Belbuca (buprenorphine) for Chronic Pain: Drug Warnings

Generic drug: buprenorphine

Brand name: Belbuca

What is Belbuca (buprenorphine), and how does it work?

Belbuca is a prescription medicine used to treat the symptoms of Chronic Severe Pain. Belbuca may be used alone or with other medications.

Belbuca belongs to a class of drugs called Analgesics, Opioid Partial Agonist.

It is not known if Belbuca is safe and effective in children.

What are the side effects of Belbuca?

WARNING

ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; and NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Addiction, Abuse, and Misuse

Belbuca exposes patients and other users to the risks of opioid addiction,
abuse, and misuse, which can lead to overdose and death. Assess each patient’s
risk prior to prescribing Belbuca, and monitor all patients regularly for the
development of these behaviors and conditions.

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression may occur with use
of Belbuca. Monitor for respiratory depression, especially during initiation of
Belbuca or following a dose increase. Misuse or abuse of Belbuca by chewing,
swallowing, snorting or injecting buprenorphine extracted from the buccal film
will result in the uncontrolled delivery of buprenorphine and pose a significant
risk of overdose and death.

Accidental Exposure

Accidental exposure to even one dose of Belbuca, especially in children, can
result in a fatal overdose of buprenorphine.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of Belbuca during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires

management according to protocols developed by neonatology experts. If opioid
use is required for a prolonged period in a pregnant woman, advise the patient
of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate
treatment will be available.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous
system (CNS) depressants, including alcohol, may result in profound sedation,
respiratory depression, coma, and death.

• Reserve concomitant prescribing of Belbuca Injection and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
• Limit dos ages and durations to the minimum required.
• Follow patients for signs and symptoms of respiratory depression and sedation

What are the possible side effects of Belbuca?

Belbuca may cause serious side effects including:

• swelling of the face, arms, hands, ankles or feet,
• blood in your urine,
• blurred vision,
• cough,
• diarrhea,
• abdominal pain,
• difficulty breathing,
• dizziness,
• fever,
• frequent urination,
• headache,
• loss of appetite,
• back pain,
• mouth pain,
• nausea,
• nervousness,
• pale skin,
• pounding in the ears,
• rapid weight gain,
• slow or fast heartbeats,
• stomach pain,
• chest pain or pressure,
• tingling in the hands or feet,
• tiredness or weakness,
• unusual bruising or bleeding,
• irregular heartbeat,
• chills,
• drowsiness,
• agitation,
• confusion,
• darkening of the skin,
• lightheadedness,
• hives,
• rash,
• depression,
• shallow breathing,
• breathing that stops in your sleep,
• pale skin,
• loss of coordination,
• swelling around the eyes, lips or tongue,
• restlessness,
• extreme excitement,
• tremors,
• muscle spasms, and
• vomiting

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Belbuca include:

• nausea,
• constipation,
• headache,
• vomiting,
• dizziness,
• drowsiness,
• fatigue,
• diarrhea,
• dry mouth,
• 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 spasm,
• back pain,
• anxiety,
• insomnia,
• depression,
• sore throat,
• increased sweating,
• itching,
• rash,
• hot flashes, and
• high blood pressure

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Belbuca. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the dosage for Belbuca?

Important Dosage And Administration Instructions

Belbuca should be prescribed only by healthcare professionals who are knowledgeable in the use of potent opioids for the management of chronic pain.

• Use the lowest effective dosage for the shortest duration consistent
  with individual patient treatment goals.
• Initiate the dosing regimen for each patient individually, taking into
  account the patient’s severity of pain, patient response, prior analgesic
  treatment experience, and risk factors for addiction, abuse, and misuse.
• Monitor patients closely for respiratory depression, especially within
  the first 24-72 hours of initiating therapy and following dosage increases
  with Belbuca and adjust the dosage accordingly.
• Belbuca buccal film is for oral buccal use only and is to be applied to the buccal mucosa every 12 hours.
• Instruct patients not to use Belbuca if the pouch seal is broken or the buccal film is cut, damaged, or changed in any way and to avoid applying
  Belbuca to areas of the mouth with any open sores or lesions.

What drugs interact with Belbuca?

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.

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, 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, 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, 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).

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.

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

Medically speaking, the term “myalgia” refers to what type of pain?
See Answer

Does Belbuca cause addiction or withdrawal symptoms?

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.
• 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.
• 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.
• 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.
• Infants born to mothers physically dependent on opioids will also be
  physically dependent and may exhibit respiratory difficulties and withdrawal
  symptoms.

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Is Belbuca safe to use while pregnant or breastfeeding?

• Inform female patients of reproductive potential that prolonged use of
  Belbuca during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.
• Belbuca can cause fetal harm. Women should inform their healthcare provider of a known or suspected pregnancy.
• Breastfeeding is not recommended during treatment with Belbuca.