Belbuca

What Is Belbuca?

Belbuca (buprenorphine) buccal film contains a partial opioid agonist and is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

What Are Side Effects of Belbuca?

Common side effects of Belbuca include:

• nausea,
• constipation,
• headache,
• vomiting,
• dizziness,
• drowsiness,
• fatigue,
• diarrhea,
• dry mouth, and
• upper respiratory tract infection,
• anemia,
• abdominal pain,
• swelling of the extremities,
• fever,
• urinary tract infection,
• runny or stuffy nose,
• sinus infection,
• bronchitis,
• loss of appetite,
• muscle spasms,
• back pain,
• anxiety,
• insomnia,
• depression,
• sore throat,
• increased sweating,
• itching,
• rash,
• hot flashes, or
• high blood pressure.

Dosage for Belbuca

For opioid-naive patients, initiate therapy with a 75 mcg dose of Belbuca once daily or every 12 hours, as tolerated, for at least 4 days before increasing dose to 150 mcg every 12 hours.

What Drugs, Substances, or Supplements Interact with Belbuca?

Belbuca may interact with:

• CNS depressants, including:
• alcohol,
• anxiolytics,
• general anesthetics,
• hypnotics,
• neuroleptics,
• phenothiazines,
• sedatives,
• tranquilizers,
• other opioids,
• benzodiazepines,
• CYP3A4 inhibitors or inducers,
• mixed agonist/antagonist and partial agonist opioid analgesics, including:
• butorphanol,
• nalbuphine,
• pentazocine,
Tell your doctor all medications and supplements you use.
• muscle relaxants,
• diuretics,
• anticholinergics, and
• antiretroviral protease inhibitors (PIs)

Belbuca During Pregnancy and Breastfeeding

Belbuca is not recommended for use during pregnancy; it may harm a fetus. Babies born to mothers who take narcotics while pregnant may experience withdrawal symptoms. Belbuca is not recommend for use while breastfeeding. Withdrawal symptoms may occur if you suddenly stop taking this medication.

Additional Information

Our Belbuca (buprenorphine) buccal film Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

 

Belbuca Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Opioid medicine can slow or stop your breathing, and death may occur. A person caring for you should seek emergency medical attention if you have slow breathing with long pauses, blue colored lips, or if you are hard to wake up.

Call your doctor at once if you have:

• noisy breathing, sighing, shallow breathing, breathing that stops during sleep;
• slow heartbeat or weak pulse;
• a light-headed feeling, like you might pass out;
• chest pain, fast heart rate, trouble breathing;
• severe constipation;
• opioid withdrawal symptoms--shivering, goose bumps, increased sweating, feeling hot or cold, runny nose, watery eyes, diarrhea, muscle pain;
• low cortisol levels-- nausea, vomiting, loss of appetite, dizziness, worsening tiredness or weakness; or
• liver problems--nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Serious side effects may be more likely in older adults and those who are overweight, malnourished, or debilitated.

Long-term use of opioid medication may affect fertility (ability to have children) in men or women. It is not known whether opioid effects on fertility are permanent.

Common side effects may include:

• constipation, nausea, vomiting;
• headache, dizziness, drowsiness;
• increased sweating;
• sleep problems (insomnia); or
• pain anywhere in your body.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Belbuca (Buprenorphine Buccal Film)

 

Belbuca Professional Information

SIDE EFFECTS

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

• Addiction, Abuse, and Misuse [see WARNINGS AND PRECAUTIONS]
• Life-Threatening Respiratory Depression [see WARNINGS AND PRECAUTIONS]
• Neonatal Opioid Withdrawal Syndrome [see WARNINGS AND PRECAUTIONS]
• Interactions with Benzodiazepines and Other CNS Depressants [see WARNINGS AND PRECAUTIONS]
• Adrenal Insufficiency [see WARNINGS AND PRECAUTIONS]
• QTc Prolongation [see WARNINGS AND PRECAUTIONS]
• Severe Hypotension [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Anaphylactic/Allergic Reactions [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2,127 patients were treated with BELBUCA in controlled and open-label chronic pain trials. There were 504 patients treated for approximately six months and 253 patients treated for approximately one year. The clinical trial population consisted of patients with chronic moderate-to-severe pain.

The most common serious adverse drug reactions (all ≤ 0.2%) occurring during clinical trials with BELBUCA were: cellulitis, pneumonia, ileus, atrial fibrillation, coronary artery disease, cerebrovascular accident, syncope, transient ischemic attack, chest pain, non-cardiac chest pain, ankle fracture, cholecystitis, osteoarthritis, and dehydration.

The most common adverse events (≥ 2%) leading to discontinuation were nausea, vomiting, and liver function test abnormality.

