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Drug overview for ZUBSOLV (buprenorphine hcl/naloxone hcl):
Generic name: BUPRENORPHINE HCL/NALOXONE HCL (BUE-pre-NOR-feen/nal-OX-one)
Drug class: Opioid Antagonists
Therapeutic class: Chemical Dependency, Agents to Treat
Buprenorphine is a synthetic opiate partial agonist analgesic. Naloxone hydrochloride is an opioid antagonist.
Buprenorphine hydrochloride is used parenterally for the relief of pain that is severe enough to require opiate analgesia and for which alternative treatment options are inadequate. Buprenorphine hydrochloride also is used buccally and buprenorphine is used transdermally for the management of pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatment options are inadequate. In the management of opiate dependence (opiate use disorder (OUD)), buprenorphine is used parenterally as an extended-release subcutaneous injection, buprenorphine hydrochloride is used sublingually or as a subdermal implant, and buprenorphine hydrochloride in fixed combination with naloxone hydrochloride is used sublingually or buccally.
Generic name: BUPRENORPHINE HCL/NALOXONE HCL (BUE-pre-NOR-feen/nal-OX-one)
Drug class: Opioid Antagonists
Therapeutic class: Chemical Dependency, Agents to Treat
Buprenorphine is a synthetic opiate partial agonist analgesic. Naloxone hydrochloride is an opioid antagonist.
Buprenorphine hydrochloride is used parenterally for the relief of pain that is severe enough to require opiate analgesia and for which alternative treatment options are inadequate. Buprenorphine hydrochloride also is used buccally and buprenorphine is used transdermally for the management of pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatment options are inadequate. In the management of opiate dependence (opiate use disorder (OUD)), buprenorphine is used parenterally as an extended-release subcutaneous injection, buprenorphine hydrochloride is used sublingually or as a subdermal implant, and buprenorphine hydrochloride in fixed combination with naloxone hydrochloride is used sublingually or buccally.
DRUG IMAGES
ZUBSOLV 5.7-1.4 MG TABLET SL
ZUBSOLV 1.4-0.36 MG TABLET SL
ZUBSOLV 2.9-0.71 MG TABLET SL
ZUBSOLV 11.4-2.9 MG TABLET SL
ZUBSOLV 0.7-0.18 MG TABLET SL
ZUBSOLV 8.6-2.1 MG TABLET SL
The following indications for ZUBSOLV (buprenorphine hcl/naloxone hcl) have been approved by the FDA:
Indications:
Opioid use disorder
Professional Synonyms:
None.
Indications:
Opioid use disorder
Professional Synonyms:
None.
The following dosing information is available for ZUBSOLV (buprenorphine hcl/naloxone hcl):
Naloxone is used for the complete or partial reversal of opioid-induced depression, including respiratory depression, caused by natural and synthetic opioids (e.g., codeine, diphenoxylate, fentanyl citrate, heroin, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone, concentrated opium alkaloids, propoxyphene) and certain opioid partial agonists (e.g., butorphanol, nalbuphine, pentazocine). Reversal of respiratory depression resulting from overdosage of opioid partial agonists (e.g., buprenorphine, pentazocine) may be incomplete and require higher or more frequent doses of naloxone.
The availability of naloxone as prefilled syringes and as nasal spray formulations facilitates administration by family members or other caregivers; such treatment is not a substitute for emergency medical care. Administration of naloxone should be accompanied by other resuscitative measures such as administration of oxygen, mechanical ventilation, or artificial respiration. When administering naloxone outside of a supervised medical setting, always seek emergency medical assistance after the first dose is administered.
Naloxone is used in both adults and pediatric adults (including neonates) to reverse the effects of opioids. Naloxone has been given to the mother shortly before delivery+, but it is preferable to administer the drug directly to the neonate if needed after delivery.
Naloxone hydrochloride injection containing 5 mg per 0.5 mL (Zimhi(R)) is a higher concentration of the drug for IM or subcutaneous use in adults and pediatric patients for emergency treatment of known or suspected opioid overdose. The preparation is commercially available as single-dose prefilled syringes that are administered using a delivery device.
Naloxone hydrochloride 5 mg/0.5 mL was developed in response to increasing reports indicating that multiple 2-mg doses of naloxone have been required in resuscitations. Efficacy of this preparation for community use is supported by pharmacokinetic bridging studies.
Naloxone is used for the diagnosis of suspected or known acute opioid overdosage.
Naloxone is commercially available as naloxone hydrochloride; dosage is expressed in terms of the salt.
Dosage of buprenorphine and buprenorphine hydrochloride usually is expressed in terms of buprenorphine. Dosage of buprenorphine hydrochloride subdermal implants may be expressed as either the salt or the base.
For the relief of pain that is severe enough to require opiate analgesia and for which alternative treatments are inadequate, the usual IM or IV dosage of buprenorphine in patients 13 years of age and older is 0.3 mg given at intervals of up to every 6 hours as necessary. The initial dose (up to 0.3 mg) may be repeated once in 30-60 minutes, if needed.
The dose should be limited to the minimum amount required in high-risk patients (e.g., geriatric or debilitated patients, those with respiratory disease) and in patients receiving other CNS depressants, including patients in the immediate postoperative period. Particular caution is necessary if the drug is administered IV, especially with initial doses. In some patients, it may be necessary to increase the dose up to 0.6
mg, but the manufacturer recommends that such relatively high doses only be administered IM and only to adults who are not considered high-risk patients. In some patients, a dosing interval greater than 6 hours may be adequate. Alternatively, a regimen including an initial dose of 0.3
mg of buprenorphine followed by another 0.3-mg dose repeated in 3 hours has been shown to be as effective as a single 0.6-mg dose in relieving postoperative pain.
There are insufficient clinical data to recommend single doses greater than 0.6 mg for long-term use.
Although children 2-12 years of age have received parenteral buprenorphine dosages of 2-6 mcg/kg every 4-6 hours, longer dosing intervals (e.g., every 6-8 hours) may be sufficient for some children, and a fixed around-the-clock dosing interval should not be used until an adequate dosing interval has been established by clinical observation of the patient. In addition, the manufacturer states that there are insufficient data in children 2-12 years of age to recommend buprenorphine doses exceeding 6 mcg/kg or administration of a repeat dose within 30-60 minutes of the initial dose.
When buprenorphine has been administered by continuous IV infusion+ in the management of postoperative pain, dosages of 25-250 mcg/hour have been used in adults.
Buprenorphine has been administered epidurally+ in the management of postoperative pain in single doses of 60 mcg, up to a mean total dose of 180 mcg administered over a 48-hour period. Buprenorphine has also been administered epidurally+ in a dose of 0.3 mg as a supplement to surgical anesthesia with a local anesthetic.
In the management of severe, chronic pain (e.g., in terminally ill patients), buprenorphine doses of 0.15-0.3 mg have been administered epidurally as frequently as every 6 hours up to a mean total daily dose of 0.86
mg (range: 0.15-7.2 mg).
The manufacturer states that data are insufficient to recommend a parenteral buprenorphine dosage for infants younger than 2 years of age. In children 9 months to 9 years of age+ undergoing circumcision, some clinicians have used an initial IM buprenorphine dose of 3 mcg/kg as an adjunct to surgical anesthesia followed by additional 3-mcg/kg doses as necessary to provide analgesia postoperatively.
Buprenorphine transdermal system should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain. Dosages of 7.5, 10, 15, and 20 mcg/hour should be reserved for patients who are opiate experienced (i.e., have been receiving oral morphine sulfate dosages of up to 80 mg or more daily (or equivalent) for one week or longer) and have developed tolerance to an opiate of comparable potency.
In opiate-naive adults with pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatments are inadequate, treatment with transdermal buprenorphine should be initiated at a dosage of 5 mcg/hour.
When patients currently receiving opiate agonist therapy are switched to transdermal buprenorphine, there is a potential for buprenorphine to precipitate withdrawal. In these patients, the current opiate regimen should be tapered over a period of up to 7 days to a total 24-hour dosage equivalent to 30 mg or less of oral morphine sulfate. For patients whose prior total daily dosage of opiates was less than 30 mg of oral morphine sulfate (or equivalent), transdermal buprenorphine may be initiated at a dosage of 5 mcg/hour.
For patients whose prior total daily dosage was 30-80 mg of oral morphine sulfate (or equivalent), transdermal buprenorphine may be initiated at a dosage of 10 mcg/hour. Patients may receive supplemental short-acting analgesics as needed until adequate analgesia is attained. For patients whose prior total daily dosage exceeded 80 mg of oral morphine sulfate (or equivalent), buprenorphine 20 mcg/hour may not provide adequate analgesia and an alternative analgesic should be considered.
When therapy with a buprenorphine transdermal system is initiated, all other around-the-clock opiate analgesics should be discontinued. Buprenorphine may be initiated at the next dosing interval following discontinuance of the current opiate regimen. Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.
Buprenorphine dosage may be titrated upward at minimum intervals of 72 hours to a level that provides adequate analgesia and minimizes adverse effects. The maximum recommended transdermal dosage of buprenorphine is 20 mcg/hour, since higher dosages have been shown to prolong the QT interval. Dosage may be adjusted in increments of 5, 7.5,
or 10 mcg/hour by simultaneously applying no more than two 5-, 7.5-, or 10-mcg/hour systems; the total combined dosage of the 2 transdermal systems should not exceed 20 mcg/hour.
Patients should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for the development of addiction, abuse, or misuse. Patients who experience episodes of 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 dosage.
Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family during periods of changing analgesic requirements, including the initial dosage titration period. During long-term therapy, the continued need for opiate analgesics should be periodically reevaluated. If unacceptable adverse effects are observed, dosage reduction should be considered.
When the patient no longer requires buprenorphine therapy, the dosage should be tapered gradually every 7 days to prevent symptoms of opiate withdrawal. The use of an appropriate short-acting opiate may be considered during the tapering process. Therapy with buprenorphine transdermal system should not be discontinued abruptly.
Buprenorphine hydrochloride buccally dissolving strips (Belbuca(R)) should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.
For the management of pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatments are inadequate, treatment with buprenorphine bucally dissolving strips should be initiated at a dosage of 75 mcg once daily or, if tolerated, 75 mcg every 12 hours in adults who are opiate-naive or are not tolerant to opiates. After at least 4 days at this initial dosage, dosage may be increased to 150 mcg every 12 hours. Use of higher initial dosages in patients who are not opiate tolerant may cause fatal respiratory depression.
When patients currently receiving opiate agonist therapy are switched to intrabuccal buprenorphine, there is a potential for buprenorphine to precipitate withdrawal. In these patients, the current opiate regimen should be tapered to a total 24-hour dosage equivalent to 30 mg or less of oral morphine sulfate. For patients whose prior total daily dosage of opiates was less than 30 mg of oral morphine sulfate (or equivalent), intrabuccal buprenorphine may be initiated at a dosage of 75 mcg once daily or 75 mcg every 12 hours.
