Belbuca

Buprenorphine is an opioid medication. An opioid is sometimes called a narcotic.

Buprenorphine oral (buccal, placed between the gum and cheek) is for around-the-clock treatment of moderate to severe chronic pain that is not controlled by other medicines. This medicine is not for use on an as-needed basis for occasional pain.

Buprenorphine may also be used for purposes not listed in this medication guide.

Buprenorphine can slow or stop your breathing. Never use this medicine in larger amounts, or for longer than prescribed. Buprenorphine may be habit-forming, even at regular doses. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

MISUSE OF NARCOTIC MEDICINE CAN CAUSE ADDICTION, OVERDOSE, OR DEATH, especially in a child or other person using the medicine without a prescription.

Tell your doctor if you are pregnant. Buprenorphine may cause life-threatening withdrawal symptoms in a newborn.

You should not use this medicine if you are allergic to buprenorphine, or:

• if you have severe asthma or trouble breathing;
• if you have a blockage in your digestive tract, including a bowel obstruction called paralytic ileus; or
• if you have used another narcotic drug within the past 4 hours.

To make sure buprenorphine is safe for you, tell your doctor if you have:

• any type of breathing problem or lung disease;
• liver disease (especially hepatitis B or C);
• kidney disease;
• enlarged prostate, urination problems;
• problems with your gallbladder, pancreas, or thyroid;
• long QT syndrome, or if you take heart rhythm medication;
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);
• mouth sores caused by cancer;
• a history of head injury, brain tumor, or seizures;
• a history of drug abuse, alcohol addiction, or mental illness; or
• a history of methadone use.

It is not known whether this medicine will harm an unborn baby. If you use buprenorphine while you are pregnant, your baby could become dependent on the drug. This can cause life-threatening withdrawal symptoms in the baby after it is born. Babies born dependent on habit-forming medicine may need medical treatment for several weeks. Tell your doctor if you are pregnant or plan to become pregnant.

Buprenorphine can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using buprenorphine.

Buprenorphine is not approved for use by anyone younger than 18 years old.

Grapefruit and grapefruit juice may interact with Belbuca and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL EXPOSURE; AND NEONATAL OPIOID WITHDRAWAL SYNDROME

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 patients regularly for the development of these behaviors or 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.

In the U.S.

• Belbuca
• Subutex

Available Dosage Forms:

• Film
• Tablet

Therapeutic Class: Analgesic

Pharmacologic Class: Opioid Agonist/Antagonist

Chemical Class: Opioid

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of buprenorphine in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of buprenorphine in the elderly. However, elderly patients are more likely to have age-related lung, kidney, or liver problems, which may require caution and an adjustment in the dose for patients receiving buprenorphine in order to avoid potentially serious side effects.