The most common adverse events (≥ 5%) reported by opioid-naive, opioid-experienced, and overall patients exposed to BELBUCA in clinical trials and compared against placebo are shown in Table 2, Table 3 and Table 4:

Table 2: Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Naive Patients

MedDRA Preferred Term	Open-Label Titration Phase	Double-Blind Treatment Phase
	BELBUCA (N=749)	BELBUCA (N=229)	Placebo (N=232)
Nausea	50%	10%	7%
Constipation	13%	4%	3%
Vomiting	8%	4%	<1%
Headache	8%	2%	3%
Dizziness	6%	2%	<1%
Somnolence	7%	1%	<1%
Fatigue	5%	0%	1%

Table 3: Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies: Opioid-Experienced Patients

MedDRA Preferred Term	Open-Label Titration Phase	Double-Blind Treatment Phase
	BELBUCA (N=810)	BELBUCA (N=254)	Placebo (N=256)
Nausea	17%	7%	7%
Constipation	8%	3%	1%
Vomiting	7%	5%	2%
Headache	7%	2%	3%
Dizziness	5%	2%	<1%
Somnolence	5%	1%	<1%
Drug Withdrawal Syndrome	0%	4%	10%

Table 4: Adverse Events Reported in ≥ 5% of Patients during the Open-Label Titration Phase and Double-Blind Treatment Phase of Controlled Studies

MedDRA Preferred Term	Open-Label Titration Phase	Double-Blind Treatment Phase
	BELBUCA (N=1889)	BELBUCA (N=600)	Placebo (N=606)
Nausea	33%	9%	8%
Constipation	11%	4%	2%
Vomiting	7%	5%	2%
Headache	8%	4%	3%
Dizziness	6%	2%	<1%
Somnolence	6%	<1%	<1%
Drug Withdrawal Syndrome	1%	2%	5%

The most common (≥ 5%), common (≥ 1% to < 5%), and least common (< 1%) adverse reactions reported by patients taking BELBUCA in the controlled and open-label clinical studies are presented below:

Most common adverse reactions (≥ 5%): nausea, constipation, headache, vomiting, fatigue, dizziness, and somnolence.

Common (≥ 1% to < 5%) adverse reactions (organized by MedDRA [Medical Dictionary for Regulatory Activities] System Organ Class):

Blood and lymphatic system disorders: anemia

Gastrointestinal disorders: abdominal pain, diarrhea, dry mouth

General disorders and administration site conditions: peripheral edema, pyrexia, drug withdrawal syndrome

Infections and infestations: upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, gastroenteritis

Injury, poisoning, and procedural complications: contusion, fall

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal and connective tissue disorders: muscle spasms, back pain

Psychiatric disorders: anxiety, insomnia, depression

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain, sinus congestion

Skin and subcutaneous tissue disorders: hyperhidrosis, pruritus, rash

Vascular disorders: hot flush, hypertension

Least common (<1%) adverse reactions:

Abdominal discomfort, acute sinusitis, dyspepsia, toothache, asthenia, chills, cellulitis, tooth abscess, excoriation, laceration, aspartate aminotransferase increased, blood pressure increased, blood testosterone decreased, electrocardiogram QT prolonged, liver function test abnormal, musculoskeletal pain, neck pain, hypoesthesia, lethargy, migraine, tremor, cough, dyspnea, nasal congestion, rhinorrhea.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 BELBUCA.

Androgen Deficiency

Cases of androgen deficiency have occurred with chronic use of opioids [see CLINICAL PHARMACOLOGY].

DRUG INTERACTIONS

Table 5 includes clinically significant drug interactions with BELBUCA.

Table 5: Clinically Significant Drug Interactions

Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of BELBUCA and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA, and warn patients to use benzodiazepines concurrently with BELBUCA only as directed by their physician.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact:	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 BELBUCA is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of BELBUCA until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BELBUCA dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BELBUCA if serotonin syndrome is suspected.
Examples:	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).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma) [see WARNINGS AND PRECAUTIONS].
Intervention:	The use of BELBUCA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of BELBUCA and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and BELBUCA for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BELBUCA and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
Examples:	cyclobenzaprine, metaxalone
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when BELBUCA is used concomitantly with anticholinergic drugs.
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic BELBUCA treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetics and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking BELBUCA and atazanavir with and without ritonavir and reduce the dose of BELBUCA if warranted.
Examples:	atazanavir, ritonavir

Drug Abuse And Dependence

Controlled Substance

BELBUCA contains buprenorphine hydrochloride, a Schedule III controlled substance.

Abuse

BELBUCA contains buprenorphine, a substance with a potential for abuse similar to other Schedule III opioids. BELBUCA can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see WARNINGS AND PRECAUTIONS].

All patients treated with opioids, including BELBUCA, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carry the risk of addiction, even under appropriate medical use.

Prescription drug abuse is the intentional, non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating healthcare providers. “Doctor shopping” (visiting multiple

prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all persons with substance use disorders. In addition, abuse of opioids can occur in the absence of true addiction.

BELBUCA, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific To Abuse Of BELBUCA

BELBUCA is intended for buccal use only. Abuse of BELBUCA poses a risk of overdose and death. This risk is increased with concurrent abuse of BELBUCA with alcohol and other substances, including other opioids and benzodiazepines [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]. Intentional compromise of the buccal film might result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see WARNINGS AND PRECAUTIONS]. Abuse may occur by applying the buccal film in the absence of legitimate purpose, or by swallowing, snorting, or injecting buprenorphine extracted from the buccal film. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects.

Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), or mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Do not abruptly discontinue BELBUCA in a patient physically dependent on opioids. Rapid tapering of BELBUCA in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing BELBUCA, gradually taper the dosage using a patient-specific plan that considers the following: the dose of BELBUCA the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for a long duration at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use In Specific Populations].

Read the entire FDA prescribing information for Belbuca (Buprenorphine Buccal Film)