For patients whose prior total daily dosage was 30-89 mg of oral morphine sulfate (or equivalent), intrabuccal buprenorphine may be initiated at a dosage of 150 mcg every 12 hours. For those whose prior total daily dosage was 90-160 mg of oral morphine sulfate (or equivalent), intrabuccal buprenorphine may be initiated at a dosage of 300 mcg every 12 hours. Patients may receive supplemental short-acting analgesics as needed until adequate analgesia is attained.
For patients whose prior total daily dosage exceeded 160 mg of oral morphine sulfate (or equivalent), buprenorphine buccally dissolving strips may not provide adequate analgesia and an alternative analgesic should be considered. When therapy with buprenorphine buccally dissolving strips is initiated, all other around-the-clock opiate analgesics should be discontinued. Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.
Buprenorphine dosage may be titrated upward in increments of no more than 150 mcg every 12 hours at minimum intervals of 4 days to a level that provides adequate analgesia and minimizes adverse effects. Doses of 600, 750, and 900 mcg should be used only following titration from lower intrabuccal dosages. Dosages of up to 450 mcg every 12 hours were studied in opiate-naive patients in clinical trials.
The maximum recommended intrabuccal dosage is 900 mcg every 12 hours because of the risk of QT-interval prolongation; if this dosage fails to provide adequate analgesia, an alternative analgesic should be considered.
Patients should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for the development of addiction, abuse, or misuse. Patients who experience episodes of 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 dosage.
Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family during periods of changing analgesic requirements, including the initial dosage titration period. During long-term therapy, the continued need for opiate analgesics should be periodically reevaluated. If unacceptable adverse effects are observed, dosage should be adjusted to obtain an appropriate balance between pain control and adverse effects.
In patients with known or suspected mucositis, the usual initial dosage and each incremental dosage during titration should be reduced by one-half because of the potential for higher peak concentrations and systemic exposure to the drug.
When the patient no longer requires buprenorphine therapy, the dosage should be tapered gradually to prevent symptoms of opiate withdrawal. Intrabuccal therapy with buprenorphine should not be discontinued abruptly. If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose.
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
When generic buprenorphine sublingual tablets (i.e., generic equivalents of Subutex(R) sublingual tablets), generic buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Suboxone(R) sublingual tablets), or buprenorphine/naloxone sublingually dissolving strips (Suboxone(R)) are used for induction therapy, the recommended induction dosage of buprenorphine on day 1 is up to 8 mg (alone or in fixed combination with up to 2 mg of naloxone). Induction should be initiated on day 1 with a buprenorphine dose of 2 or 4 mg (alone or in fixed combination with naloxone 0.5 or 1 mg, respectively), with additional doses of 2 or 4 mg administered at approximately 2-hour intervals if there are continued withdrawal symptoms and sedation is not observed. Use of an opiate withdrawal scale (e.g., COWS) during induction can be helpful in assessing the effects of administered doses.
On day 2, a single dose of up to 16 mg of buprenorphine (alone or in fixed combination with up to 4 mg of naloxone) is given. Other induction dosages that also employ a low initial dose with rapid titration to an effective maintenance dosage have been used.
For oral transmucosal maintenance treatment, buprenorphine/naloxone is preferred over buprenorphine alone. (See initial paragraphs of Opiate Dependence under Dosage and Administration: Dosage.) From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of 2 or 4 mg of buprenorphine in fixed combination with 0.5 or 1 mg, respectively, of naloxone daily to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment.
The maintenance buprenorphine/naloxone dosage generally ranges from 4-24 mg of buprenorphine in fixed combination with 1-6 mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 16 mg of buprenorphine and 4 mg of naloxone as a single daily dose. Dosages exceeding 24 mg of buprenorphine in fixed combination with 6 mg of naloxone daily have not been shown to provide any additional clinical advantage.
The manufacturers make no specific recommendations at this time for dosage When Zubsolv(R) sublingual tablets are used for induction and maintenance in diagnosis of suspected or known acute opioid overdosage. However, if no treatment, the recommended induction dosage on day 1 is up to 5.7 mg of response is observed after administration of 10 mg of naloxone, the buprenorphine in fixed combination with up to 1.4
mg of naloxone. Induction diagnosis of opioid-induced toxicity should be questioned. should be initiated with a buprenorphine/naloxone dose of 1.4
mg of
buprenorphine in fixed combination with 0.36 mg of naloxone, with the remainder of the day 1 dosage (up to 4.2 mg of buprenorphine and up to 1.08 mg of naloxone) administered in divided doses as 1 or 2 tablets containing buprenorphine 1.4 mg and naloxone 0.36
mg at intervals of 1.5-2 hours. Some patients (e.g., those who recently received buprenorphine) may tolerate up to 3 tablets containing buprenorphine 1.4
mg and naloxone 0.36 mg as a single second dose. On day 2, a single dose of up to 11.4
mg of buprenorphine and 2.9 mg of naloxone is recommended.
From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of no more than 2.9 mg of buprenorphine and 0.71 mg of naloxone to a level that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment.
After induction and stabilization, the maintenance buprenorphine/naloxone dosage generally ranges from 2.9-17.2 mg of buprenorphine in fixed combination with 0.71-4.2
mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 11.4 mg of buprenorphine and 2.9
mg of naloxone as a single daily dose. Dosages exceeding 17.2 mg of buprenorphine in fixed combination with 4.2
mg of naloxone daily have not been shown to provide any additional clinical advantage.
When Bunavail(R) buccally dissolving strips are used for induction and maintenance treatment, the recommended induction dosage on day 1 is up to 4.2 mg of buprenorphine in fixed combination with up to 0.7 mg of naloxone.
Induction should be initiated with a buprenorphine/naloxone dose of 2.1 mg of buprenorphine in fixed combination with 0.3 mg of naloxone; a second dose of the same strength is administered approximately 2 hours later based on control of acute withdrawal symptoms.
On Day 2, a single dose of up to 8.4 mg of buprenorphine in fixed combination with 1.4 mg of naloxone is recommended.
From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of 2.1 mg of buprenorphine and 0.3 mg of naloxone to a level that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment.
After induction and stabilization, the maintenance buprenorphine/naloxone dosage generally ranges from 2.1-12.6 mg of buprenorphine in fixed combination with 0.3-2.1
mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 8.4 mg of buprenorphine and 1.4
mg of naloxone as a single daily dose. Dosages exceeding 12.6 mg of buprenorphine in fixed combination with 2.1
mg of naloxone daily have not been shown to provide any additional clinical advantage.
Not all formulations, strengths, or dose combinations of oral transmucosal buprenorphine/naloxone preparations are bioequivalent.
Patients who currently are receiving generic buprenorphine or buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Subutex(R) or Suboxone(R) sublingual tablets) and are switching to buprenorphine/naloxone sublingually dissolving strips (Suboxone(R)), or vice versa, should continue to receive the same drug dosage. However, not all strengths and dose combinations of the strips and sublingual tablets are bioequivalent. Because of potentially greater bioavailability with the strips relative to the tablets, patients should be monitored for underdosage (e.g., manifestations of withdrawal) or overdosage when switching between sublingual dosage forms and the dosage should be adjusted when indicated.
The 4 strengths of Suboxone(R) sublingually dissolving strips differ in size and buprenorphine and naloxone concentrations (on a % (w/w) basis). Switching between various combinations of lower- and higher-strength strips to obtain the same total dose may result in changes in systemic exposure to buprenorphine and naloxone and require that the patient be monitored for underdosage or overdosage. Therefore, substitution of one or more strip strengths for another without the prescriber's approval is not recommended.
Because systemic exposure to naloxone is somewhat higher after buccal compared with sublingual administration of the strips, sublingual administration is recommended during induction to minimize the risk of precipitated withdrawal. However, exposure to buprenorphine is similar following either buccal or sublingual administration, and once induction is complete, patients can switch between buccal and sublingual administration without substantial risk of underdosage or overdosage.
Bunavail(R) and Zubsolv(R) have different bioavailabilities than Suboxone(R) (or generic equivalent) sublingual tablets. Patients switching between these preparations should receive a different dosage strength (see Table 1 and Table 2) and should be monitored for underdosage or overdosage. Dosage adjustments may be necessary.
Systemic buprenorphine exposure following administration of one Suboxone(R) sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg is equivalent to that achieved following administration of one Bunavail(R) buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7 mg or one Zubsolv(R) sublingual tablet containing buprenorphine 5.7
mg and naloxone 1.4 mg.
Table 1. Corresponding Doses and Strengths of Suboxone(R) Sublingual Tablets and Bunavail(R) Buccally Dissolving Strips
Suboxone(R) Sublingual Dose or Corresponding Bunavail(R) Strip Tablet Strength Strength Buprenorphine 4 mg and naloxone 1 mg Buprenorphine 2.1 mg and naloxone 0.3 mg Buprenorphine 8 mg and naloxone 2 mg Buprenorphine 4.2
mg and naloxone 0.7 mg Buprenorphine 12 mg and naloxone 3 Buprenorphine 6.3 mg and naloxone 1 mg mg
Table 2. Corresponding Dosage Strengths of Suboxone(R) Sublingual Tablets (or Generic Equivalent) and Zubsolv(R) Sublingual Tablets
Suboxone(R) (or Generic Equivalent) Corresponding Zubsolv(R) Sublingual Sublingual Dose (Tablet Strength) Tablet Strength Buprenorphine 2 mg and naloxone 0.5 One 1.4-mg/0.36-mg
tablet mg (as one 2-mg/0.5-mg tablet) Buprenorphine 4 mg and naloxone 1 mg One 2.9-mg/0.71-mg tablet (as two 2-mg/0.5-mg tablets) Buprenorphine 8 mg and naloxone 2 mg One 5.7-mg/1.4-mg
tablet (as one 8-mg/2-mg tablet) Buprenorphine 12 mg and naloxone 3 One 8.6-mg/2.1-mg tablet mg (as one 8-mg/2-mg tablet and two 2-mg/0.5-mg tablets) Buprenorphine 16 mg and naloxone 4 One 11.4-mg/2.9-mg
tablet mg (as two 8-mg/2-mg tablets)
Maintenance treatment with buprenorphine extended-release subcutaneous injection may be initiated in patients who have initiated buprenorphine induction therapy with an oral transmucosal buprenorphine-containing preparation followed by dosage adjustment over a least 7 days to an oral transmucosal buprenorphine dosage of 8-24 mg daily (as Subutex(R) or Suboxone(R) (or equivalent generic buprenorphine or buprenorphine/naloxone preparation)) or a dosage of another oral transmucosal preparation that provides equivalent buprenorphine exposure. One Bunavail(R) buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7
mg or one Zubsolv(R) sublingual tablet containing buprenorphine 5.7 mg and naloxone 1.4 mg provides equivalent buprenorphine exposure as one Suboxone(R) sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg or one Subutex(R) sublingual tablet containing buprenorphine 8 mg.
