who died of an opioid-related cause matched cases to up to 4 controls who also used opioids. Use of gabapentin in the 120 days prior to death resulted in a significant increase in odds of opioid-related death (OR 1.99, CI=1.61-2.47, p<0.001), compared to opioid use alone. Use of moderate dose (900 mg to 1,799 mg daily) or high dose (>= 1,800 mg daily) gabapentin increased the odds of opioid-related death 60% compared to opioid use without gabapentin. Review of gabapentin prescriptions from calendar year 2013 found that 46% of gabapentin users received at least 1 opioid prescription.(3) Among 49 case reports submitted to FDA over a 5 year period (2012-2017), 12 people died from respiratory depression with gabapentinoids. Two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals were reviewed. A trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function. Three observational studies showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after surgery. Several animal studies also showed that pregabalin plus opioids can depress respiratory function.(7) A retrospective cohort study evaluated the risk of mortality among Medicare beneficiaries aged 65 and older who were taking gabapentin with or without concurrent use of opioids. All-cause mortality in gabapentin users compared to duloxetine users was 12.16 per 1,000 person years vs. 9.94 per 1,000 person years, respectively. Adjusted for covariates, the risk of all-cause mortality among gabapentin users on high-dose opioids was more than double the control group (hazard ratio (HR) 2.03, CI=1.19-3.46).(10)

Opioids/Buprenorphine; Pentazocine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Buprenorphine is a partial agonist at mu-opiate receptors, exhibiting a ceiling effect at which higher doses produce no further effect. Pentazocine is a mixed agonist-antagonist at opiate receptors.(1) Full mu-opioid agonists (e.g., morphine, methadone) continue to have increased effects at higher doses without ceiling effects.(2)

CLINICAL EFFECTS: Concurrent use of buprenorphine or pentazocine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.

PREDISPOSING FACTORS: Patients dependent on opioids or who take higher dosages of opioids may be more likely to experience withdrawal symptoms with concurrent use.

PATIENT MANAGEMENT: Use buprenorphine and pentazocine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. The manufacturer of Sublocade states buprenorphine may precipitate opioid withdrawal in patients who are currently physically dependent on full opioid agonists. The risk of withdrawal may be increased if buprenorphine is given less than 6 hours after short-acting opioids (such as heroin, morphine) and less than 24 hours after long-acting opioids (such as methadone).(3)

DISCUSSION: Concurrent use of buprenorphine with other opioids in opioid dependent patients could result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.(2) In clinical trials, administration of buprenorphine injection produced withdrawal symptoms in patients maintained on methadone (30 mg daily) when administered 2 hours post-methadone,(4) but not when administered 20 hours post-methadone.(5) In another study, sublingual buprenorphine produced withdrawal symptoms in patients maintained on methadone. Symptoms were more pronounced in patients maintained on 60 mg daily doses than in patients maintained on 30 mg daily doses.(6) In a study of 10 patients maintained on methadone (100 mg daily), only three were able to tolerate escalating sublingual doses of buprenorphine/naloxone up to 32/8 mg. Split doses produced less withdrawal symptoms than full doses.(7) In a case report, a heroin-user maintained in a buprenorphine-maintenance program began stockpiling his buprenorphine instead of ingesting it and began using heroin. He then decided to re-initiate treatment on his own and ingested between 80 and 88 mg of buprenorphine over a two day period and experienced extreme withdrawal symptoms, despite restarting heroin during these symptoms. Methadone relieved his withdrawal symptoms.(8)

Opioids/Butorphanol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Butorphanol antagonize mu-opiate receptors. Other opioids agonize mu-opiate receptors.(1)

CLINICAL EFFECTS: Concurrent use of butorphanol with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.

PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. Patients using higher doses of opioids may also be at a higher risk.

PATIENT MANAGEMENT: Use butorphanol with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects.

DISCUSSION: Because butorphanol antagonizes mu-opiate receptors and other opioids agonize mu-opiate receptors, concurrent use of buprenorphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia and decreased opioid side effects.(1) In a study in patients maintained on methadone, butorphanol produced withdrawal symptoms comparable to naloxone.(2) In a case report, the use of remifentanil for conscious sedation in a patient maintained on butorphanol produced severe withdrawal symptoms.(3)

Opioids/Nalbuphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nalbuphine(1) antagonizes mu-opiate receptors. Other opioids agonize mu-opiate receptors.

CLINICAL EFFECTS: Concurrent use of nalbuphine with other opioids in opioid dependent patients may result in withdrawal symptoms. Concurrent use in other patients may result in additive or decreased analgesia, decreased opioid side effects, and/or renarcotization.

