Expanding Access to Opioid Use Disorder Treatment

INDICATIONS AND USAGE

Buprenorphine and naloxone sublingual tablets are indicated for maintenance treatment
of opioid dependence. Buprenorphine and naloxone sublingual tablets should be used as part of a complete treatment plan that includes counseling and psychosocial support.

IMPORTANT SAFETY INFORMATION

Contraindications

Buprenorphine and naloxone sublingual tablet is contraindicated in patients with a history of hypersensitivity to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, have been reported.

WARNINGS AND PRECAUTIONS

Addiction, Abuse, and Misuse
Buprenorphine and naloxone sublingual tablets contain buprenorphine, a schedule III controlled substance that can be abused in a manner similar to other opioids. 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.

Life-threatening Respiratory Depression and Central Nervous System (CNS) Depression
Buprenorphine has been associated with life-threatening respiratory depression and death. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants, including alcohol, while under treatment with buprenorphine and naloxone sublingual tablets. Use with caution in patients with compromised respiratory function. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA), and sleep-related hypoxemia. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Patient Access to Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose
Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene) and discuss the importance of having access to an opioid overdose reversal agent. Strongly consider recommending or prescribing an opioid overdose reversal agent for the emergency treatment of an opioid overdose, both when initiating and renewing treatment with buprenorphine and naloxone sublingual tablets. Also consider recommending or prescribing such an agent if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Risks from Concomitant Use with Benzodiazepine or Other CNS Depressants
Concomitant use of buprenorphine and benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids) increases the risk of adverse reactions including overdose, respiratory depression, and death. If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine treatment for opioid use disorder.

Unintentional Pediatric Exposure
Buprenorphine can cause severe, possibly fatal, respiratory depression in children. Store buprenorphine and naloxone sublingual tablet safely out of the sight and reach of children.

Neonatal Opioid Withdrawal Syndrome
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. Advise pregnant women receiving opioid addiction treatment with buprenorphine and naloxone sublingual tablets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Adrenal Insufficiency
Cases of adrenal insufficiency have been reported with opioid use. If diagnosed, treat with physiologic replacement doses of corticosteroids and wean the patient off the opioid.

Risk of Opioid Withdrawal with Abrupt Discontinuation
If treatment with buprenorphine and naloxone sublingual tablets is temporarily interrupted or discontinued, monitor patients for withdrawal and treat appropriately. When discontinuing buprenorphine and naloxone sublingual tablets, gradually taper the dosage.

Risk of Hepatitis, Hepatic Events
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through postmarketing 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. 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 are 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, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use. Strict monitoring of the patient should be initiated. Monitor liver function tests prior to initiation and during treatment and evaluate suspected hepatic events.

Hypersensitivity Reactions
Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both in clinical trials and in the postmarketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus.

Precipitation of Opioid Withdrawal Signs and Symptoms
An opioid withdrawal syndrome is likely to occur with parenteral misuse of buprenorphine and naloxone sublingual tablet by individuals physically dependent on full opioid agonists or by sublingual administration before the agonist effects of other opioids have subsided.

Risk of Overdose in Opioid-Naïve Patients
There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic.

Use in Patients with Impaired Hepatic Function
Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. Use of buprenorphine/naloxone may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment.

Dental Adverse Events
Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with buprenorphine and naloxone sublingual tablets.

QTc Prolongation
Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤15 msec. The risk of combining buprenorphine with other QT prolonging agents is not known. Consider these observations in clinical decisions when prescribing buprenorphine and naloxone sublingual tablets to patients with QT-related risk factors.

Impairment of Ability to Drive or Operate Machinery
Caution patients that buprenorphine and naloxone sublingual tablets 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.

Orthostatic Hypotension
Like other opioids, buprenorphine and naloxone 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.

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.

ADVERSE REACTIONS

Adverse events reported by at least 5% of patients administered buprenorphine and naloxone sublingual tablets from a 4-week clinical study include: headache, withdrawal syndrome, pain, nausea, insomnia, sweating, constipation, pain abdomen, vasodilation, chills, vomiting, asthenia, and infection.

Adverse events reported by at least 5% of patients administered buprenorphine from a 16-week clinical study include: abscess, asthenia, chills, fever, flu syndrome, headache, infection, injury accidental, pain, pain back, withdrawal syndrome, constipation, diarrhea, dyspepsia, nausea, vomiting, anxiety, depression, dizziness, insomnia, nervousness, somnolence, cough increase, pharyngitis, rhinitis, sweat, runny eyes.

DRUG INTERACTIONS

Clinically significant drug interactions with buprenorphine and naloxone sublingual tablets include:

Benzodiazepines or other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Use with caution in patients receiving benzodiazepines or other CNS depressants and warn patients against concomitant self-administration and misuse. If concomitant use is warranted, strongly consider recommending or prescribing an opioid overdose reversal agent, as is recommended for all patients on buprenorphine and naloxone treatment for opioid use disorder.

CYP3A4 Inhibitors: Monitor patients starting or ending CYP3A4 inhibitors for potential over- or under- dosing. The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine and naloxone sublingual tablet is achieved.

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.

CYP3A4 Inducers: Monitor patients starting or ending CYP3A4 inducers for potential over- or under- dosing. The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence on buprenorphine.

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase, which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.

Antiretrovirals: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Significant pharmacokinetic interactions between NNRTIs and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. Patients who are on chronic buprenorphine treatment should have their dose monitored if NNRTIs are added to their treatment regimen.

Antiretrovirals: Protease inhibitors (PIs): Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. Monitor patients taking buprenorphine and atazanavir with and without ritonavir and reduce dose of buprenorphine if warranted.

Antiretrovirals: Nucleoside Reverse Transcriptase Inhibitors (NRTIs): Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Discontinue buprenorphine and naloxone sublingual tablets if serotonin syndrome is suspected.

Monoamine Oxidase Inhibitors (MAOIs): MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). The use of buprenorphine and naloxone sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Muscle Relaxants: Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and buprenorphine and naloxone sublingual tablets for signs of respiratory depression and decrease the dosage of buprenorphine and naloxone sublingual tablets and/or the muscle relaxant as necessary.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs: The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention or reduced gastric motility

USE IN SPECIFIC POPULATIONS

Pregnancy
Risk Summary
The data on use of buprenorphine, one of the active ingredients in buprenorphine and naloxone sublingual tablets in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. The extremely limited data on sublingual naloxone exposure in pregnancy are not sufficient to evaluate a drug-associated risk.

Clinical Considerations
Disease-associated Maternal and Embryo-Fetal Risk
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death.

Dose Adjustment during Pregnancy and the Postpartum Period
Dosage adjustments of buprenorphine, such as using higher doses, may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy.

Fetal/Neonatal Adverse Reactions
Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with buprenorphine and naloxone sublingual tablets.

Labor or Delivery
Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

Lactation
Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

Females and Males of Reproductive Potential
Infertility
Chronic use of opioids may cause reduced fertility in females and males of reproductive potential.

Pediatric Use
The safety and effectiveness of buprenorphine and naloxone 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
Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine and naloxone sublingual tablets 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.

Hepatic Impairment
Buprenorphine/naloxone products should be avoided in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment.

Renal Impairment
The effects of renal failure on naloxone pharmacokinetics are unknown.

Please read Full Prescribing Information.

To report SUSPECTED ADVERSE REACTIONS, contact Knoa Pharma LLC at 1-888-726-7535, option 2, or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.