The recommended dosage of buprenorphine extended-release subcutaneous injection following induction and dosage adjustment with oral transmucosal buprenorphine is 300 mg monthly for the first 2 months followed by a maintenance dosage of 100 mg monthly. The maintenance dosage may be increased to 300 mg monthly in patients who tolerate the 100-mg monthly dosage but do not achieve a satisfactory clinical response, as evidenced by self-reports or urine drug test results indicating illicit opiate use. If a dose is missed, the dose should be administered as soon as possible, with the following dose given no less than 26 days later.
Occasional delays in dosing of up to 2 weeks are not expected to substantially alter the treatment effect. If a subcutaneous depot of the drug must be surgically excised, the patient should be monitored for manifestations of withdrawal and appropriate treatment (e.g., an oral transmucosal preparation of the drug) should be instituted as clinically indicated.
Maintenance treatment with buprenorphine subdermal implants may be initiated in patients who have achieved and maintained prolonged clinical stability on oral transmucosal buprenorphine therapy; are currently receiving an oral transmucosal buprenorphine maintenance dosage of 8 mg daily or less (as Subutex(R) or Suboxone(R) (or equivalent generic buprenorphine or buprenorphine/naloxone preparation) or a dosage of another oral transmucosal preparation that provides comparable blood buprenorphine concentrations (e.g., Bunavail(R) buccally dissolving strips at a dosage of buprenorphine 4.2 mg and naloxone 0.7 mg daily or less, Zubsolv(R) sublingual tablets at a dosage of buprenorphine 5.7
mg and naloxone 1.4 mg daily or less)); and have received a stable oral transmucosal buprenorphine maintenance dosage of 8 mg daily or less for at least 3 months without the need for supplemental doses of the drug or dosage adjustments. The dosage of oral transmucosal buprenorphine should not be tapered to this dosage level solely for the purpose of transitioning to implant therapy.
The 8-mg oral transmucosal dosage provides blood buprenorphine concentrations that are similar to or less than those provided by the recommended implant dosage.
Each buprenorphine dose consists of 4 implants (each containing 80 mg of buprenorphine hydrochloride (equivalent to 74.2 mg of the base)) inserted subdermally in the inner aspect of the upper arm; the implants are intended to be left in place for 6 months and then removed by the end of the sixth month. If continued implant therapy is desired at the time the initial implants are removed, new implants may be inserted subdermally in the contralateral arm. If new implants are not inserted on the same day that the current ones are removed, patients should receive their previous dosage of oral transmucosal buprenorphine (i.e., the dosage they received prior to initiation of implant therapy) prior to additional implant therapy.
After one insertion in each arm, most patients should be transitioned back to oral transmucosal buprenorphine therapy, since experience is lacking with insertion of implants at other sites in the arm or with insertion of new implants at prior administration sites (where potential effects of scarring and fibrosis on efficacy and safety are unknown).
Although some patients may require occasional supplemental dosing with buprenorphine, the manufacturer states that patients should not be provided with prescriptions for oral transmucosal buprenorphine-containing preparations for use on as-needed basis. Instead, patients who feel the need for supplemental dosing should be evaluated promptly by a clinician. An ongoing need for supplemental dosing indicates that the amount of buprenorphine delivered by the implants is not adequate for stable maintenance treatment; use of an alternative buprenorphine preparation for maintenance treatment should be considered.
If an implant is expelled spontaneously, the patient should be carefully monitored until the implant is replaced for withdrawal manifestations or other indications that supplemental oral transmucosal dosing may be required.
Transdermal buprenorphine has not been studied in patients with severe hepatic impairment; use of an alternative analgesic regimen that allows for greater dosage flexibility should be considered in these patients.
When buprenorphine buccally dissolving strips (Belbuca(R)) are used for analgesia in patients with severe hepatic impairment (i.e., Child-Pugh class C), the usual initial dosage should be reduced and each incremental change in dosage during titration should be reduced by one-half (i.e., from 150 mcg to 75 mcg). No dosage adjustment is required in patients with moderate hepatic impairment, but patients with either moderate or severe hepatic impairment should be monitored for overdosage and toxicity.
When buprenorphine or buprenorphine/naloxone is used sublingually or buccally for the management of opiate dependence in patients with mild hepatic impairment, plasma concentrations and half-lives of the drugs are not substantially altered. However, in individuals with moderate or severe hepatic impairment, plasma concentrations of both buprenorphine and naloxone are increased and half-lives of the drugs are prolonged. Naloxone is affected to a greater degree than buprenorphine, and the magnitude of the difference in effect is greater in individuals with severe hepatic impairment than in those with moderate hepatic impairment.
(See Pharmacokinetics: Elimination.) This may result in an increased risk of precipitated withdrawal during induction and interference with buprenorphine's efficacy throughout treatment. Buprenorphine/naloxone should be avoided in patients with severe hepatic impairment and may not be appropriate for those with moderate hepatic impairment. In patients with moderate hepatic impairment, buprenorphine/naloxone is not recommended for induction therapy but may be used with caution and careful monitoring for maintenance treatment following induction therapy with buprenorphine alone.
The manufacturer states that the initial dose and titration increments of buprenorphine administered as the single-entity sublingual tablets should be reduced by one-half in patients with severe hepatic impairment and recommends that patients with either moderate or severe hepatic impairment be monitored for buprenorphine overdosage or toxicity.
Use of buprenorphine extended-release subcutaneous injection or buprenorphine subdermal implants is not recommended in patients with preexisting moderate to severe hepatic impairment since the extended-release injection does not allow for rapid adjustment of plasma buprenorphine concentrations and the implant dosage cannot be titrated.
Following the use of opioids during surgery, excessive doses of naloxone hydrochloride may result in significant reversal of analgesia and cause agitation.
The availability of naloxone as prefilled syringes and as nasal spray formulations facilitates administration by family members or other caregivers; such treatment is not a substitute for emergency medical care. Administration of naloxone should be accompanied by other resuscitative measures such as administration of oxygen, mechanical ventilation, or artificial respiration. When administering naloxone outside of a supervised medical setting, always seek emergency medical assistance after the first dose is administered.
Naloxone is used in both adults and pediatric adults (including neonates) to reverse the effects of opioids. Naloxone has been given to the mother shortly before delivery+, but it is preferable to administer the drug directly to the neonate if needed after delivery.
Naloxone hydrochloride injection containing 5 mg per 0.5 mL (Zimhi(R)) is a higher concentration of the drug for IM or subcutaneous use in adults and pediatric patients for emergency treatment of known or suspected opioid overdose. The preparation is commercially available as single-dose prefilled syringes that are administered using a delivery device.
Naloxone hydrochloride 5 mg/0.5 mL was developed in response to increasing reports indicating that multiple 2-mg doses of naloxone have been required in resuscitations. Efficacy of this preparation for community use is supported by pharmacokinetic bridging studies.
Naloxone is used for the diagnosis of suspected or known acute opioid overdosage.
Naloxone is commercially available as naloxone hydrochloride; dosage is expressed in terms of the salt.
Dosage of buprenorphine and buprenorphine hydrochloride usually is expressed in terms of buprenorphine. Dosage of buprenorphine hydrochloride subdermal implants may be expressed as either the salt or the base.
For the relief of pain that is severe enough to require opiate analgesia and for which alternative treatments are inadequate, the usual IM or IV dosage of buprenorphine in patients 13 years of age and older is 0.3 mg given at intervals of up to every 6 hours as necessary. The initial dose (up to 0.3 mg) may be repeated once in 30-60 minutes, if needed.
The dose should be limited to the minimum amount required in high-risk patients (e.g., geriatric or debilitated patients, those with respiratory disease) and in patients receiving other CNS depressants, including patients in the immediate postoperative period. Particular caution is necessary if the drug is administered IV, especially with initial doses. In some patients, it may be necessary to increase the dose up to 0.6
mg, but the manufacturer recommends that such relatively high doses only be administered IM and only to adults who are not considered high-risk patients. In some patients, a dosing interval greater than 6 hours may be adequate. Alternatively, a regimen including an initial dose of 0.3
mg of buprenorphine followed by another 0.3-mg dose repeated in 3 hours has been shown to be as effective as a single 0.6-mg dose in relieving postoperative pain.
There are insufficient clinical data to recommend single doses greater than 0.6 mg for long-term use.
Although children 2-12 years of age have received parenteral buprenorphine dosages of 2-6 mcg/kg every 4-6 hours, longer dosing intervals (e.g., every 6-8 hours) may be sufficient for some children, and a fixed around-the-clock dosing interval should not be used until an adequate dosing interval has been established by clinical observation of the patient. In addition, the manufacturer states that there are insufficient data in children 2-12 years of age to recommend buprenorphine doses exceeding 6 mcg/kg or administration of a repeat dose within 30-60 minutes of the initial dose.
When buprenorphine has been administered by continuous IV infusion+ in the management of postoperative pain, dosages of 25-250 mcg/hour have been used in adults.
Buprenorphine has been administered epidurally+ in the management of postoperative pain in single doses of 60 mcg, up to a mean total dose of 180 mcg administered over a 48-hour period. Buprenorphine has also been administered epidurally+ in a dose of 0.3 mg as a supplement to surgical anesthesia with a local anesthetic.
In the management of severe, chronic pain (e.g., in terminally ill patients), buprenorphine doses of 0.15-0.3 mg have been administered epidurally as frequently as every 6 hours up to a mean total daily dose of 0.86
mg (range: 0.15-7.2 mg).
The manufacturer states that data are insufficient to recommend a parenteral buprenorphine dosage for infants younger than 2 years of age. In children 9 months to 9 years of age+ undergoing circumcision, some clinicians have used an initial IM buprenorphine dose of 3 mcg/kg as an adjunct to surgical anesthesia followed by additional 3-mcg/kg doses as necessary to provide analgesia postoperatively.
Buprenorphine transdermal system should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain. Dosages of 7.5, 10, 15, and 20 mcg/hour should be reserved for patients who are opiate experienced (i.e., have been receiving oral morphine sulfate dosages of up to 80 mg or more daily (or equivalent) for one week or longer) and have developed tolerance to an opiate of comparable potency.
In opiate-naive adults with pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatments are inadequate, treatment with transdermal buprenorphine should be initiated at a dosage of 5 mcg/hour.
When patients currently receiving opiate agonist therapy are switched to transdermal buprenorphine, there is a potential for buprenorphine to precipitate withdrawal. In these patients, the current opiate regimen should be tapered over a period of up to 7 days to a total 24-hour dosage equivalent to 30 mg or less of oral morphine sulfate. For patients whose prior total daily dosage of opiates was less than 30 mg of oral morphine sulfate (or equivalent), transdermal buprenorphine may be initiated at a dosage of 5 mcg/hour.
For patients whose prior total daily dosage was 30-80 mg of oral morphine sulfate (or equivalent), transdermal buprenorphine may be initiated at a dosage of 10 mcg/hour. Patients may receive supplemental short-acting analgesics as needed until adequate analgesia is attained. For patients whose prior total daily dosage exceeded 80 mg of oral morphine sulfate (or equivalent), buprenorphine 20 mcg/hour may not provide adequate analgesia and an alternative analgesic should be considered.