PREDISPOSING FACTORS: Patients dependent on opioids may be more likely to experience withdrawal symptoms with concurrent use. In opioid naive patients, higher doses of nalbuphine may result in decreased analgesic effects.

PATIENT MANAGEMENT: Use nalbuphine with caution in patients maintained or dependent on other opioids and monitor for signs of withdrawal. In other patients, also monitor for changes in analgesic effects. If nalbuphine is used to reverse opioid anesthesia, monitor patients for renarcotization.

DISCUSSION: Nalbuphine has been successfully used as an adjunct to morphine without decreasing analgesic effects.(2,3) However, other studies reported increased morphine requirements in patients who had initially received nalbuphine.(4,5) Nalbuphine has been used to reverse fentanyl anesthesia;(8-13) however, patients often required additional pain medication(5-7) and some studies reported renarcotization after the effects of nalbuphine wore off.(9,10) Nalbuphine has also been used to prevent epidural fentanyl,(13) morphine(14-16), and hydromorphone induced pruritus;(17-18) however, one study reported shortening of the duration of analgesia(16) and another reported increased PCA demands.(17) In methadone-dependent subjects, administration of nalbuphine produced withdrawal symptoms similar to naloxone.(19,20) Administration of nalbuphine to patients maintained on controlled-release morphine resulted in withdrawal symptoms.(20,21)

Oxycodone/Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may alter the metabolism of oxycodone.(1) Oxycodone is primarily metabolized by CYP3A4 to noroxycodone then by CYP2D6 to noroxymorphone as well as by CYP2D6 to oxymorphone. Noroxycodone, oxymorphone, and noroxymorphone are active metabolites.(1-3)

CLINICAL EFFECTS: The concurrent administration of oxycodone and a strong inhibitor of CYP2D6 may result in decreased efficacy or increased effects and toxicity of oxycodone. Parent and metabolite concentrations of oxycodone may be altered.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with oxycodone and a strong CYP2D6 inhibitor should be observed for decreased effectiveness as well as signs of increased effects and opioid toxicity. An alternative analgesic, such as morphine or nonopioid analgesics, may need to be considered.

DISCUSSION: Strong inhibitors of CYP2D6 have been shown to alter the metabolism of oxycodone.(1-3) A study in 10 healthy subjects who were CYP2D6 extensive metabolizers were given oxycodone 20 mg with either quinidine 200 mg or placebo, followed by quinidine 100 mg 6 hours later. Levels of oxymorphone were undetectable at any time point after quinidine administration. The psychomotor or subjective drug effects of oxycodone were unchanged.(4) A study in 10 healthy subjects received a single dose of quinidine 100 mg (a strong CYP2D6 inhibitor) followed by oxycodone 0.2 mg/kg oral drops. Oxymorphone (CYP2D6 dependent metabolite) concentration maximum (Cmax) and area-under-curve (AUC) were both decreased by 40% with quinidine administration compared to oxycodone alone. Oxycodone AUC and AUC at 90 minutes post administration were increased 1.5-fold and 8.5-fold, respectively. Total clearance of oxycodone was decreased by 20-30%. A compensatory 70% increase of noroxycodone (CYP3A4 dependent metabolite) AUC was also observed.(5) A study in 11 healthy subjects evaluated the effects of paroxetine 20 mg daily on single dose oxycodone 10 mg. Paroxetine decreased the mean AUC of CYP2D6 dependent metabolite oxymorphone by 44% (p<0.05) and increased the mean AUC of CYP3A4 dependent metabolite noroxycodone by 68% (p<0.001). Administration of paroxetine increased the VAS score for deterioration of performance for the first 6 hours following oxycodone.(6) A randomized crossover trial in 10 healthy subjects with differing CYP2D6 metabolizer statuses received oxycodone with either placebo, quinidine, ketoconazole, or both quinidine and ketoconazole. CYP2D6 activity correlated with oxymorphone and noroxymorphone AUCs and Cmax.(7) A retrospective cohort study in 111 patients found patients who received oxycodone with either a CYP2D6 or CYP3A4 inhibitor had an increased risk of gastrointestinal, dizziness, and drowsiness adverse reactions. Use of either a CYP2D6 or CYP3A4 inhibitor increase the risk by 20.4 and 25.4 times, respectively. Concurrent use of both a CYP2D6 and CYP3A4 inhibitor increased the risk with an adjusted OR of 48.6.(8) A cohort study evaluated the use of concurrent oxycodone and SSRIs that inhibit CYP2D6 on the risk of opioid overdose. The adjusted incidence rate of opioid overdose in patients on SSRIs that inhibit CYP2D6 when initiated on oxycodone was higher than SSRIs that do not inhibit CYP2D6 (9.47 per 1000 person years vs 7.66 per 1000 person years, respectively).(9) The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines state that CYP2D6 poor metabolizers have a lower peak concentration of oxymorphone (CYP2D6 dependent metabolite) after a dose of oxycodone compared to extensive metabolizers; however, clinical significance of metabolizer status on analgesia or risk of toxicity is unknown.(10) CPIC recommends selecting alternative drugs other than oxycodone for CYP2D6 poor and intermediate metabolizers, or be alert to insufficient pain relief; for CYP2D6 ultrarapid metabolizers, select an alternative to oxycodone, or be alert for adverse events.(10) Strong CYP2D6 inhibitors linked to this monograph include: bupropion, dacomitinib, fluoxetine, hydroquinidine, paroxetine, and quinidine.(11)

