Drug Safety-related Labeling Changes (SrLC)

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ZUBSOLV (NDA-204242)

(BUPRENORPHINE HYDROCHLORIDE; NALOXONE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/15/2023 (SUPPL-27)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Post-marketing Experience

Newly added information:

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

06/17/2022 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Dental Adverse Events

Newly added subsection:

Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.

Refer patients to dental care services and encourage them to have regular dental checkups while taking Zubsolv. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after Zubsolv has been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking Zubsolv before brushing teeth [see Dosing and Administration (2.6), Information for Patients (17), Medication Guide].

5.14 QTc Prolongation

Newly added subsection:

Thorough QT studies with buprenorphine products have demonstrated QT prolongation less than or equal to 15 msec. This QTc prolongation effect does not appear to be mediated by hERG chanels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT prolonging agents is not known.

Consider these observations in clinical decisions when prescribing Zubsolv to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Local reactions: Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What should I tell my doctor before taking ZUBSOLV?

Before taking ZUBSOLV, tell your healthcare provider about all of your medical conditions, including if you have:

…          

• tooth problems, including a history of cavities

…

How should I take ZUBSOLV?
Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to take ZUBSOLV
…

• After ZUBSOLV is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.

• Report any problems with your teeth immediately to your healthcare provider and schedule an appointment with a dentist. Tell your dentist that you have started taking ZUBSOLV.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Safe Use       
Before initiating treatment with ZUBSOLV, 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.

…

• Advise patients that, after ZUBSOLV has completely dissolved in the oral mucosa, to take a sip of water, swish it gently around their teeth and gums, and swallow. Advise patients to wait for at least one hour after taking ZUBSOLV before brushing teeth [see Warnings and Precautions (5.X)].

• Refer patients to dental care services and encourage them to have regular dental checkups while taking ZUBSOLV. Instruct patients to inform their dentist that they have started therapy on ZUBSOLV [see Warnings and Precautions (5.X)].

…

03/04/2021 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Additions and/or revisions underlined:

… Use ZUBSOLV 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).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.9)].

Newly added information:

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with ZUBSOLV. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.3)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with ZUBSOLV itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of ZUBSOLV and its affinity for the mu receptor [see Overdosage (10)].

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

5.3 Managing Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Additions and/or revisions underlined:

… Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.2)].

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions with ZUBSOLV

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Under Intervention, the following language is added:

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder [see Warnings and Precautions (5.2)].

Muscle Relaxants

Under Intervention, the following language is added:

Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.3), Warnings and Precautions (5.2, 5.3)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

IMPORTANT: Keep ZUBSOLV in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally uses ZUBSOLV, get emergency help or call 911 right away. Tell your healthcare provider if you are living in a household where there are small children.

What is the most important information I should know about ZUBSOLV?

Additions and/or revisions underlined:

• ZUBSOLV contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.

• Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of ZUBSOLV by a child.

PATIENT COUNSELING INFORMATION

Safe Use

Newly added information:

• Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2)].

• Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

  Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

  Inform patients and caregivers of the options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

  Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

  Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving ZUBSOLV, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.2), Overdosage (10)].

  If naloxone is prescribed, also advise patients and caregivers:

• How to treat with naloxone in the event of an opioid overdose

• To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency

• To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.

10/07/2019 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Risk of Life-Threatening Respiratory and Central Nervous System (CNS) Depression

Newly added information to end of subsection:

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

7 Drug Interactions

Table 4: Clinically Significant Drug Interactions

Serotonergic Drugs

Additions and/or revisions underlined:

Example: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined in bulleted information:

What is the most important information I should know about ZUBSOLV?

• Store ZUBSOLV securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.

PATIENT COUNSELING INFORMATION

Storage and Disposal:

Additions and/or revisions underlined:

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ZUBSOLV securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving ZUBSOLV unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused ZUBSOLV should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

02/01/2018 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

ZUBSOLV is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone …

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Addiction, Abuse, and Misuse

ZUBSOLV contains buprenorphine, a Schedule III controlled substance that can be abused in a manner …

5.2 Risk of Respiratory and Central Nervous System (CNS) Depression

Buprenorphine has been associated with life-threating respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuses by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with ZUBSOLV.

Use ZUBSOLV with caution in patients …

5.3 Managing Risks from Concomitant Use of Benzodiazepines or Other CNS Depressants

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Newly added information:

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines.

5.7 Risk of Opioid Withdrawal with Abrupt Discontinuation

Additions and/or revisions underlined:

The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. When discontinuing ZUBSOLV, gradually taper the dosage.

5.8 Risk of Hepatitis, Hepatic Events

5.9 Hypersensitivity Reactions

5.11 Risk of Overdose in Opioid Naïve Patients

5.12 Use in Patients With Impaired Hepatic Function

… Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended   for initiation of treatment (induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment …

6 Adverse Reactions

Addition of the following:

The following serious adverse reactions are described elsewhere in the labeling:

• Addiction, Abuse, and Misuse
• Respiratory and CNS Depression
• Neonatal Opioid Withdrawal Syndrome
• Adrenal Insufficiency
• Opioid Withdrawal
• Hepatitis, Hepatic Events
• Hypersensitivity Reactions
• Orthostatic Hypotension
• Elevation of Cerebrospinal Fluid Pressure
• Elevation of Intracholedochal Pressure

6.2 Postmarketing Experience

Newly added information:

Local reactions: Glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Risk Summary

… In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related. Based on animal data, advise pregnant women of the potential risk to a fetus.