When therapy with a buprenorphine transdermal system is initiated, all other around-the-clock opiate analgesics should be discontinued. Buprenorphine may be initiated at the next dosing interval following discontinuance of the current opiate regimen. Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.
Buprenorphine dosage may be titrated upward at minimum intervals of 72 hours to a level that provides adequate analgesia and minimizes adverse effects. The maximum recommended transdermal dosage of buprenorphine is 20 mcg/hour, since higher dosages have been shown to prolong the QT interval. Dosage may be adjusted in increments of 5, 7.5,
or 10 mcg/hour by simultaneously applying no more than two 5-, 7.5-, or 10-mcg/hour systems; the total combined dosage of the 2 transdermal systems should not exceed 20 mcg/hour.
Patients should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for the development of addiction, abuse, or misuse. Patients who experience episodes of 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 dosage.
Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family during periods of changing analgesic requirements, including the initial dosage titration period. During long-term therapy, the continued need for opiate analgesics should be periodically reevaluated. If unacceptable adverse effects are observed, dosage reduction should be considered.
When the patient no longer requires buprenorphine therapy, the dosage should be tapered gradually every 7 days to prevent symptoms of opiate withdrawal. The use of an appropriate short-acting opiate may be considered during the tapering process. Therapy with buprenorphine transdermal system should not be discontinued abruptly.
Buprenorphine hydrochloride buccally dissolving strips (Belbuca(R)) should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.
For the management of pain that is severe enough to require daily, around-the-clock, long-term opiate analgesia and for which alternative treatments are inadequate, treatment with buprenorphine bucally dissolving strips should be initiated at a dosage of 75 mcg once daily or, if tolerated, 75 mcg every 12 hours in adults who are opiate-naive or are not tolerant to opiates. After at least 4 days at this initial dosage, dosage may be increased to 150 mcg every 12 hours. Use of higher initial dosages in patients who are not opiate tolerant may cause fatal respiratory depression.
When patients currently receiving opiate agonist therapy are switched to intrabuccal buprenorphine, there is a potential for buprenorphine to precipitate withdrawal. In these patients, the current opiate regimen should be tapered to a total 24-hour dosage equivalent to 30 mg or less of oral morphine sulfate. For patients whose prior total daily dosage of opiates was less than 30 mg of oral morphine sulfate (or equivalent), intrabuccal buprenorphine may be initiated at a dosage of 75 mcg once daily or 75 mcg every 12 hours.
For patients whose prior total daily dosage was 30-89 mg of oral morphine sulfate (or equivalent), intrabuccal buprenorphine may be initiated at a dosage of 150 mcg every 12 hours. For those whose prior total daily dosage was 90-160 mg of oral morphine sulfate (or equivalent), intrabuccal buprenorphine may be initiated at a dosage of 300 mcg every 12 hours. Patients may receive supplemental short-acting analgesics as needed until adequate analgesia is attained.
For patients whose prior total daily dosage exceeded 160 mg of oral morphine sulfate (or equivalent), buprenorphine buccally dissolving strips may not provide adequate analgesia and an alternative analgesic should be considered. When therapy with buprenorphine buccally dissolving strips is initiated, all other around-the-clock opiate analgesics should be discontinued. Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.
Buprenorphine dosage may be titrated upward in increments of no more than 150 mcg every 12 hours at minimum intervals of 4 days to a level that provides adequate analgesia and minimizes adverse effects. Doses of 600, 750, and 900 mcg should be used only following titration from lower intrabuccal dosages. Dosages of up to 450 mcg every 12 hours were studied in opiate-naive patients in clinical trials.
The maximum recommended intrabuccal dosage is 900 mcg every 12 hours because of the risk of QT-interval prolongation; if this dosage fails to provide adequate analgesia, an alternative analgesic should be considered.
Patients should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for the development of addiction, abuse, or misuse. Patients who experience episodes of 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 dosage.
Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family during periods of changing analgesic requirements, including the initial dosage titration period. During long-term therapy, the continued need for opiate analgesics should be periodically reevaluated. If unacceptable adverse effects are observed, dosage should be adjusted to obtain an appropriate balance between pain control and adverse effects.
In patients with known or suspected mucositis, the usual initial dosage and each incremental dosage during titration should be reduced by one-half because of the potential for higher peak concentrations and systemic exposure to the drug.
When the patient no longer requires buprenorphine therapy, the dosage should be tapered gradually to prevent symptoms of opiate withdrawal. Intrabuccal therapy with buprenorphine should not be discontinued abruptly. If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose.
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
When generic buprenorphine sublingual tablets (i.e., generic equivalents of Subutex(R) sublingual tablets), generic buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Suboxone(R) sublingual tablets), or buprenorphine/naloxone sublingually dissolving strips (Suboxone(R)) are used for induction therapy, the recommended induction dosage of buprenorphine on day 1 is up to 8 mg (alone or in fixed combination with up to 2 mg of naloxone). Induction should be initiated on day 1 with a buprenorphine dose of 2 or 4 mg (alone or in fixed combination with naloxone 0.5 or 1 mg, respectively), with additional doses of 2 or 4 mg administered at approximately 2-hour intervals if there are continued withdrawal symptoms and sedation is not observed. Use of an opiate withdrawal scale (e.g., COWS) during induction can be helpful in assessing the effects of administered doses.
On day 2, a single dose of up to 16 mg of buprenorphine (alone or in fixed combination with up to 4 mg of naloxone) is given. Other induction dosages that also employ a low initial dose with rapid titration to an effective maintenance dosage have been used.
For oral transmucosal maintenance treatment, buprenorphine/naloxone is preferred over buprenorphine alone. (See initial paragraphs of Opiate Dependence under Dosage and Administration: Dosage.) From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of 2 or 4 mg of buprenorphine in fixed combination with 0.5 or 1 mg, respectively, of naloxone daily to a dosage that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment.
The maintenance buprenorphine/naloxone dosage generally ranges from 4-24 mg of buprenorphine in fixed combination with 1-6 mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 16 mg of buprenorphine and 4 mg of naloxone as a single daily dose. Dosages exceeding 24 mg of buprenorphine in fixed combination with 6 mg of naloxone daily have not been shown to provide any additional clinical advantage.
The manufacturers make no specific recommendations at this time for dosage When Zubsolv(R) sublingual tablets are used for induction and maintenance in diagnosis of suspected or known acute opioid overdosage. However, if no treatment, the recommended induction dosage on day 1 is up to 5.7 mg of response is observed after administration of 10 mg of naloxone, the buprenorphine in fixed combination with up to 1.4
mg of naloxone. Induction diagnosis of opioid-induced toxicity should be questioned. should be initiated with a buprenorphine/naloxone dose of 1.4
mg of
buprenorphine in fixed combination with 0.36 mg of naloxone, with the remainder of the day 1 dosage (up to 4.2 mg of buprenorphine and up to 1.08 mg of naloxone) administered in divided doses as 1 or 2 tablets containing buprenorphine 1.4 mg and naloxone 0.36
mg at intervals of 1.5-2 hours. Some patients (e.g., those who recently received buprenorphine) may tolerate up to 3 tablets containing buprenorphine 1.4
mg and naloxone 0.36 mg as a single second dose. On day 2, a single dose of up to 11.4
mg of buprenorphine and 2.9 mg of naloxone is recommended.
From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of no more than 2.9 mg of buprenorphine and 0.71 mg of naloxone to a level that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment.
After induction and stabilization, the maintenance buprenorphine/naloxone dosage generally ranges from 2.9-17.2 mg of buprenorphine in fixed combination with 0.71-4.2
mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 11.4 mg of buprenorphine and 2.9
mg of naloxone as a single daily dose. Dosages exceeding 17.2 mg of buprenorphine in fixed combination with 4.2
mg of naloxone daily have not been shown to provide any additional clinical advantage.
When Bunavail(R) buccally dissolving strips are used for induction and maintenance treatment, the recommended induction dosage on day 1 is up to 4.2 mg of buprenorphine in fixed combination with up to 0.7 mg of naloxone.
Induction should be initiated with a buprenorphine/naloxone dose of 2.1 mg of buprenorphine in fixed combination with 0.3 mg of naloxone; a second dose of the same strength is administered approximately 2 hours later based on control of acute withdrawal symptoms.
On Day 2, a single dose of up to 8.4 mg of buprenorphine in fixed combination with 1.4 mg of naloxone is recommended.
From day 3 onward, buprenorphine/naloxone dosage should be adjusted in increments or decrements of 2.1 mg of buprenorphine and 0.3 mg of naloxone to a level that suppresses opiate withdrawal symptoms and ensures that the patient continues buprenorphine treatment.
After induction and stabilization, the maintenance buprenorphine/naloxone dosage generally ranges from 2.1-12.6 mg of buprenorphine in fixed combination with 0.3-2.1
mg of naloxone daily. The recommended buprenorphine/naloxone target dosage during maintenance treatment is 8.4 mg of buprenorphine and 1.4
mg of naloxone as a single daily dose. Dosages exceeding 12.6 mg of buprenorphine in fixed combination with 2.1
mg of naloxone daily have not been shown to provide any additional clinical advantage.
Not all formulations, strengths, or dose combinations of oral transmucosal buprenorphine/naloxone preparations are bioequivalent.
Patients who currently are receiving generic buprenorphine or buprenorphine/naloxone sublingual tablets (i.e., generic equivalents of Subutex(R) or Suboxone(R) sublingual tablets) and are switching to buprenorphine/naloxone sublingually dissolving strips (Suboxone(R)), or vice versa, should continue to receive the same drug dosage. However, not all strengths and dose combinations of the strips and sublingual tablets are bioequivalent. Because of potentially greater bioavailability with the strips relative to the tablets, patients should be monitored for underdosage (e.g., manifestations of withdrawal) or overdosage when switching between sublingual dosage forms and the dosage should be adjusted when indicated.
The 4 strengths of Suboxone(R) sublingually dissolving strips differ in size and buprenorphine and naloxone concentrations (on a % (w/w) basis). Switching between various combinations of lower- and higher-strength strips to obtain the same total dose may result in changes in systemic exposure to buprenorphine and naloxone and require that the patient be monitored for underdosage or overdosage. Therefore, substitution of one or more strip strengths for another without the prescriber's approval is not recommended.
Because systemic exposure to naloxone is somewhat higher after buccal compared with sublingual administration of the strips, sublingual administration is recommended during induction to minimize the risk of precipitated withdrawal. However, exposure to buprenorphine is similar following either buccal or sublingual administration, and once induction is complete, patients can switch between buccal and sublingual administration without substantial risk of underdosage or overdosage.
Bunavail(R) and Zubsolv(R) have different bioavailabilities than Suboxone(R) (or generic equivalent) sublingual tablets. Patients switching between these preparations should receive a different dosage strength (see Table 1 and Table 2) and should be monitored for underdosage or overdosage. Dosage adjustments may be necessary.