Selected Opioid Analgesics/Cimetidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The metabolism of selected opioid analgesics may be inhibited by cimetidine.(1-15) At doses of 800-2400 mg daily, cimetidine is a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP1A2, CYP2C19, CYP2C9, and CYP2D6.(16) Benzhydrocodone is a prodrug of hydrocodone.(12)

CLINICAL EFFECTS: The effect of selected opioid analgesics may be increased including profound sedation, respiratory depression, coma, and/or death. Opioid analgesics have been associated with histamine release and is dependent on dose, route of administration, and rate of administration. Histamine release can cause arteriole dilation and contribute to a profound decrease in systemic blood pressure. The cardiovascular effects of histamine release occurring with the opioid analgesics may be decreased by giving cimetidine concurrently.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cimetidine use at higher doses of 200-400 mg four times daily would have an increased risk of inhibiting the metabolism of opioid analgesics. Lower doses and over-the-counter doses of cimetidine would be expected to have a diminished effect. Consider using alternative H2 antagonists when long-term concurrent therapy with opioid analgesics is indicated. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(15) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(17) Monitor the patient for increased adverse effects of the opioid analgesic including respiratory and central nervous system depression, unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(18)

DISCUSSION: Severe respiratory depression has been reported with the concurrent administration of opioid analgesics and cimetidine. Systemic levels of opioid analgesics metabolized by CYP3A4 may be increased during concurrent use with cimetidine, a CYP3A4 inhibitor.(1-15) In a study of 6 healthy subjects, the effects of ketoconazole (a strong CYP3A4 inhibitor) 400 mg daily for 3 days on alfentanil were studied. The maximum concentration (Cmax) and area-under-curve (AUC) of alfentanil were increased with both sequential and simultaneous dosing of alfentanil with concurrent ketoconazole.(19) In a study of 16 healthy subjects, the effects of ketoconazole 300 mg twice daily for 2 days on fentanyl 5 mcg/kg single dose were examined. Fentanyl AUC was increased by 133% and clearance was reduced to 78%. The metabolism of fentanyl to norfentanyl by CYP3A4 was delayed and partial metabolic clearance decreased by 18% with concurrent ketoconazole.(20) In vitro results of the effects of ketoconazole on hydrocodone confirmed CYP3A4 is responsible for the metabolism of hydrocodone to norhydrocodone.(21) A review discussed the metabolism of hydrocodone by CYP2D6 to O-demethylated hydromorphone and by CYP3A4 to N-demethylated norhydrocodone. CYP3A4 activity is reported as higher in women resulting in higher fractions of the norhydrocodone metabolite in women than in men.(22) A case report of a 46 year old hemodialysis patient was on routine therapy with phenytoin 100 mg three times daily and cimetidine 300 mg three times daily. Four days after starting cimetidine, morphine 15 mg IM every 4 hours was initiated for pain. After the sixth dose of morphine, the patient was apneic with a respiratory rate of 3 breaths/minute and had a grand mal seizure. The patient responded to naloxone 0.4 mg IV single dose with improvement in respiratory rate to 12 breaths/minute. Cimetidine was stopped and phenytoin decreased to 100 mg twice daily with improvement after 80 hours from initial episode. A month later the patient required surgery and was given cimetidine 150 mg twice daily followed by Pantopon 15 mg IM every 3-6 hours postoperatively for pain. The patient again became apneic, confused, and developed muscle twitching which responded to naloxone 0.4 mg for 4 doses over the next 24 hours with complete recovery.(23) In a study of 8 healthy subjects, the effects of cimetidine on morphine were studied. Subjects were evaluated in three study periods: morphine 10 mg IM single dose; cimetidine 600 mg oral given one hour before morphine 10 mg IM single dose; and cimetidine 600 mg oral single dose. Morphine reduced resting ventilation and increased end-tidal CO2 with peak effects at 120 minutes and resolution at 12 hours. Morphine with cimetidine pretreatment had similar effects on resting ventilation and end-tidal CO2, however the recovery ratio from 120 to 720 minutes was significantly different than morphine alone (p<0.05).(24) In a study of 7 healthy subjects, the effects of cimetidine 300 mg oral four times daily for 4 days on morphine 10 mg IV single dose were evaluated. No significant differences were found in morphine concentrations at any time point from zero to ten hours after dose administration with and without cimetidine. Morphine elimination half-life (t1/2), systemic clearance, volume of distribution, and AUC with and without cimetidine had no statistical differences.