8.5 Geriatric Use

… Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe ZUBSOLV should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Newly added section; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Safe Use

Additions and/or revisions underlined:

• ZUBSOLV must be administered whole.  Advise patients not to cut, chew, or swallow ZUBSOLV.
• Inform patients and caregivers that potentially fatal additive effects may occur if ZUBSOLV is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a health care provider.

09/08/2017 (SUPPL-11)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

The data on use of buprenorphine, one of the active ingredients in ZUBSOLV, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure…

Clinical Considerations

Dose Adjustment during Pregnancy and the Postpartum Period

Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy…

Data

Human Data

…

In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups…

Animal Data

…Following oral administration to rats, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day (estimated exposure approximately 150 times the human sublingual dose of 16 mg ) in the presence of maternal toxicity (mortality). Following oral administration to rabbits, no teratogenic effects were observed at buprenorphine doses up to 40 mg/kg/day (estimated exposure approximately 50 times the human sublingual dose of 16 mg) in the absence of clear maternal toxicity… Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits… Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed.…Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant.

…No maternal toxicity was noted at doses causing post-implantation loss in this study.

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg)…

8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

…The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZUBSOLV sublingual tablet and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise patients to read the FDA-approved patient labeling. (Medication Guide)

Safe Use

• Warn patients that it is extremely dangerous to self-administer non-prescribed benzodiazepines or other CNS depressants (including alcohol) while taking ZUBSOLV sublingual tablets. Caution patients prescribed benzodiazepines or other CNS depressants s to use them only as directed by their physician.
• Advise patients should be advised that ZUBSOLV sublingual tablets contain an opioid…
• Instruct patients 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. Advise patients to seek medical attention immediately if a child is exposed to ZUBSOLV sublingual tablets.
• Advise patients never to give ZUBSOLV sublingual tablets to anyone else…
• Advise patients that selling or giving away this medication is against the law.
• Caution patients that ZUBSOLV sublingual tablets may impair the mental or physical abilities…
• Advise patients not to change the dosage of ZUBSOLV sublingual tablets without consulting their healthcare provider.
• Advise patients to take ZUBSOLV sublingual tablets once a day, after induction.
• Advise patients that if they miss a dose of ZUBSOLV they should take it as soon as they remember…
• Inform patients that ZUBSOLV sublingual tablets can cause drug dependence…
• Advise patients seeking to discontinue treatment with buprenorphine for opioid dependence to…
• Caution patients that, like other opioids, ZUBSOLV sublingual tablets may produce orthostatic hypotension in ambulatory individuals.
• Advise patients to inform their healthcare provider if…

12/16/2016 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Dependence

Additions and/or revisions underlined:

Buprenorphine is a partial agonist at the mu-opioid receptor … 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.

7 Drug Interactions

Table 4. Includes clinically significant drug interactions with ZUBSOLV

(Information has been converted to table format; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

… Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre-and postnatal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of organogenesisdoses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in ats and rabbits administered buprenorphine daily during organogenesis at indoses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide has been added; please refer to label.

10/04/2016 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Neonatal Opioid Withdrawal Syndrome (new subsection)

            Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly.

            Advise pregnant women receiving opioid addiction treatment with ZUBSOLV of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

5.7 Adrenal Insufficiency (new subsection)

            Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency

6 Adverse Reactions

6.1 Clinical Trials Experience

            The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 3 shows adverse events 5% of subjects in any dose group in the dose-controlled study.

            Table 3 has been reformatted and adverse effects have been added; please refer to label.

            Table 2 has been revised; please refer to label.

6.2 Post-marketing Experience

            The following adverse reactions have been identified during post- approval use of buprenorphine and naloxone sublingual tablets…

Addition of the following:

            Serotonin syndrome: Cases of serotonin syndrome, a potentially life- threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

            Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

            Anaphylaxis: Anaphylaxis has been reported with ingredients contained in ZUBSOLV.

            Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

7 Drug Interactions

7.4 Serotonergic Drugs (new subsection)

            The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome.

            If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ZUBSOLV if serotonin syndrome is suspected.

8 Use in Specific Populations

8.1 Pregnancy (PLLR Conversion)

            Extensive changes; please refer to label.       

8.2 Lactation (PLLR Conversion – revised subsection)

Risk Summary

            Based on two studies in 13 lactating women, maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were 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 limited. 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 breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

Data

            Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

            In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose [(relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent]).

            Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that, the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 ml/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

8.3 Females and Males of Reproductive Potential (PLLR Conversion – new subsection)

Infertility

            Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

8.4 Pediatric Use (revision underlined)

            This product is not appropriate for the treatment of neonatal opioid withdrawal syndrome in neonates, because it contains naloxone, an opioid antagonist.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

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.

• Inform patients that ZUBSOLV could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications.
• Inform patients that ZUBSOLV could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms.
• Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.