Systemic buprenorphine exposure following administration of one Suboxone(R) sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg is equivalent to that achieved following administration of one Bunavail(R) buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7 mg or one Zubsolv(R) sublingual tablet containing buprenorphine 5.7
mg and naloxone 1.4 mg.
Table 1. Corresponding Doses and Strengths of Suboxone(R) Sublingual Tablets and Bunavail(R) Buccally Dissolving Strips
Suboxone(R) Sublingual Dose or Corresponding Bunavail(R) Strip Tablet Strength Strength Buprenorphine 4 mg and naloxone 1 mg Buprenorphine 2.1 mg and naloxone 0.3 mg Buprenorphine 8 mg and naloxone 2 mg Buprenorphine 4.2
mg and naloxone 0.7 mg Buprenorphine 12 mg and naloxone 3 Buprenorphine 6.3 mg and naloxone 1 mg mg
Table 2. Corresponding Dosage Strengths of Suboxone(R) Sublingual Tablets (or Generic Equivalent) and Zubsolv(R) Sublingual Tablets
Suboxone(R) (or Generic Equivalent) Corresponding Zubsolv(R) Sublingual Sublingual Dose (Tablet Strength) Tablet Strength Buprenorphine 2 mg and naloxone 0.5 One 1.4-mg/0.36-mg
tablet mg (as one 2-mg/0.5-mg tablet) Buprenorphine 4 mg and naloxone 1 mg One 2.9-mg/0.71-mg tablet (as two 2-mg/0.5-mg tablets) Buprenorphine 8 mg and naloxone 2 mg One 5.7-mg/1.4-mg
tablet (as one 8-mg/2-mg tablet) Buprenorphine 12 mg and naloxone 3 One 8.6-mg/2.1-mg tablet mg (as one 8-mg/2-mg tablet and two 2-mg/0.5-mg tablets) Buprenorphine 16 mg and naloxone 4 One 11.4-mg/2.9-mg
tablet mg (as two 8-mg/2-mg tablets)
Maintenance treatment with buprenorphine extended-release subcutaneous injection may be initiated in patients who have initiated buprenorphine induction therapy with an oral transmucosal buprenorphine-containing preparation followed by dosage adjustment over a least 7 days to an oral transmucosal buprenorphine dosage of 8-24 mg daily (as Subutex(R) or Suboxone(R) (or equivalent generic buprenorphine or buprenorphine/naloxone preparation)) or a dosage of another oral transmucosal preparation that provides equivalent buprenorphine exposure. One Bunavail(R) buccally dissolving strip containing buprenorphine 4.2 mg and naloxone 0.7
mg or one Zubsolv(R) sublingual tablet containing buprenorphine 5.7 mg and naloxone 1.4 mg provides equivalent buprenorphine exposure as one Suboxone(R) sublingual tablet containing buprenorphine 8 mg and naloxone 2 mg or one Subutex(R) sublingual tablet containing buprenorphine 8 mg.
The recommended dosage of buprenorphine extended-release subcutaneous injection following induction and dosage adjustment with oral transmucosal buprenorphine is 300 mg monthly for the first 2 months followed by a maintenance dosage of 100 mg monthly. The maintenance dosage may be increased to 300 mg monthly in patients who tolerate the 100-mg monthly dosage but do not achieve a satisfactory clinical response, as evidenced by self-reports or urine drug test results indicating illicit opiate use. If a dose is missed, the dose should be administered as soon as possible, with the following dose given no less than 26 days later.
Occasional delays in dosing of up to 2 weeks are not expected to substantially alter the treatment effect. If a subcutaneous depot of the drug must be surgically excised, the patient should be monitored for manifestations of withdrawal and appropriate treatment (e.g., an oral transmucosal preparation of the drug) should be instituted as clinically indicated.
Maintenance treatment with buprenorphine subdermal implants may be initiated in patients who have achieved and maintained prolonged clinical stability on oral transmucosal buprenorphine therapy; are currently receiving an oral transmucosal buprenorphine maintenance dosage of 8 mg daily or less (as Subutex(R) or Suboxone(R) (or equivalent generic buprenorphine or buprenorphine/naloxone preparation) or a dosage of another oral transmucosal preparation that provides comparable blood buprenorphine concentrations (e.g., Bunavail(R) buccally dissolving strips at a dosage of buprenorphine 4.2 mg and naloxone 0.7 mg daily or less, Zubsolv(R) sublingual tablets at a dosage of buprenorphine 5.7
mg and naloxone 1.4 mg daily or less)); and have received a stable oral transmucosal buprenorphine maintenance dosage of 8 mg daily or less for at least 3 months without the need for supplemental doses of the drug or dosage adjustments. The dosage of oral transmucosal buprenorphine should not be tapered to this dosage level solely for the purpose of transitioning to implant therapy.
The 8-mg oral transmucosal dosage provides blood buprenorphine concentrations that are similar to or less than those provided by the recommended implant dosage.
Each buprenorphine dose consists of 4 implants (each containing 80 mg of buprenorphine hydrochloride (equivalent to 74.2 mg of the base)) inserted subdermally in the inner aspect of the upper arm; the implants are intended to be left in place for 6 months and then removed by the end of the sixth month. If continued implant therapy is desired at the time the initial implants are removed, new implants may be inserted subdermally in the contralateral arm. If new implants are not inserted on the same day that the current ones are removed, patients should receive their previous dosage of oral transmucosal buprenorphine (i.e., the dosage they received prior to initiation of implant therapy) prior to additional implant therapy.
After one insertion in each arm, most patients should be transitioned back to oral transmucosal buprenorphine therapy, since experience is lacking with insertion of implants at other sites in the arm or with insertion of new implants at prior administration sites (where potential effects of scarring and fibrosis on efficacy and safety are unknown).
Although some patients may require occasional supplemental dosing with buprenorphine, the manufacturer states that patients should not be provided with prescriptions for oral transmucosal buprenorphine-containing preparations for use on as-needed basis. Instead, patients who feel the need for supplemental dosing should be evaluated promptly by a clinician. An ongoing need for supplemental dosing indicates that the amount of buprenorphine delivered by the implants is not adequate for stable maintenance treatment; use of an alternative buprenorphine preparation for maintenance treatment should be considered.
If an implant is expelled spontaneously, the patient should be carefully monitored until the implant is replaced for withdrawal manifestations or other indications that supplemental oral transmucosal dosing may be required.
Transdermal buprenorphine has not been studied in patients with severe hepatic impairment; use of an alternative analgesic regimen that allows for greater dosage flexibility should be considered in these patients.
When buprenorphine buccally dissolving strips (Belbuca(R)) are used for analgesia in patients with severe hepatic impairment (i.e., Child-Pugh class C), the usual initial dosage should be reduced and each incremental change in dosage during titration should be reduced by one-half (i.e., from 150 mcg to 75 mcg). No dosage adjustment is required in patients with moderate hepatic impairment, but patients with either moderate or severe hepatic impairment should be monitored for overdosage and toxicity.
When buprenorphine or buprenorphine/naloxone is used sublingually or buccally for the management of opiate dependence in patients with mild hepatic impairment, plasma concentrations and half-lives of the drugs are not substantially altered. However, in individuals with moderate or severe hepatic impairment, plasma concentrations of both buprenorphine and naloxone are increased and half-lives of the drugs are prolonged. Naloxone is affected to a greater degree than buprenorphine, and the magnitude of the difference in effect is greater in individuals with severe hepatic impairment than in those with moderate hepatic impairment.
(See Pharmacokinetics: Elimination.) This may result in an increased risk of precipitated withdrawal during induction and interference with buprenorphine's efficacy throughout treatment. Buprenorphine/naloxone should be avoided in patients with severe hepatic impairment and may not be appropriate for those with moderate hepatic impairment. In patients with moderate hepatic impairment, buprenorphine/naloxone is not recommended for induction therapy but may be used with caution and careful monitoring for maintenance treatment following induction therapy with buprenorphine alone.
The manufacturer states that the initial dose and titration increments of buprenorphine administered as the single-entity sublingual tablets should be reduced by one-half in patients with severe hepatic impairment and recommends that patients with either moderate or severe hepatic impairment be monitored for buprenorphine overdosage or toxicity.
Use of buprenorphine extended-release subcutaneous injection or buprenorphine subdermal implants is not recommended in patients with preexisting moderate to severe hepatic impairment since the extended-release injection does not allow for rapid adjustment of plasma buprenorphine concentrations and the implant dosage cannot be titrated.
Following the use of opioids during surgery, excessive doses of naloxone hydrochloride may result in significant reversal of analgesia and cause agitation.
Naloxone may be administered by IV, subcutaneous, or IM injection; by IV infusion; or intranasally. The drug also has been administered via endotracheal tube+ and by intraosseous+ (IO) injection.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ZUBSOLV 11.4-2.9 MG TABLET SL | Maintenance | Adults place 1 tablet by sublingual route once daily allow to dissolve slowly in mouth without chewing or swallowing |
| ZUBSOLV 0.7-0.18 MG TABLET SL | Maintenance | Adults place 1 tablet by sublingual route once daily allow to dissolve slowly in mouth without chewing or swallowing |
| ZUBSOLV 1.4-0.36 MG TABLET SL | Maintenance | Adults place 2 tablets by sublingual route once daily allow to dissolve slowly in mouth without chewing or swallowing |
| ZUBSOLV 2.9-0.71 MG TABLET SL | Maintenance | Adults place 1 tablet by sublingual route once daily allow to dissolve slowly in mouth without chewing or swallowing |
| ZUBSOLV 5.7-1.4 MG TABLET SL | Maintenance | Adults place 1 tablet by sublingual route once daily allow to dissolve slowly in mouth without chewing or swallowing |
| ZUBSOLV 8.6-2.1 MG TABLET SL | Maintenance | Adults place 1 tablet by sublingual route once daily allow to dissolve slowly in mouth without chewing or swallowing |
No generic dosing information available.