(25) In a study of 40 patients undergoing elective coronary artery bypass graft surgery were randomized to receive either cimetidine 4 mg/kg, diphenhydramine 1 mg/kg, a combination of both cimetidine and diphenhydramine, or placebo, followed by morphine 1 mg/kg. Patients were randomized to one of four groups: 1. placebo plus morphine; 2. cimetidine plus morphine; 3. diphenhydramine plus morphine; or 4. cimetidine plus diphenhydramine plus morphine. Patients in group 1 had a 10-fold increase in plasma histamine levels within 2 minutes of morphine with a decrease in mean BP, diastolic BP, and systemic vascular resistance (SVR). Group 2 has similar effects with a peak change in SVR and plasma histamine rise within 2 minutes of morphine. The change in SVR was significant when compared to placebo but less than group 1. Group 3 patients had an increase in heart rate (HR) from diphenhydramine alone as well as peak effects within 2 minutes of morphine with decreases in BP and SVR but were less than morphine alone. Group 4 patients had a 7-fold increase in histamine with a significant increase in HR, diastolic BP, and BP. When group 4 is compared to group 1, patients had a decrease in SVR and diastolic BP that was significantly less despite comparable increases in plasma histamine.(26) In vitro testing of oxycodone and methadone, cimetidine caused a greater than 50% inhibition in all pathways: CYP2B6, CYP3A4, CYP2C18, and CYP2D6. Cimetidine was found to be a weak reversible inhibitor in vitro. Extrapolation of the data to in vivo inhibition is unlikely to produce significant inhibition unless concentrations exceed normal doses by 10-fold.(27) Two studies examined the effects of CYP2D6 and CYP3A4 on the metabolism of oxycodone as well as genetic polymorphism influences. After concurrent administration of oxycodone with ketoconazole, the Cmax of the metabolites noroxycodone and noroxymorphone were decreased by 80% from baseline.(28,29) A review discussed the metabolism of oxycodone by CYP3A4 to noroxycodone, the major metabolite with weak antinociceptive properties, and by CYP2D6 to the active minor metabolite oxymorphone.(30) In a study of 8 male subjects, effects of cimetidine 600 mg twice daily for seven days on pethidine 70 mg IV single dose was evaluated. Concurrent use with cimetidine was associated with a 22% decrease in clearance, 11% decrease in elimination rate, and a 13% decrease in volume of distribution of pethidine. Changes were also seen in norpethidine, the primary metabolite, with a 23% decrease in AUC and 29% decrease in Cmax.(31) Opioid analgesics linked to this monograph include: alfentanil, benzhydrocodone, dihydrocodeine, fentanyl, hydrocodone, meperidine, meptazinol, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, and sufentanil.

Selected Opioids (Immediate Release)/Metaxalone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and metaxalone may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as the muscle relaxant metaxalone, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as the muscle relaxant metaxalone to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(4) A retrospective cohort study compared the risk of opioid overdose associated with concomitant use of opioids and skeletal muscle relaxants versus opioid use alone. The study examined two types of opioid users (naive opioid use and prevalent opioid use) with and without exposure to skeletal muscle relaxants. The adjusted hazard ratios (HR) were 1.09 and 1.26 in the naive and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21. The risk increased with treatment duration (less than or equal to 14 days: 0.91; 15-60 days: 1.37; and greater than 60 days: 1.80) and for the use of baclofen and carisoprodol (HR 1.83 and 1.84, respectively). Elevated risk was associated with concomitant users with daily opioid dose greater than 50 mg and benzodiazepine use (HR 1.50 and 1.39, respectively).(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Selected Opioids/Barbiturates; Phenobarbital; Primidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: There are two mechanisms involved in this interaction. Pharmacokinetic: alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are primarily metabolized by CYP3A4/5 and glucuronidation pathways.(1-8) Phenobarbital is an inducer of these pathways. Pharmacodynamic: both opioids and barbiturates are associated with respiratory depression; these effects may be additive.(1,3,9) Benzhydrocodone is a prodrug of hydrocodone.(2) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Short term or intermittent use of phenobarbital and opioids metabolized by CYP3A4 may be associated with respiratory suppression or other CNS depression. Continuous, longer term use of phenobarbital may result in decreased levels and effectiveness of the opioid. Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(6,10)