Pregnancy

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Nalmefene
• Naltrexone
• Safinamide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acepromazine
• Alfentanil
• Almotriptan
• Alprazolam
• Amineptine
• Amisulpride
• Amitriptyline
• Amitriptylinoxide
• Amobarbital
• Amoxapine
• Amphetamine
• Aripiprazole
• Asenapine
• Atazanavir
• Baclofen
• Benperidol
• Benzphetamine
• Bromazepam
• Bromopride
• Brompheniramine
• Buspirone
• Butabarbital
• Butorphanol
• Carbamazepine
• Carbinoxamine
• Carisoprodol
• Carphenazine
• Chloral Hydrate
• Chlordiazepoxide
• Chlorpheniramine
• Chlorpromazine
• Chlorzoxazone
• Citalopram
• Clobazam
• Clomipramine
• Clonazepam
• Clorazepate
• Clozapine
• Cocaine
• Codeine
• Cyclobenzaprine
• Desipramine
• Desmopressin
• Desvenlafaxine
• Dexmedetomidine
• Dextroamphetamine
• Dextromethorphan
• Dezocine
• Diazepam
• Dibenzepin
• Dichloralphenazone
• Difenoxin
• Diphenhydramine
• Diphenoxylate
• Dolasetron
• Donepezil
• Doxepin
• Doxylamine
• Droperidol
• Duloxetine
• Eletriptan
• Enflurane
• Escitalopram
• Estazolam
• Eszopiclone
• Ethchlorvynol
• Ethopropazine
• Ethylmorphine
• Fentanyl
• Flibanserin
• Fluoxetine
• Fluphenazine
• Flurazepam
• Fluspirilene
• Fluvoxamine
• Fospropofol
• Frovatriptan
• Furazolidone
• Granisetron
• Halazepam
• Haloperidol
• Halothane
• Hexobarbital
• Hydrocodone
• Hydromorphone
• Hydroxytryptophan
• Hydroxyzine
• Imipramine
• Iproniazid
• Isocarboxazid
• Isoflurane
• Ketamine
• Ketazolam
• Ketobemidone
• Levomilnacipran
• Levorphanol
• Linezolid
• Lisdexamfetamine
• Lithium
• Lofepramine
• Lorazepam
• Lorcaserin
• Loxapine
• Meclizine
• Melitracen
• Melperone
• Meperidine
• Mephobarbital
• Meprobamate
• Meptazinol
• Mesoridazine
• Metaxalone
• Methadone
• Methamphetamine
• Methdilazine
• Methocarbamol
• Methohexital
• Methotrimeprazine
• Methylene Blue
• Midazolam
• Milnacipran
• Mirtazapine
• Moclobemide
• Molindone
• Moricizine
• Morphine
• Nalbuphine
• Naratriptan
• Nefazodone
• Nialamide
• Nicomorphine
• Nitrazepam
• Nitrous Oxide
• Nortriptyline
• Olanzapine
• Ondansetron
• Opipramol
• Opium
• Opium Alkaloids
• Orphenadrine
• Oxazepam
• Oxycodone
• Oxymorphone
• Palonosetron
• Papaveretum
• Paregoric
• Paroxetine
• Pentazocine
• Pentobarbital
• Perampanel
• Perazine
• Periciazine
• Perphenazine
• Phenelzine
• Phenobarbital
• Pimozide
• Piperacetazine
• Pipotiazine
• Piritramide
• Prazepam
• Primidone
• Procarbazine
• Prochlorperazine
• Promazine
• Promethazine
• Propofol
• Protriptyline
• Quazepam
• Quetiapine
• Ramelteon
• Rasagiline
• Remifentanil
• Remoxipride
• Rizatriptan
• Secobarbital
• Selegiline
• Sertindole
• Sertraline
• Sibutramine
• Sodium Oxybate
• St John's Wort
• Sufentanil
• Sulpiride
• Sumatriptan
• Suvorexant
• Tapentadol
• Temazepam
• Thiethylperazine
• Thiopental
• Thiopropazate
• Thioridazine
• Tianeptine
• Tilidine
• Tizanidine
• Tolonium Chloride
• Topiramate
• Tramadol
• Tranylcypromine
• Trazodone
• Triazolam
• Trifluoperazine
• Trifluperidol
• Triflupromazine
• Trimeprazine
• Trimipramine
• Tryptophan
• Venlafaxine
• Vilazodone
• Vortioxetine
• Zaleplon
• Ziprasidone
• Zolpidem
• Zopiclone
• Zotepine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Addison disease (adrenal gland problem) or
• Alcohol abuse, or history of or
• Asthma, severe or
• Brain tumor, history of or
• Breathing problems, severe (eg, hypercapnia, hypoxia, apnea) or
• Chronic obstructive pulmonary disease (COPD) or
• Cor pulmonale (serious heart condition) or
• Drug dependence, especially with narcotics, or history of or
• Enlarged prostate (BPH, prostatic hypertrophy) or
• Gallbladder disease or gallstones or
• Head injury, history of or
• Heart disease (eg, angina, congestive heart failure) or
• Heart rhythm problems (eg, atrial fibrillation, slow heartbeat, long QT syndrome) or
• Hepatitis B or C, history of or
• Hypokalemia (low potassium in the blood) or
• Hypomagnesemia (low magnesium in the blood) or
• Hypothyroidism (an underactive thyroid) or
• Hypovolemia (low blood volume) or
• Kyphoscoliosis (curvature of the spine with breathing problems) or
• Problems with passing urine—Use with caution. May increase risk for more serious side effects.

• Constipation or
• Hypotension (low blood pressure) or
• Pancreatitis (inflammation of the pancreas), history of or
• Respiratory depression (very slow breathing) or
• Seizures, history of—Use with caution. May make these conditions worse.

• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Mucositis (mouth sores or ulcers)—Use with caution. The effects of the Belbuca™ film may be increased because of more drug being absorbed.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Trouble breathing, slow breathing, or shallow breathing.
• Very bad dizziness or passing out.
• Too much sweat.
• Fast or slow heartbeat.
• A heartbeat that does not feel normal.
• Feeling confused.
• Very hard stools (constipation).
• Feeling very tired or weak.
• Feeling nervous and excitable.
• Fever or chills.
• Sore throat.
• Change in balance.
• Mood changes.
• Very bad belly pain.
• Extra muscle action or slow movement.
• Slurred speech.
• Swelling in the arms or legs.
• Change in eyesight.
• A burning, numbness, or tingling feeling that is not normal.
• Trouble speaking.
• Chest pain or pressure.
• Trouble passing urine.
• Hallucinations (seeing or hearing things that are not there).
• Muscle or joint pain.
• Memory problems or loss.
• Seizures.
• Very bad headache.
• Shakiness.
• Feeling very sleepy.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen if you take Belbuca with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• Taking an opioid drug like this medicine may lead to a rare but very bad adrenal gland problem. Call your doctor right away if you have very bad dizziness or passing out, very bad upset stomach or throwing up, or if you feel less hungry, very tired, or very weak.

The 75 mcg dosage form is a buccal film, white on one side with E0 printed in black and yellow on the other side.

The 150 mcg dosage form is a buccal film, white on one side with E1 printed in black and yellow on the other side.

The 300 mcg dosage form is a buccal film, white on one side with E3 printed in black and yellow on the other side.

The 450 mcg dosage form is a buccal film, white on one side with E4 printed in black and yellow on the other side.

The 600 mcg dosage form is a buccal film, white on one side with E6 printed in black and yellow on the other side.

The 750 mcg dosage form is a buccal film, white on one side with E7 printed in black and yellow on the other side.

The 900 mcg dosage form is a buccal film, white on one side with E9 printed in black and yellow on the other side.

Belbuca is contraindicated in patients with:

• Significant respiratory depression [see Warnings and Precautions (5.2)]
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.5)]
• Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13)]
• Hypersensitivity (e.g., anaphylaxis) to buprenorphine [see Warnings and Precautions (5.12), and Adverse Reactions (6)]

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

• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
• Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions (5.4)]
• Adrenal Insufficiency [see Warnings and Precautions (5.6)]
• QTc Prolongation [see Warnings and Precautions (5.7)]
• Severe Hypotension [see Warnings and Precautions (5.8)]
• Hepatotoxicity [see Warnings and Precautions (5.10)]
• Anaphylactic/Allergic Reactions [see Warnings and Precautions (5.12)]
• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13)]
• Seizures [see Warnings and Precautions (5.14)]

 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 naïve, opioid experienced, and overall patients exposed to Belbuca in clinical trials and compared against placebo are shown in Tables 2, 3 and 4:

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, somnolence, diarrhea, dry mouth, and upper respiratory tract infection.

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

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

Infections and infestations: 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 (12.2)].

The efficacy of Belbuca has been evaluated in three 12-week double-blind, placebo-controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate-to-severe chronic low back pain using pain scores as the primary efficacy variable.  Two of these studies, described below, demonstrated efficacy in patients with low back pain.  One study in low back pain did not show a statistically significant pain reduction for Belbuca compared to placebo. 

12-Week Study in Opioid-Naïve Patients with Chronic Low Back Pain

A total of 749 patients with chronic low back pain entered an open-label, dose-titration period for up to eight weeks.  Potential subjects were excluded from participation for QTcF interval of 450 ms or more, hypokalemia, clinically unstable cardiac disease, a history of Long QT Syndrome or an immediate family member with this condition, or taking Class IA or Class III antiarrhythmic medications. Patients initiated therapy with a single 75 mcg dose of Belbuca on Day 1 and continued taking Belbuca 75 mcg either once daily or every 12 hours for 4-8 days as tolerated. The dose was then increased to 150 mcg every 12 hours, and patients could continue to dose escalate in 150 mcg dose increments every 4-8 days for up to 6 weeks if the adverse effects were tolerable and the analgesic effects were not adequate. Patients who achieved adequate analgesia and tolerable adverse effects on Belbuca for at least 2 weeks were then randomized to continue their titrated dose of Belbuca or matching placebo. Sixty-one percent (61%) of the patients who entered the open-label dose titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Fifteen percent of patients discontinued due to an adverse event and 4% discontinued due to lack of a therapeutic effect. The remaining 20% of patients discontinued due to various non-drug related administrative reasons. 

During the first 2 weeks of double-blind treatment, patients were allowed up to 2 tablets per day of hydrocodone/acetaminophen 5/325 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to 1 to 2 tablets of acetaminophen 500 mg per day. Seventy-six percent  of the patients treated with Belbuca completed the 12-week treatment compared to 73% of the patients treated with placebo. Of the 209 patients randomized to Belbuca, 4% discontinued due to lack of efficacy and 8% due to adverse events. Of the 211 patients randomized to placebo, 11% discontinued due to lack of efficacy and 4% due to adverse events. 