The following drug interaction information is available for ZUBSOLV (buprenorphine hcl/naloxone hcl):
There are 1 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Opioid Antagonists/Opioid Analgesics 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) |
CONTRAVE, LOTREXONE, LYBALVI, NALTREX, NALTREXONE BASE MONOHYDRATE, NALTREXONE HCL, NALTREXONE HCL DIHYDRATE, NALTREXONE HCL MICRONIZED, OPVEE, VIVITROL |
There are 3 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Sodium Oxybate/Agents that May Cause Respiratory Depression 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. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
LUMRYZ, LUMRYZ STARTER PACK, SODIUM OXYBATE, XYREM, XYWAV |
| Chronic Opioids/Buprenorphine; Pentazocine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Buprenorphine antagonizes mu-opiate receptors.(1) Pentazocine is a mixed agonist-antagonist at opiate receptors.(2) Other opioids agonize mu-opiate receptors. 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, decreased opioid side effects, and/or renarcotization. PREDISPOSING FACTORS: Patients dependent on opioids or taking higher doses 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: 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) |
CONZIP, DISKETS, FENTANYL, FENTANYL CITRATE, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYDROMORPHONE HCL, HYSINGLA ER, METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL, METHADONE INTENSOL, METHADOSE, MORPHINE SULFATE, MORPHINE SULFATE ER, MS CONTIN, NUCYNTA ER, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, TRAMADOL HCL ER, XTAMPZA ER |
| Eluxadoline/Anticholinergics; Opioids 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) |
VIBERZI |
There are 12 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| 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. |
BRAFTOVI, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EPITOL, EQUETRO, ERLEADA, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, ORKAMBI, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, RIFADIN, RIFAMPIN, TEGRETOL, TEGRETOL XR, TIBSOVO, XTANDI |
| 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) |
ACETAMIN-CAFF-DIHYDROCODEINE, ACETAMINOPHEN-CODEINE, APADAZ, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BELLADONNA-OPIUM, BENZHYDROCODONE-ACETAMINOPHEN, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTORPHANOL TARTRATE, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, DEMEROL, DIHYDROCODEINE BITARTRATE, DILAUDID, DIPHENOXYLATE-ATROPINE, DSUVIA, DURAMORPH, ENDOCET, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, FIORICET WITH CODEINE, HYCODAN, HYDROCODONE BITARTRATE, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROCODONE-IBUPROFEN, HYDROMET, HYDROMORPHONE HCL, HYDROMORPHONE HCL-0.9% NACL, HYDROMORPHONE HCL-D5W, HYDROMORPHONE HCL-NACL, HYDROMORPHONE HCL-WATER, INFUMORPH, LEVORPHANOL TARTRATE, LOMOTIL, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, MOTOFEN, NALBUPHINE HCL, NALOCET, NUCYNTA, OLINVYK, OPIUM TINCTURE, OXYCODONE HCL, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYMORPHONE HCL, PENTAZOCINE-NALOXONE HCL, PERCOCET, PRIMLEV, PROLATE, PROMETHAZINE-CODEINE, QDOLO, REMIFENTANIL HCL, ROXICODONE, ROXYBOND, SUFENTANIL CITRATE, TRAMADOL HCL, TRAMADOL HCL-ACETAMINOPHEN, TREZIX, TUXARIN ER, ULTIVA |
| Gabapentinoids/Opioids (IR & ER) 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 inadequate.(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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
GABAPENTIN, GABAPENTIN ER, GABARONE, GRALISE, HORIZANT, LYRICA, LYRICA CR, NEURONTIN, PREGABALIN, PREGABALIN ER |
| Buprenorphine/Benzodiazepines 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-opioid receptors leading to ceiling effects which limit agonist activity, including respiratory depression, at high doses. However, concomitant benzodiazepine use (e.g. taken shortly after buprenorphine dose) or high doses of benzodiazepines may lead to potentiation of respiratory depression, counteracting the ceiling effect.(1,2) Concurrent use of buprenorphine and benzodiazepines may result in additive CNS depression.(3) CLINICAL EFFECTS: Concurrent use may result in profound sedation, respiratory depression, coma, and/or death. Fatal respiratory depression has occurred with the combination of buprenorphine and a benzodiazepine.(1-2,4-7) High benzodiazepine levels have been identified in 80% or more of buprenorphine fatalities.(6) PREDISPOSING FACTORS: Patients with a history of alcohol or benzodiazepine abuse may be at risk for relapse and overuse or abuse of prescribed benzodiazepines.(1,2,4,6) Individuals with significant obstructive pulmonary disease (COPD), sleep apnea, the elderly, and debilitated patients are at greater risk for respiratory depression from either agent.(1,2,8) PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS depressants such as benzodiazepines to patients for whom alternatives are inadequate.(3) For buprenorphine patients newly starting a benzodiazepine, consider beginning the benzodiazepine at a lower than usual dose, especially if predisposing factors (e.g. COPD, sleep apnea, debilitation, elderly) are present. High doses of benzodiazepines are associated with a greater risk for respiratory depression. Use the lowest effective dose and monitor for excessive sedation or respiratory depression, particularly in patients with predisposing risk factors for respiratory compromise.(1,2) Buprenorphine-naloxone combination products are used for maintenance treatment of opioid dependence. Patients with comorbid benzodiazepine dependence, on high doses of benzodiazepines, or a history of benzodiazepine abuse may require benzodiazepine detoxification prior to initiation of office-based buprenorphine treatment.(3) For patients receiving opioid maintenance treatment, it would be prudent to assure all controlled substance prescriptions are approved or written by the buprenorphine-naloxone provider.(5) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(9) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(3) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(10) DISCUSSION: Buprenorphine is a partial agonist at mu-opioid receptors leading to ceiling effects which limits agonist activity, including respiratory depression, at high doses. However, concomitant benzodiazepine use (e.g. taking shortly after buprenorphine dose) or high doses of benzodiazepines may counteract the ceiling effect leading to potentiation of respiratory depression or sedative effects. High benzodiazepine levels have identified in 80% or more of buprenorphine fatalities.(6) 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.(11) 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.(12) 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.(13) 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.(14) 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.(15) 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.(16) 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.(17) |
ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, BYFAVO, CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLOBAZAM, CLONAZEPAM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, ESTAZOLAM, FLURAZEPAM HCL, HALCION, KLONOPIN, LIBRAX, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, ONFI, OXAZEPAM, QUAZEPAM, RESTORIL, SYMPAZAN, TEMAZEPAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR |
| 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. Consider this risk 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 naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, FIORICET WITH CODEINE, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON |
| Desmopressin/Agents with Hyponatremia Risk 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) |
DDAVP, DESMOPRESSIN ACETATE, NOCDURNA |
| Selected Opioids for MAT/Sleep Drugs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of buprenorphine or diacetylmorphine and sleep drugs may result in additive CNS depression and sleep-related disorders.(1-3) CLINICAL EFFECTS: Concurrent use of buprenorphine or diacetylmorphine and other CNS depressants, such as sleep drugs, may result in profound sedation, respiratory depression, coma, and/or death.(1-3) 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.(4) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine or diacetylmorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Consider other medications and nonpharmacologic treatments to address anxiety or insomnia. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or diacetylmorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(5) 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.(4) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(6) 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.(7) 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.(8) 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.(9) 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.(10) 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.(11) 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.(12) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) 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.(4) |
AMBIEN, AMBIEN CR, BELSOMRA, DAYVIGO, EDLUAR, ESZOPICLONE, LUNESTA, QUVIVIQ, RAMELTEON, ROZEREM, ZALEPLON, ZOLPIDEM TARTRATE, ZOLPIDEM TARTRATE ER |
| Buprenorphine for MAT/Muscle Relaxants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of buprenorphine and muscle relaxants may result in additive CNS depression.(1,2) CLINICAL EFFECTS: Concurrent use of buprenorphine and other CNS depressants, such as muscle relaxants, may result in profound sedation, respiratory depression, coma, and/or death.(1,2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine is not contraindicated in patients taking CNS depressants; however, discontinuation of CNS depressants is preferred in most cases. In some cases, monitoring at a higher level of care for tapering may be appropriate. In others, gradual tapering or decreasing to the lowest effective dose of the CNS depressant is appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk 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) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(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) 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).(6) 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.(7) 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.(8) 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.(9) 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.(10) 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.(11) While concomitant use of MAT with CNS depressants increases the risk of adverse reactions, barriers to MAT can pose a greater risk of morbidity and mortality due to opioid use disorder.(2) |
AMRIX, BACLOFEN, CARISOPRODOL, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CHLORZOXAZONE, CYCLOBENZAPRINE HCL, CYCLOBENZAPRINE HCL ER, CYCLOPAK, CYCLOTENS, DANTRIUM, DANTROLENE SODIUM, FEXMID, FLEQSUVY, LORZONE, LYVISPAH, MEPROBAMATE, METAXALONE, METHOCARBAMOL, NORGESIC, NORGESIC FORTE, ORPHENADRINE CITRATE, ORPHENADRINE CITRATE ER, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OZOBAX, OZOBAX DS, REVONTO, ROBAXIN, RYANODEX, SOMA, TANLOR, TIZANIDINE HCL, VANADOM, ZANAFLEX |
| Selected Opioids for MAT/Antipsychotics 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 may result in additive CNS depression.(1-3) Levomethadone is an enantiomer of methadone.(4) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, may result in profound sedation, respiratory depression, coma, and/or death.(1-3) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine, diacetylmorphine, or methadone is not contraindicated in patients taking CNS depressants; however, gradual tapering or decreasing to the lowest effective dose of the CNS depressant may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine, diacetylmorphine, or methadone treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(5) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(6) 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.(7) 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.(8) 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.(9) 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.(10) 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.(11) 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.(12) 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.(13) |
ABILIFY, ABILIFY ASIMTUFII, ABILIFY MAINTENA, ADASUVE, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, ARISTADA, ARISTADA INITIO, ASENAPINE MALEATE, CAPLYTA, COMPAZINE, COMPRO, FLUPHENAZINE DECANOATE, FLUPHENAZINE HCL, LATUDA, LOXAPINE, LURASIDONE HCL, MOLINDONE HCL, OLANZAPINE, OLANZAPINE ODT, OLANZAPINE-FLUOXETINE HCL, OPIPZA, PERPHENAZINE, PERPHENAZINE-AMITRIPTYLINE, PERSERIS, PHENERGAN, PROCHLORPERAZINE, PROCHLORPERAZINE EDISYLATE, PROCHLORPERAZINE MALEATE, PROMETHAZINE HCL, PROMETHAZINE HCL-0.9% NACL, PROMETHAZINE VC, PROMETHAZINE-CODEINE, PROMETHAZINE-DM, PROMETHAZINE-PHENYLEPHRINE HCL, PROMETHEGAN, RISPERDAL, RISPERDAL CONSTA, RISPERIDONE, RISPERIDONE ER, RISPERIDONE ODT, RYKINDO, SAPHRIS, SECUADO, THIOTHIXENE, TRIFLUOPERAZINE HCL, UZEDY, VRAYLAR, ZYPREXA |