PREDISPOSING FACTORS: Patients with a history of alcohol or sedative abuse may be at risk for relapse and overuse or abuse of prescribed phenobarbital.(1,3,5,11) Individuals with significant obstructive pulmonary disease, the elderly, and debilitated patients are at greater risk for respiratory depression from either agent.(1,3) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients on chronic therapy with phenobarbital who are newly starting opioids metabolized by CYP3A4 may need higher than usual doses of the opioid for analgesia or opioid maintenance.(1,3,12) Opioid-treated patients newly started on phenobarbital should be monitored initially for additive CNS sedation or respiratory depression, particularly when predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are present. Continued use of phenobarbital leads to induction of the opioids' metabolism. The onset is gradual and may not peak for several weeks. Monitor patient for possible loss of efficacy or opioid withdrawal. If a patient has been maintained on concurrent treatment with an opioid metabolized by CYP3A4 and phenobarbital, and the phenobarbital is discontinued, opioid levels will gradually rise as induction effects diminish. Monitor for increased opioid effects and adjust the dose accordingly.(1,3,12) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(13) For patients receiving opioid maintenance treatment, it would be prudent to assure all controlled substance prescriptions are approved or written by the opioid provider. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(14)

DISCUSSION: Alfentanil, benzhydrocodone, fentanyl, hydrocodone, meperidine, oxycodone, and sufentanil are metabolized by CYP3A4, and barbiturates, phenobarbital, and primidone would be expected to induce their metabolism.(1,2,4-6) Newer metabolites and minor metabolic pathways for buprenorphine have been recently described. Phenobarbital, an inducer of multiple enzyme pathways (e.g. CYP2B, CYP2C, CYP3A and UGT) could potentially lower systemic buprenorphine levels via major and minor pathways.(12)

Selected Opioids/Selected Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of alfentanil, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2) oxycodone,(3) and sufentanil.(4)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, benzhydrocodone, fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4), including somnolence and potentially fatal respiratory depression.

PREDISPOSING FACTORS: Heat.

PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(4) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(6) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat.(1)

DISCUSSION: Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4 isoenzyme. Moderate and strong inhibitors of this isoenzyme are expected to increase fentanyl(1) and oxycodone(3) levels. In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(4) In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min) infusion had no effect on epidural fentanyl consumption when compared to placebo. There were no significant differences in Visual Analogue Scores (VAS), Verbal Rating Scores (VRS), or incidence of side effects, although there was a trend towards increased nausea with concurrent diltiazem.(5) In a randomized study of coronary artery bypass patients, concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of alfentanil by 40% and 50%, respectively, when compared to placebo. Patients who received diltiazem were extubated an average of 2.5 hours later than in patients who received placebo.(8) In a study in 13 patients, administration of a single dose of verapamil (75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic effects of a single dose of fentanyl; however, individual patients had modest decreases in blood pressure.(9) In a case report, concurrent diltiazem and fentanyl produced delirium.(10) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(11,12)

Selected Opioids/Selected Strong Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of alfentanil, benzhydrocodone, buprenorphine,(1) fentanyl, hydrocodone, meperidine,(2-4) morphine,(5) oxycodone, papaveretum, and sufentanil.(6)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in decreased levels of alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(1-6) Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(2,3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients maintained on alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil may require dosage adjustments if a strong CYP3A4 inducer is initiated or discontinued. The effects of the interaction may last for several weeks after the discontinuation of the inducer. Patients who transfer to Sublocade (extended release subcutaneous syringe buprenorphine) from transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level produced by Sublocade is adequate. If patients already on Sublocade require newly-initiated treatment with CYP3A4 inducer, the patient should be monitored for withdrawal. If the dose of Sublocade is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, the patient should be transitioned back to a formulation of buprenorphine that permits dose adjustment. If a patient has been stabilized on Sublocade with a CYP3A4 inducer and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of Sublocade administration, if the dose provided by Sublocade is excessive in the absence of the concomitant inducer, it may be necessary to remove the Sublocade and treat the patient with a formulation of buprenorphine that permits dose adjustments.(15) The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inducers is necessary, consider use of an alternate agent that allows dose adjustment.(6)