Of the patients who were randomized, the mean pain (SD) scores on a 0 to 10 numeric rating scale (NRS) were 7.1 (1.06) and 7.2 (1.05) prior to open-label titration and 2.8 (1.01) and 2.8 (1.12) at the beginning of the double-blind period for Belbuca and placebo, respectively. The change from double-blind baseline to week 12 in mean pain (SD) NRS score was statistically significant favoring patients treated with Belbuca, compared with patients treated with placebo. 

A higher proportion of Belbuca patients (62%) had at least a 30% reduction in pain score from prior to open-label titration to study endpoint when compared to patients who received placebo buccal film (47%). A higher proportion of Belbuca patients (41%) also had at least a 50% reduction in pain score from prior to open-label titration to study endpoint compared to patients who received placebo (33%). 

The proportion of patients with various degrees of improvement, from prior to open-label titration (Titration-Baseline) to study endpoint, is shown in Figure 1 below.

Figure 1: Percentage Improvement in Pain Intensity from Titration-Baseline to Week 12

12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain

Eight hundred and ten (810) patients on chronic opioid therapy (total daily dose 30-160 mg in oral morphine sulfate equivalents (MSE) for at least 4 weeks) entered an open-label, dose-titration period with Belbuca for up to 8 weeks, following taper of their prior opioids to 30 mg oral MSE daily. Potential subjects were excluded from participation for QTcF interval of 450 ms or more, hypokalemia, clinically unstable cardiac disease, a history of Long QT Syndrome or an immediate family member with this condition, or taking Class IA or Class III antiarrhythmic medications.  Patients were initiated with Belbuca 150 mcg every 12 hours if they were on 30 to 89 mg oral MSE daily and 300 mcg every 12 hours if they were on 90 to160 mg oral MSE daily prior to taper. If a patient tolerated the adverse events and the analgesic effects were not adequate, the dose was increased in increments of 150 mcg every 12 hours after 4 to 8 days for up to 6 weeks.  Patients were permitted to take hydrocodone/acetaminophen 5/325 mg as analgesic rescue as needed up to a maximum of 4 doses per day during the open-label dose titration period. After a dose was reached with adequate analgesia and tolerable adverse effects for a period of 2 weeks, patients were randomized to continue their titrated dose of Belbuca or matching placebo. Sixty-three percent (63%) of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week double-blind treatment phase. Ten percent (10%) of patients discontinued due to an adverse event, 8% discontinued due to lack of a therapeutic effect, and 0.1% discontinued due to opioid withdrawal during the open-label titration period. The remaining 20% of patients discontinued due to various non drug related administrative reasons. 

During the double-blind period, patients were permitted to take up to 2 doses of 5/325 mg or 10/650 mg of hydrocodone/acetaminophen per day for the first 2 weeks to minimize opioid withdrawal symptoms in patients randomized to placebo.  After the first 2 weeks, patients were permitted to take 1 dose of 5/325 mg or 10/650 mg per day. Eighty-three percent of patients treated with Belbuca and 57% of patients treated with placebo buccal film completed the 12-week treatment period. Of the 243 patients randomized to Belbuca, 8% discontinued due to lack of efficacy and 2% due to adverse events. Of the 248 patients randomized to placebo buccal film, 25% discontinued due to lack of efficacy and 5% due to adverse events.

Of the patients who were randomized into the double-blind period, the mean pain (SD) NRS scores were 6.8 (1.28) and 6.6 (1.32) prior to open-label titration and 2.9 (0.985) and 2.8 (1.05) at the beginning of the double-blind period for Belbuca and placebo, respectively. The change from baseline to week 12 in mean pain (SD) NRS score was statistically significant in favor of patients treated with Belbuca compared with patients treated with placebo.

A higher proportion of Belbuca patients (64%) had at least a 30% reduction in pain score from prior to open-label titration to study endpoint when compared to patients who received placebo buccal film (31%).  A higher proportion of Belbuca patients (39%) also had at least a 50% reduction in pain score from prior to open-label titration to study endpoint compared to patients who received placebo (17%). 

The proportion of patients with various degrees of improvement from prior to open-label titration (Titration-Baseline) to study endpoint is shown in Figure 2 below.

Figure 2: Percentage Improvement in Pain Intensity from Titration-Baseline to Week 12