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Zubsolv

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Zubsolv

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Abuse Potential

Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient's level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits. [see Drug Abuse and Dependence].

Respiratory Depression

Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other CNS depressants (including alcohol), has been associated with significant respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death associated with the concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have also been reported in association with concomitant administration of buprenorphine with other depressants such as alcohol or other CNS depressant drugs. Patients should be warned of the potential danger of self-administration of benzodiazepines or other depressants while under treatment with ZUBSOLV sublingual tablets. [see DRUG INTERACTIONS]

In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.

ZUBSOLV sublingual tablets should be used with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).

CNS Depression

Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants (including alcohol) may exhibit increased CNS depression. Consider dose reduction of CNS depressants, ZUBSOLV sublingual tablets, or both in situations of concomitant prescription. [see DRUG INTERACTIONS]

Unintentional Pediatric Exposure

Buprenorphine can cause fatal respiratory depression in children who are accidentally exposed to it. Store buprenorphine containing medications safely out of the sight and reach of children and destroy any unused medication appropriately. [see PATIENT INFORMATION]

Dependence

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. [see Drug Abuse and Dependence]

Hepatitis, Hepatic Events

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, ZUBSOLV sublingual tablet may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

Allergic Reactions

Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or naloxone is a contraindication to the use of ZUBSOLV sublingual tablet.

Precipitation of Opioid Withdrawal Signs and Symptoms

Because it contains naloxone, ZUBSOLV sublingual tablet is likely to produce withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Because of the partial agonist properties of buprenorphine, ZUBSOLV sublingual tablet may precipitate opioid withdrawal signs and symptoms in such persons if administered sublingually before the agonist effects of the opioid have subsided.

Neonatal Abstinence Syndrome

Neonatal abstinence syndrome has been reported in the infants of women treated with buprenorphine during pregnancy. From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from Day 1 to Day 8 of life with most cases occurring on Day 1. Adverse events associated with the neonatal abstinence syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and there have been reports of convulsions, apnea, respiratory depression, and bradycardia.

Use in Opioid Na´ve Patients

There have been reported deaths of opioid naive individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. ZUBSOLV sublingual tablet is not appropriate as an analgesic.

Impairment of Ability to Drive or Operate Machinery

ZUBSOLV sublingual tablet may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Patients should be cautioned about driving or operating hazardous machinery until they are reasonably certain that ZUBSOLV sublingual tablet therapy does not adversely affect his or her ability to engage in such activities.

Orthostatic Hypotension

Like other opioids, ZUBSOLV sublingual tablets may produce orthostatic hypotension in ambulatory patients.

Elevation of Cerebrospinal Fluid Pressure

Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Elevation of Intracholedochal Pressure

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Effects in Acute Abdominal Conditions

As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

General Precautions

ZUBSOLV sublingual tablet should be administered with caution in debilitated patients and those with myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; or kyphoscoliosis.

Patient Counseling Information

See FDA-approved patient labeling. (Medication Guide)

Safe Use

Before initiating treatment with ZUBSOLV sublingual tablets, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time ZUBSOLV is dispensed because new information may be available.

  • Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking ZUBSOLV sublingual tablets. Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use them only as directed by their physician. [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]
  • Patients should be advised that ZUBSOLV sublingual tablets contain an opioid that can be a target for people who abuse prescription medications or street drugs. Patients should be cautioned to keep their tablets in a safe place, and to protect them from theft.
  • Patients should be instructed to keep ZUBSOLV sublingual tablets in a secure place, out of the sight and reach of children. Accidental or deliberate ingestion by a child may cause respiratory depression that can result in death. Patients should be advised that if a child is exposed to ZUBSOLV sublingual tablets, medical attention should be sought immediately.
  • Patients should be advised never to give ZUBSOLV sublingual tablets to anyone else, even if he or she has the same signs and symptoms. It may cause harm or death.
  • Patients should be advised that selling or giving away this medication is against the law.
  • Patients should be cautioned that ZUBSOLV sublingual tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating machinery. Caution should be taken especially during drug induction and dose adjustment and until individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage in such activities. [see WARNINGS AND PRECAUTIONS]
  • Patients should be advised not to change the dosage of ZUBSOLV sublingual tablets without consulting their physician.
  • Patients should be advised to take ZUBSOLV sublingual tablets once a day.
  • Patients should be advised that if they miss a dose of ZUBSOLV they should take it as soon as they remember. If it is almost time for the next dose, they should skip the missed dose and take the next dose at the regular time.
  • Patients should be informed that ZUBSOLV sublingual tablets can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued.
  • Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised to work closely with their physician on a tapering schedule and should be apprised of the potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist medication-assisted treatment.
  • Patients should be cautioned that, like other opioids, ZUBSOLV sublingual tablets may produce orthostatic hypotension in ambulatory individuals. [see WARNINGS AND PRECAUTIONS]
  • Patients should inform their physician if any other prescription medications, over-the-counter medications, or herbal preparations are prescribed or currently being used. [see DRUG INTERACTIONS]
  • Advise females of reproductive potential, who become pregnant or are planning to become pregnant, to consult their physician regarding the possible effects of using ZUBSOLV sublingual tablets during pregnancy. [see Use In Specific Populations]
  • Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see Use In Specific Populations].
  • Patients should inform their family members that, in the event of emergency, the treating physician or emergency room staff should be informed that the patient is physically dependent on an opioid and that the patient is being treated with ZUBSOLV sublingual tablets.
  • Refer to the Medication Guide for additional information regarding the counseling information.