DISCUSSION: In a study in 12 opoid-dependent patients, rifampin (600 mg daily) decreased the area-under-curve (AUC) of buprenorphine by 70%. Half of the subjects experienced withdrawal symptoms. When compared to historical values, there was no effect on rifampin levels.(1) In a study of four healthy volunteers, phenytoin increased meperidine clearance from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min and decreased half-life from 6.4 hours to 4.3 hours. Phenytoin also increased normeperidine AUC by 1.53-fold after IV meperidine and by 1.25-fold after oral meperidine.(3) In a study in 10 healthy subjects, pretreatment with rifampin (600 mg daily) for 13 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of morphine by 28% and 41%, respectively. The AUCs of morphine-3-glucuronide and morphine-6-glucuronide were proportionally decreased as well. Following rifampin pretreatment, no analgesic effects of morphine were seen.(5) In a randomized controlled trial of 12 healthy participants St. John's wort decreased the oxycodone AUC by 50%, shortened the oxycodone elimination half-life, and decreased the self-reported drug effect of oxycodone compared to placebo.(7) In a study in 12 healthy subjects, pretreatment with rifampin had no effect on fentanyl Cmax or time to Cmax (Tmax) after administration of oral transmucosal fentanyl. However, fentanyl AUC decreased 62%.(8) In a study in 9 healthy subjects, rifampin increased the clearance of alfentanil by 169%. Alfentanil half-life decreased 61%.(9) In a study of patients undergoing craniotomy, higher fentanyl maintenance doses were required in patients receiving carbamazepine and phenytoin compared to control subjects not receiving enzyme-inducing agents.(10) There are case reports of decreased levels and effectiveness of oxycodone with concurrent phenytoin(11) and rifampin(12) and with concurrent fentanyl and rifampin.(13-14) Selected strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's Wort.

Slt Opioids (Immediate Release)/Antipsychotics;Phenothiazine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics, including phenothiazine derivatives, may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, including phenothiazine derivatives, may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including phenothiazine derivatives, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

Slt Opioids (Immediate Release)/Ziprasidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of opioids and antipsychotics such as ziprasidone may result in additive CNS depression.(1)

CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants such as ziprasidone may result in profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as antipsychotics, including ziprasidone, to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.(1) If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. If starting a CNS depressant (for an indication other than epilepsy) with an opioid analgesic, prescribe a lower initial dose of the CNS depressant than indicated in the absence of an opioid and titrate based upon clinical response. If an opioid analgesic is indicated in a patient already taking a CNS depressant, prescribe a lower dose of the opioid and titrate based upon clinical response.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. 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. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: A nested case-control study looked at the relationship between antipsychotic use and risk of acute respiratory failure. Current use of antipsychotics was associated with a 2.33-fold increase in risk of respiratory failure compared to no use of antipsychotics. The risk was also significantly increased in patients with recent use of antipsychotics (within the past 15-30 days, OR = 1.79) and recent past use (within 31-90 days OR = 1.41). The risk increased with higher doses and longer duration of use.(4) Between 2002 and 2014, the number of patients receiving an opioid analgesic increased 8%, from 75 million to 81 million patients, and the number of patients receiving a benzodiazepine increased 31%, from 23 million to 30 million patients. During this time, the proportion of patients receiving concurrent therapy increased 31%, from 23 million to 30 million patients.(5) From 2004 to 2011, the rate of nonmedical use-related emergency room visits involving both opioids and benzodiazepines increased from 11 to 34.2 per 100,000 and drug overdose deaths involving both opioids and benzodiazepines increased from 0.6 to 1.7 per 100,000. The proportion of prescription opioid analgesic deaths which also involved benzodiazepines increased from 18% to 31% during this time.(6) A prospective observational cohort study in North Carolina found that the rates of overdose death among patients co-dispensed opioid analgesics and benzodiazepines were 10 times higher than patients receiving opioid analgesics alone.(7) A case-cohort study of VA data from 2004-2009 found that the risk of death from overdose increased with concomitant opioid analgesics and benzodiazepines. Compared to patients with no history of benzodiazepines, patients with a history of benzodiazepine use (hazard ratio [HR] = 2.33) and patients with a current benzodiazepine prescription (HR=3.86) had an increased risk of fatal overdose.(8) A study found that opioid analgesics contributed to 77% of deaths in which benzodiazepines were determined to be a cause of death and that benzodiazepines contributed to 30% of deaths in which opioid analgesics were determined to be a cause of death. This study also found that other CNS depressants (including barbiturates, antipsychotic and neuroleptic drugs, antiepileptic and antiparkinsonian drugs, anesthetics, autonomic nervous system drugs, and muscle relaxants) were contributory to death in many cases where opioid analgesics were also implicated.(9) A study found that alcohol was involved in 18.5% of opioid analgesic abuse-related ED visits and 22.1 percent of opioid analgesic-related deaths.(10)

*Significant respiratory depression.

*Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.

*Known or suspected GI obstruction, including paralytic ileus.

*Hypersensitivity to oxycodone, acetaminophen, or any other component of the product (e.g., anaphylaxis).

*Known hypersensitivity to acetaminophen or any ingredient in the formulation.