| 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: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, 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 inadequate. 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. Consider this risk when using concurrently with stimulants.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. 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) |
ADDERALL, ADDERALL XR, ADZENYS XR-ODT, AMPHETAMINE SULFATE, APTENSIO XR, AZSTARYS, CONCERTA, COTEMPLA XR-ODT, DAYTRANA, DESOXYN, DEXEDRINE, DEXMETHYLPHENIDATE HCL, DEXMETHYLPHENIDATE HCL ER, DEXTROAMPHETAMINE SULFATE, DEXTROAMPHETAMINE SULFATE ER, DEXTROAMPHETAMINE-AMPHET ER, DEXTROAMPHETAMINE-AMPHETAMINE, DYANAVEL XR, EVEKEO, FOCALIN, FOCALIN XR, JORNAY PM, LISDEXAMFETAMINE DIMESYLATE, METADATE CD, METADATE ER, METHAMPHETAMINE HCL, METHYLIN, METHYLPHENIDATE, METHYLPHENIDATE ER, METHYLPHENIDATE ER (LA), METHYLPHENIDATE HCL, METHYLPHENIDATE HCL CD, METHYLPHENIDATE HCL ER (CD), MYDAYIS, PROCENTRA, QUILLICHEW ER, QUILLIVANT XR, RELEXXII, RITALIN, RITALIN LA, VYVANSE, XELSTRYM, ZENZEDI |
| Selected Opioids for MAT/Selected Antipsychotics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of buprenorphine or diacetylmorphine and antipsychotics may result in additive CNS depression.(1-3) CLINICAL EFFECTS: Concurrent use of buprenorphine or diacetylmorphine and antipsychotics may result in profound sedation, respiratory depression, coma, and/or death.(1-3) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine or diacetylmorphine is not contraindicated in patients taking CNS depressants, such as antipsychotics; however, gradual tapering or decreasing to the lowest effective dose of the antipsychotic may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine or diacetylmorphine treatment.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(5) 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.(6) 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.(7) 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.(8) 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.(9) 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.(10) 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.(11) 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.(12) Selected antipsychotics linked include: amsulpride, chlorpromazine, chlorprothixene, clozapine, droperidol, haloperidol, iloperidone, mesoridazine, paliperidone, pimavanserin, pimozide, pipamperone, promethazine, quetiapine, sertindole, sulpiride, sultopride, thioridazine, ziprasidone, and zuclopenthixol. |
BARHEMSYS, CHLORPROMAZINE HCL, CLOZAPINE, CLOZAPINE ODT, CLOZARIL, DROPERIDOL, ERZOFRI, FANAPT, GEODON, HALDOL DECANOATE 100, HALDOL DECANOATE 50, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL DECANOATE 100, HALOPERIDOL LACTATE, INVEGA, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA, NUPLAZID, PALIPERIDONE ER, PIMOZIDE, QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, SEROQUEL, SEROQUEL XR, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, VERSACLOZ, ZIPRASIDONE HCL, ZIPRASIDONE MESYLATE |
| Selected Opioids for MAT/Brexpiprazole 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 brexpiprazole, may result in additive CNS depression.(1,2) CLINICAL EFFECTS: Concurrent use of opioids and other CNS depressants, such as antipsychotics, may result in profound sedation, respiratory depression, coma, and/or death.(1,2) PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Medication assisted treatment (MAT) with buprenorphine, diacetylmorphine or methadone is not contraindicated in patients taking CNS depressants; however, gradual tapering or decreasing to the lowest effective dose of the CNS depressant may be appropriate. Ensure that other health care providers prescribing other CNS depressants are aware of the patient's buprenorphine, diacetylmorphine, or methadone treatment.(2,3) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. Consider this risk when using concurrently with other agents that may cause CNS depression.(4) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.(1) Discuss naloxone with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing naloxone to patients prescribed medicines to treat OUD or opioid analgesics (such as those taking CNS depressants) who are at increased risk of opioid overdose and when a patient has household members/close contacts at risk for accidental overdose.(5) 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.(6) 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.(7) 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.(8) 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.(9) 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.(10) 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.(11) 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.(12) |
REXULTI |
The following contraindication information is available for ZUBSOLV (buprenorphine hcl/naloxone hcl):
Drug contraindication overview.
*Patients with known hypersensitivity to the drug or any ingredient in the formulation. Buprenorphine is contraindicated in patients with known hypersensitivity to the drug or any components of the formulation. In addition, buprenorphine/naloxone is contraindicated in patients with known hypersensitivity to naloxone. Buprenorphine formulations labeled for analgesic use are contraindicated in patients with known or suspected GI obstruction (including paralytic ileus), substantial respiratory depression, or acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
*Patients with known hypersensitivity to the drug or any ingredient in the formulation. Buprenorphine is contraindicated in patients with known hypersensitivity to the drug or any components of the formulation. In addition, buprenorphine/naloxone is contraindicated in patients with known hypersensitivity to naloxone. Buprenorphine formulations labeled for analgesic use are contraindicated in patients with known or suspected GI obstruction (including paralytic ileus), substantial respiratory depression, or acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Child-pugh class C hepatic impairment |
There are 13 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Alcohol intoxication |
| Chronic hepatitis B |
| Chronic hepatitis C |
| Congenital long QT syndrome |
| Disease of liver |
| Exacerbation of chronic obstructive pulmonary disease |
| History of opioid overdose |
| Intracranial hypertension |
| Kyphoscoliosis with respiratory compromise |
| Respiratory depression |
| Seizure disorder |
| Sleep apnea |
| Urinary retention |
There are 10 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Adrenocortical insufficiency |
| Alcohol withdrawal delirium |
| Benign prostatic hyperplasia |
| Biliary tract disorder |
| Cor pulmonale |
| Debilitation |
| Lower seizure threshold |
| Orthostatic hypotension |
| Toxic psychosis |
| Untreated hypothyroidism |
The following adverse reaction information is available for ZUBSOLV (buprenorphine hcl/naloxone hcl):
Adverse reaction overview.
Intranasal naloxone: Adverse effects reported in clinical trials of intranasally administered naloxone include abdominal pain, asthenia, dizziness, headache, increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, nasal congestion, nasal discomfort, nasal dryness, nasal edema, nasal inflammation, presyncope, rhinalgia, and xeroderma. Parenteral naloxone: Adverse effects, including serious and fatal cases, reported in clinical trials of parenterally administered naloxone for postoperative patients include cardiac arrest, dyspnea, hypotension, hypertension, pulmonary edema, and ventricular tachycardia and fibrillation. Excessive doses of naloxone in postoperative patients may result in agitation caused by significant reversal of analgesia.
Adverse effects reported in clinical trials of parenterally administered naloxone after abrupt reversal of dependence are related to acute withdrawal syndrome, which may include the following signs and symptoms: abdominal cramps, body aches, diarrhea, fever, increased blood pressure, nausea or vomiting, nervousness, runny nose, piloerection, restlessness or irritability, shivering or trembling, sneezing, sweating, tachycardia, weakness, yawning. Abrupt reversal of opioid depression may result in cardiac arrest, increased blood pressure, nausea, pulmonary edema, seizures, sweating, tachycardia, tremulousness, ventricular tachycardia and fibrillation, and vomiting. In the neonate, opioid withdrawal may also include convulsions, excessive crying, and hyperactive reflexes. Adverse effects reported in clinical trials of naloxone hydrochloride injection for IM or subcutaneous use (Zimhi(R)) included dizziness, elevated bilirubin, lightheadedness, and nausea.
Intranasal naloxone: Adverse effects reported in clinical trials of intranasally administered naloxone include abdominal pain, asthenia, dizziness, headache, increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, nasal congestion, nasal discomfort, nasal dryness, nasal edema, nasal inflammation, presyncope, rhinalgia, and xeroderma. Parenteral naloxone: Adverse effects, including serious and fatal cases, reported in clinical trials of parenterally administered naloxone for postoperative patients include cardiac arrest, dyspnea, hypotension, hypertension, pulmonary edema, and ventricular tachycardia and fibrillation. Excessive doses of naloxone in postoperative patients may result in agitation caused by significant reversal of analgesia.
Adverse effects reported in clinical trials of parenterally administered naloxone after abrupt reversal of dependence are related to acute withdrawal syndrome, which may include the following signs and symptoms: abdominal cramps, body aches, diarrhea, fever, increased blood pressure, nausea or vomiting, nervousness, runny nose, piloerection, restlessness or irritability, shivering or trembling, sneezing, sweating, tachycardia, weakness, yawning. Abrupt reversal of opioid depression may result in cardiac arrest, increased blood pressure, nausea, pulmonary edema, seizures, sweating, tachycardia, tremulousness, ventricular tachycardia and fibrillation, and vomiting. In the neonate, opioid withdrawal may also include convulsions, excessive crying, and hyperactive reflexes. Adverse effects reported in clinical trials of naloxone hydrochloride injection for IM or subcutaneous use (Zimhi(R)) included dizziness, elevated bilirubin, lightheadedness, and nausea.
There are 17 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Hypotension Infection |
CNS depression Respiratory depression |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acquired absence of tooth Adrenocortical insufficiency Anaphylaxis Androgen deficiency Dental abscess Drug dependence Hepatic failure Hepatitis Hepatorenal syndrome Hypersensitivity drug reaction Jaundice Sleep apnea |
There are 63 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Back pain Constipation Depression Erythema of mouth mucous membrane Headache disorder Hyperhidrosis Insomnia Nausea Oral hypoesthesia Pain Sore tongue Symptoms of anxiety Vomiting |
Accidental fall Acute abdominal pain Anemia Anorexia Bruising Chills Cough Diarrhea Dizziness Drowsy Dyspepsia Eye tearing Fever Flu-like symptoms Gastroenteritis General weakness Muscle spasm Nervousness Pain in oropharynx Peripheral edema Rhinitis Upper respiratory infection Urinary tract infection |
| Rare/Very Rare |
|---|
|
Acute oral cavity infection Dental caries Disturbance of attention Drug-induced hot flash Elevated serum amylase Erectile dysfunction Euphoria Hostility Hypoesthesia Hypoglycemic disorder Infertility Lethargy Libido changes Memory impairment Migraine Musculoskeletal pain Nasal congestion Neck pain Opioid induced allodynia Opioid induced hyperalgesia Orthostatic hypotension Paresthesia Pharyngitis Rhinorrhea Tooth disorder Tremor Vasodilation of blood vessels |
The following precautions are available for ZUBSOLV (buprenorphine hcl/naloxone hcl):
Naloxone hydrochloride injection may be used to reverse the effects of opioids in pediatric patients, including neonates. In addition, safety and efficacy of naloxone hydrochloride prefilled syringes for IM or subcutaneous use (Zimhi(R)) or nasal spray (e.g., Narcan(R), Kloxxado(R)) have been established in pediatric patients of all ages for the emergency treatment of known or suspected opioid overdosage manifested by respiratory and/or CNS depression. Use of naloxone for reversal of opioid effects in pediatric patients is supported by adult bioequivalence studies and evidence from the safe and effective use of other naloxone hydrochloride products.
As in adults, naloxone may precipitate opiate withdrawal in pediatric patients who are physically dependent on opiates; however, unlike opiate withdrawal in adults, neonatal opiate withdrawal may be life-threatening and should be treated according to protocols developed by neonatology experts. To avoid abrupt precipitation of neonatal opiate withdrawal syndrome, use of a naloxone preparation that can be dosed based on weight and titrated to effect may be preferred over a preparation that delivers a fixed dose of the drug (e.g., auto-injector, nasal spray) in neonates with known or suspected exposure to maternally administered opiates. Absorption of naloxone following intranasal administration or IM or subcutaneous injection in pediatric patients may be erratic or delayed.