Disposal of Unused ZUBSOLV Sublingual Tablets

Unused ZUBSOLV sublingual tablets should be disposed of as soon as they are no longer needed. Unused tablets should be flushed down the toilet.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

ZUBSOLV has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m²) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via ZUBSOLV.

Carcinogenicity

A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in Alderley Park rats. Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the recommended human sublingual dose based on buprenorphine AUC comparisons). A statistically significant increase in Leydig cell adenomas was observed in all dose groups. No other drug-related tumors were noted.

Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately 0.4, 3, and 35 times the recommended human sublingual dose) for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rat, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30 times the recommended human sublingual dose).

Mutagenicity

The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay (Ames test) using four strains of S. typhimurium and two strains of E. coli. The combination was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the rat.

Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.

Impairment of Fertility

Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended human sublingual dose) produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (equivalent to approximately 10 mg/kg/day; estimated exposure approximately 6 times the recommended human sublingual dose) had no adverse effect on fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C
Risk Summary

There are no adequate and well-controlled studies of ZUBSOLV sublingual tablets or buprenorphine/naloxone in pregnant women. . Limited published data on use of buprenorphine, the active ingredient in Zubsolv, in pregnancy, have not shown an increased risk of major malformations. All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant doses. Pre-and postnatal development studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits.

ZUBSOLV sublingual tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-associated maternal and embryo-fetal risk

Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death.

Fetal/neonatal adverse reactions

Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly. [See WARNINGS AND PRECAUTIONS]

Labor or Delivery

As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.

Data

Human Data

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited published data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.

Animal Data

ZUBSOLV has been shown to have differences in bioavailability compared to other buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m²) to the recommended human sublingual dose of 16 mg buprenorphine via Suboxone, which is equivalent to a human sublingual dose of 11.4 mg buprenorphine via Zubsolv.

Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the recommended human sublingual dose). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the recommended human sublingual dose). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the recommended human sublingual dose). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day. Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended human sublingual dose), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the recommended human sublingual dose), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the recommended human sublingual dose) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the recommended human sublingual dose). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the recommended human sublingual dose), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the recommended human sublingual dose) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the recommended human sublingual dose) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human sublingual dose).

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day (approximately 3 times the recommended human sublingual dose). Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended human sublingual dose), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the recommended human sublingual dose), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human sublingual dose). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the recommended human sublingual dose).

Nursing Mothers

Risk Summary

Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine, and available data have not shown adverse reactions in breastfed infants . There are no data on the combination product buprenorphine/naloxone in breastfeeding , however oral absorption of naloxone is minimal. Caution should be exercised when Zubsolv is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Zubsolv and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise the nursing mother taking Zubsolv to monitor the infant for increased drowsiness and breathing difficulties.

Data

Based on limited data from a study of 6 lactating women who were taking a median oral dose of buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mg/kg/day of norbuprenorphine, which are equal to 0.2% and 0.12% of the maternal weight-adjusted dose.

Based on limited data from a study of 7 lactating women who were taking a median oral dose of buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.

No adverse reactions were observed in the infants in these two studies.

Pediatric Use

The safety and effectiveness of ZUBSOLV sublingual tablets have not been established in pediatric patients. This product is not appropriate for the treatment of neonatal abstinence syndrome in neonates, because it contains naloxone, an opioid antagonist.

Geriatric Use

Clinical studies of buprenorphine/naloxone sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both drugs are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. However, it is not known whether both drugs are affected to the same degree. Therefore, dosage should be adjusted and patients should be watched for signs and symptoms of precipitated opioid withdrawal.

Renal Impairment

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine. The effects of renal failure on naloxone pharmacokinetics are unknown.

Last reviewed on RxList: 7/18/2013
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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