*Severe hepatic impairment or severe active liver disease.

• Acetaminophen overdose
• Acute asthma attack
• Acute hepatic failure
• Acute hepatitis C
• Paralytic ileus

• Acute pancreatitis
• Alcohol intoxication
• Alcohol use disorder
• Alcohol withdrawal delirium
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Coma
• Cor pulmonale
• Debilitation
• Dehydration
• Disease of liver
• Drug abuse
• Exacerbation of chronic obstructive pulmonary disease
• Familial dysautonomia
• Gastrointestinal obstruction
• History of opioid overdose
• Hypotension
• Intracranial hypertension
• Neoplasm of brain
• Primary adrenocortical insufficiency
• Respiratory depression
• Shock
• Sleep apnea
• Suicidal ideation
• Systemic mastocytosis

• Adrenocortical insufficiency
• Benign prostatic hyperplasia
• Biliary tract disorder
• Chronic obstructive pulmonary disease
• Constipation
• Gallbladder disease
• Lower seizure threshold
• Protein-calorie malnutrition
• Seizure disorder
• Shock
• Toxic psychosis
• Untreated hypothyroidism
• Urethral stricture
• Urinary retention

The most common adverse effects reported in clinical trials in >=5% of patients receiving IV acetaminophen were nausea, vomiting, headache, and insomnia in adults and nausea, vomiting, constipation, and pruritus in pediatric patients.

Common adverse effects associated with oral or rectal administration of acetaminophen include skin rash, hypersensitivity reactions, nephrotoxicity, and hematologic abnormalities (e.g., anemia, leukopenia, neutropenia, and pancytopenia).

More Frequent

• Hypotension

Less Frequent

• Abnormal hepatic function tests
• Biliary spasm
• Opioid dependence
• Orthostatic hypotension
• Vasodilation of blood vessels

Rare or Very Rare

• Accidental fall
• Accidental injury
• Acute cognitive impairment
• Acute generalized exanthematous pustulosis
• Acute hepatic failure
• Acute respiratory failure
• Adrenocortical insufficiency
• Agranulocytosis
• Allergic dermatitis
• Allergic dermatitis
• Anaphylaxis
• Anemia
• Angioedema
• Angioedema
• Apnea
• Atelectasis
• Bronchospastic pulmonary disease
• Depression
• Disorder of adrenal gland
• Drug dependence
• Drug-induced hepatitis
• Dyspnea
• Hallucinations
• Heart failure
• Hypertonia
• Ileus
• Laryngeal edema
• Laryngeal edema
• Laryngismus
• Leukopenia
• Leukopenia
• Maculopapular rash
• Neutropenic disorder
• Pharyngeal edema
• Respiratory depression
• Shock
• Skin rash
• Sleep apnea
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Thrombophlebitis
• Toxic epidermal necrolysis
• Urticaria

More Frequent

• Constipation
• Dizziness
• Drowsy
• Fatigue
• General weakness
• Headache disorder
• Malaise
• Nausea
• Syncope
• Vomiting

Less Frequent

• Acute abdominal pain
• Diarrhea
• Dyspepsia
• Fever
• Flushing
• Gastroesophageal reflux disease
• Hyperhidrosis
• Irritability
• Nervousness
• Night sweats
• Peripheral edema
• Pruritus of skin
• Sleep disorder
• Xerostomia

Rare or Very Rare

• Abnormal hepatic function tests
• Agitation
• Androgen deficiency
• Anorexia
• Arthralgia
• Arthritis
• Chills
• Dry skin
• Dysphagia
• Dysuria
• Edema
• Erectile dysfunction
• Erythema
• Euphoria
• Flatulence
• Flu-like symptoms
• Glossitis
• Hyperglycemia
• Hypothalamic-pituitary insufficiency
• Increased appetite
• Infertility
• Insomnia
• Libido changes
• Medication overuse headache
• Migraine
• Non-cardiac chest pain
• Opioid induced allodynia
• Opioid induced hyperalgesia
• Palpitations
• Pharyngitis
• Skin photosensitivity
• Skin rash
• Stomatitis
• Symptoms of anxiety
• Tachycardia
• Tinnitus
• Toxic amblyopia
• Urinary retention
• Urinary tract infection
• Urticaria
• Visual changes
• Voice change

No enhanced messaging available.

The safety and effectiveness of oxycodone/acetaminophen in pediatric patients have not been established.

Use of IV acetaminophen for analgesia in pediatric patients >=2 years of age is supported by evidence from adequate and well-controlled studies of IV acetaminophen in adults and additional safety and pharmacokinetic data from 483 pediatric patients ranging in age from neonates to adolescents. Efficacy of IV acetaminophen for analgesia has not been established in pediatric patients <2 years of age.