Pediatric patients who have responded to naloxone must be carefully monitored for at least 24 hours, since relapse may occur as the opioid antagonist is metabolized. Safety and efficacy of naloxone hydrochloride injection in the management of hypotension associated with septic shock have not been established in pediatric patients. In a study of 2 neonates with septic shock, treatment with naloxone produced a positive pressor response; however, one patient subsequently died after intractable seizures.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
As in adults, naloxone may precipitate opiate withdrawal in pediatric patients who are physically dependent on opiates; however, unlike opiate withdrawal in adults, neonatal opiate withdrawal may be life-threatening and should be treated according to protocols developed by neonatology experts. To avoid abrupt precipitation of neonatal opiate withdrawal syndrome, use of a naloxone preparation that can be dosed based on weight and titrated to effect may be preferred over a preparation that delivers a fixed dose of the drug (e.g., auto-injector, nasal spray) in neonates with known or suspected exposure to maternally administered opiates. Absorption of naloxone following intranasal administration or IM or subcutaneous injection in pediatric patients may be erratic or delayed.
Pediatric patients who have responded to naloxone must be carefully monitored for at least 24 hours, since relapse may occur as the opioid antagonist is metabolized. Safety and efficacy of naloxone hydrochloride injection in the management of hypotension associated with septic shock have not been established in pediatric patients. In a study of 2 neonates with septic shock, treatment with naloxone produced a positive pressor response; however, one patient subsequently died after intractable seizures.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
There are limited data to date on use of naloxone in pregnant women. Naloxone should be used during pregnancy only when clearly needed. Reproduction studies in mice and rats using naloxone hydrochloride dosages of 4 and 8 times, respectively, a human dosage of 10 mg daily in a 50-kg individual demonstrated no embryotoxic or teratogenic effects.
Furthermore, no adverse effects were reported in the offspring of rats receiving naloxone hydrochloride subcutaneously at dosages of 2 or 10 mg/kg (up to 12 times a human dosage of 8 mg daily) from gestation day 15 to postnatal day 21. No embryotoxic or teratogenic effects were observed in mice and rats during the period of organogenesis with the 8 mg/0.1 mL nasal spray at doses 3 and 6 times a human dose of 16 mg.
The risk-benefit ratio must be considered before naloxone is administered to a pregnant woman who is known or suspected to be dependent on opioids, since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta and may precipitate withdrawal symptoms in both the fetus and the pregnant woman. Use of naloxone in opioid-dependent pregnant women should be accompanied by monitoring for fetal distress.
It is not known if naloxone affects the duration of labor and/or delivery. However, published reports indicate that administration of naloxone during labor did not adversely affect maternal or neonatal status. Carefully monitor patients with mild to moderate hypertension who receive naloxone during labor, as severe hypertension may occur.
Furthermore, no adverse effects were reported in the offspring of rats receiving naloxone hydrochloride subcutaneously at dosages of 2 or 10 mg/kg (up to 12 times a human dosage of 8 mg daily) from gestation day 15 to postnatal day 21. No embryotoxic or teratogenic effects were observed in mice and rats during the period of organogenesis with the 8 mg/0.1 mL nasal spray at doses 3 and 6 times a human dose of 16 mg.
The risk-benefit ratio must be considered before naloxone is administered to a pregnant woman who is known or suspected to be dependent on opioids, since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta and may precipitate withdrawal symptoms in both the fetus and the pregnant woman. Use of naloxone in opioid-dependent pregnant women should be accompanied by monitoring for fetal distress.
It is not known if naloxone affects the duration of labor and/or delivery. However, published reports indicate that administration of naloxone during labor did not adversely affect maternal or neonatal status. Carefully monitor patients with mild to moderate hypertension who receive naloxone during labor, as severe hypertension may occur.
It is not known whether naloxone is distributed into milk or has any effect on the breast-fed infant or on milk production; use naloxone with caution in nursing women. The drug does not affect prolactin or oxytocin concentrations in nursing women, and oral bioavailability of naloxone is minimal. Buprenorphine is distributed into milk in humans.
In 2 studies that included 13 nursing women receiving maintenance treatment with sublingual buprenorphine (2.4-24 mg daily) for opiate dependence, buprenorphine and its metabolite norbuprenorphine were present in low concentrations in milk and in the breast-fed infant's urine; the infants were exposed to less than 1% of the maternal daily buprenorphine dosage. In the first study in 6 women receiving buprenorphine (median dosage of 0.29 mg/kg daily) at 5-8 days postpartum, breast milk provided a median infant dosage of 0.42 mcg/kg daily of buprenorphine and 0.33
mcg/kg daily of norbuprenorphine (0.2 and 0.12%, respectively, of the maternal weight-adjusted dosage). In the other study in 7 women receiving buprenorphine (median dosage of 7 mg daily) at an average of 1.12 months postpartum, mean milk concentrations of buprenorphine and norbuprenorphine were 3.65
and 1.94 mcg/L, respectively; based on the results of this study, an exclusively breast-fed infant consuming 150 mL/kg daily of milk would receive a mean estimated dosage of 0.55 mcg/kg daily of buprenorphine and 0.29
mcg/kg daily of norbuprenorphine (0.38 and 0.18%, respectively, of the maternal weight-adjusted dosage). Adverse reactions in nursing infants were not observed. Experts recommend that women who are stable on buprenorphine or buprenorphine/naloxone treatment for opiate dependence, are not using other illicit drugs, and have no contraindications to nursing be encouraged to breast-feed their infants; to lower the risk of return to substance use, women receiving buprenorphine should be encouraged to continue treatment during the postpartum period.
Breast-feeding has been associated with decreased severity of neonatal opiate withdrawal syndrome, decreased need for pharmacotherapy, and shorter hospital stays for the neonate. The manufacturers of buprenorphine-containing preparations used for treatment of opiate dependence state that developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for buprenorphine or buprenorphine/naloxone and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in nursing infants, the manufacturers of buprenorphine preparations labeled for use as analgesics state that women should be advised not to nurse an infant while receiving the drug.
Infants who are exposed to buprenorphine through breast milk should be monitored for excess sedation and respiratory depression. Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.
In 2 studies that included 13 nursing women receiving maintenance treatment with sublingual buprenorphine (2.4-24 mg daily) for opiate dependence, buprenorphine and its metabolite norbuprenorphine were present in low concentrations in milk and in the breast-fed infant's urine; the infants were exposed to less than 1% of the maternal daily buprenorphine dosage. In the first study in 6 women receiving buprenorphine (median dosage of 0.29 mg/kg daily) at 5-8 days postpartum, breast milk provided a median infant dosage of 0.42 mcg/kg daily of buprenorphine and 0.33
mcg/kg daily of norbuprenorphine (0.2 and 0.12%, respectively, of the maternal weight-adjusted dosage). In the other study in 7 women receiving buprenorphine (median dosage of 7 mg daily) at an average of 1.12 months postpartum, mean milk concentrations of buprenorphine and norbuprenorphine were 3.65
and 1.94 mcg/L, respectively; based on the results of this study, an exclusively breast-fed infant consuming 150 mL/kg daily of milk would receive a mean estimated dosage of 0.55 mcg/kg daily of buprenorphine and 0.29
mcg/kg daily of norbuprenorphine (0.38 and 0.18%, respectively, of the maternal weight-adjusted dosage). Adverse reactions in nursing infants were not observed. Experts recommend that women who are stable on buprenorphine or buprenorphine/naloxone treatment for opiate dependence, are not using other illicit drugs, and have no contraindications to nursing be encouraged to breast-feed their infants; to lower the risk of return to substance use, women receiving buprenorphine should be encouraged to continue treatment during the postpartum period.
Breast-feeding has been associated with decreased severity of neonatal opiate withdrawal syndrome, decreased need for pharmacotherapy, and shorter hospital stays for the neonate. The manufacturers of buprenorphine-containing preparations used for treatment of opiate dependence state that developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for buprenorphine or buprenorphine/naloxone and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in nursing infants, the manufacturers of buprenorphine preparations labeled for use as analgesics state that women should be advised not to nurse an infant while receiving the drug.
Infants who are exposed to buprenorphine through breast milk should be monitored for excess sedation and respiratory depression. Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.
Clinical studies of naloxone did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.
The following prioritized warning is available for ZUBSOLV (buprenorphine hcl/naloxone hcl):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for ZUBSOLV (buprenorphine hcl/naloxone hcl)'s list of indications:
| Opioid use disorder | |
| F11.1 | Opioid abuse |
| F11.10 | Opioid abuse, uncomplicated |
| F11.12 | Opioid abuse with intoxication |
| F11.120 | Opioid abuse with intoxication, uncomplicated |
| F11.121 | Opioid abuse with intoxication delirium |
| F11.122 | Opioid abuse with intoxication with perceptual disturbance |
| F11.129 | Opioid abuse with intoxication, unspecified |
| F11.13 | Opioid abuse with withdrawal |
| F11.14 | Opioid abuse with opioid-induced mood disorder |
| F11.15 | Opioid abuse with opioid-induced psychotic disorder |
| F11.150 | Opioid abuse with opioid-induced psychotic disorder with delusions |
| F11.151 | Opioid abuse with opioid-induced psychotic disorder with hallucinations |
| F11.159 | Opioid abuse with opioid-induced psychotic disorder, unspecified |
| F11.18 | Opioid abuse with other opioid-induced disorder |
| F11.181 | Opioid abuse with opioid-induced sexual dysfunction |
| F11.182 | Opioid abuse with opioid-induced sleep disorder |
| F11.188 | Opioid abuse with other opioid-induced disorder |
| F11.19 | Opioid abuse with unspecified opioid-induced disorder |
| F11.92 | Opioid use, unspecified with intoxication |
| F11.920 | Opioid use, unspecified with intoxication, uncomplicated |
| F11.921 | Opioid use, unspecified with intoxication delirium |
| F11.922 | Opioid use, unspecified with intoxication with perceptual disturbance |
| F11.929 | Opioid use, unspecified with intoxication, unspecified |
| F11.93 | Opioid use, unspecified with withdrawal |
| F11.94 | Opioid use, unspecified with opioid-induced mood disorder |
| F11.95 | Opioid use, unspecified with opioid-induced psychotic disorder |
| F11.950 | Opioid use, unspecified with opioid-induced psychotic disorder with delusions |
| F11.951 | Opioid use, unspecified with opioid-induced psychotic disorder with hallucinations |
| F11.959 | Opioid use, unspecified with opioid-induced psychotic disorder, unspecified |
| F11.98 | Opioid use, unspecified with other specified opioid-induced disorder |
| F11.981 | Opioid use, unspecified with opioid-induced sexual dysfunction |
| F11.982 | Opioid use, unspecified with opioid-induced sleep disorder |
| F11.988 | Opioid use, unspecified with other opioid-induced disorder |
| F11.99 | Opioid use, unspecified with unspecified opioid-induced disorder |
Formulary Reference Tool