Use of IV acetaminophen for fever in pediatric patients <2 years of age, including premature neonates (postmenstrual age of at least 32 weeks) is supported by evidence from adequate and well-controlled studies of IV acetaminophen in adults, clinical data in pediatric patients >=2 years of age, and additional safety and pharmacokinetic data from 239 patients <2 years of age, including neonates with a postmenstrual age of at least 32 weeks.

Animal reproductive studies have not been conducted with oxycodone/acetaminophen. It is also not known whether oxycodone/acetaminophen can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Oxycodone/acetaminophen should not be given to a pregnant woman unless in the judgment of the physician, the potential benefits outweigh the possible hazards.

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

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.

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. Oxycodone/acetaminophen is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including oxycodone/acetaminophen, 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.

Epidemiologic data regarding oral acetaminophen use in pregnant females have shown no increased risk of major congenital malformations in infants exposed in utero to the medication. In a large population-based prospective cohort study involving more than 26,000 females with live-born singleton infants who were exposed to oral acetaminophen during the first trimester of pregnancy, no increase in the risk of congenital malformations was observed in exposed children compared with a control group of unexposed children; rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, case-control study from the National Birth Defects Prevention Study also found no increase in the risk of major birth defects in a group of 11,610 children who had been exposed to acetaminophen during the first trimester of pregnancy compared with a control group of 4,500 children.

Animal reproduction studies in pregnant rats given oral acetaminophen during organogenesis at dosages up to 0.85 times the maximum recommended human daily dosage (4 g daily, based on body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations (reduced ossification and rudimentary rib changes); the offspring showed no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at a dosage of 1.2 times the maximum recommended human daily dosage, areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses; these effects did not occur in animals given acetaminophen at dosages of 0.3 times the maximum recommended human dosage.

In a continuous breeding study in which pregnant mice were given acetaminophen at dosages approximately equivalent to 0.43, 0.87, or 1.7 times the maximum recommended human daily dosage (based on body surface area comparison), a dose-related reduction in body weight of the fourth and fifth litter offspring of the treated mating pair occurred during lactation and following weaning at all dosages studied. Animals receiving the highest dosage had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next-generation pups.

The manufacturer states that there are no animal reproductive studies with IV acetaminophen.

A correlation between acetaminophen use during pregnancy and neurodevelopmental disorders in children, including autism and attention-deficit/hyperactivity disorder (ADHD), has been observed in studies; however, inconsistent findings have been reported in the literature and a causal relationship has not been established. Results of 2 high-quality studies with sibling controls indicate prenatal exposure to acetaminophen was not associated with an increased risk of a neurodevelopmental diagnosis. There are unmeasured familial confounding factors that may explain the apparent association observed in some studies. Acetaminophen is considered the preferred analgesic/antipyretic for use during pregnancy because of its relatively favorable safety profile compared with other common analgesics. The American College of Obstetricians and Gynecologists (ACOG) supports use of acetaminophen during pregnancy when taken as needed in moderation and after consultation with a doctor. There is no evidence to support any risk associated with appropriate use of acetaminophen during pregnancy. However, untreated maternal fever and pain pose risks such as neural tube defects and preterm birth, necessitating a balanced approach.

Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose. In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression. There are no data on the effects of the oxycodone on milk production.

Acetaminophen is excreted in breast milk in low concentrations.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for oxycodone/acetaminophen and any potential adverse effects on the breastfed infant from the drugs or from the underlying maternal condition.

Infants exposed to oxycodone/acetaminophen 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 breastfeeding is stopped.

It is not known if IV acetaminophen is excreted into human milk; however, data suggest following oral administration of acetaminophen, infant exposure is approximately 1-2% of the weight-adjusted maternal daily dosage. Limited published studies report acetaminophen passes rapidly into human milk with similar levels noted in milk and plasma. A case of rash in a breast-fed infant has been reported; the rash resolved when the mother discontinued acetaminophen use and recurred when she resumed acetaminophen therapy. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for acetaminophen and any potential adverse effects on the breast-fed infant from exposure to the medication or to the underlying maternal condition.

The manufacturer makes no specific dosage recommendations for geriatric patients. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to IV acetaminophen cannot be ruled out.

Elderly patients (65 years of age or older) may have increased sensitivity to oxycodone/acetaminophen. 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 oxycodone/acetaminophen slowly in geriatric patients and frequently reevaluate the patient for signs of CNS depression.

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

When the total number of patients studied in clinical trials of IV acetaminophen is considered, 15% were >=65 years of age, while 5% were >=75 years of age. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility some older patients may exhibit increased sensitivity to acetaminophen cannot be ruled out.