Zubsolv

Clinical Trials 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.

ZUBSOLV for use as initial treatment was evaluated in two clinical trials that had identical, blinded, two-day induction phases, comparing ZUBSOLV to generic buprenorphine. On the first day, subjects received an initial dose of ZUBSOLV 1.4 mg/0.36 mg or generic buprenorphine 2 mg, followed by ZUBSOLV 4.2 mg/1.08 mg or generic buprenorphine 6 mg 1.5 hours later. In total, safety data were available for 538 opioid-dependent subjects exposed to ZUBSOLV (buprenorphine/naloxone) sublingual tablets when used for initial treatment.

Table 1. Adverse Reactions in ≥ 5% of Patients During the Induction Phase by System Organ Class and Preferred Term (Safety Population)

The safety of buprenorphine/naloxone for longer-term use (up to 16 weeks of treatment) was evaluated in previous studies in 497 opioid-dependent subjects. The prospective evaluation of buprenorphine/naloxone was supported by clinical trials using buprenorphine tablets without naloxone and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction. See Table 2.

Table 2. Adverse Events > 5% by Body System and Treatment Group in a 4-week Study

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 reported by at least 5% of subjects in any dose group in the dose-controlled study.

Table 3. Adverse Events (≥ 5%) by Body System and Treatment Group in a 16-week Study

Post-Marketing Experience

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

The most frequently reported post-marketing adverse event not observed in clinical trials was peripheral edema.

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 [see CLINICAL PHARMACOLOGY].

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

Naloxone blocks the effects of opioid medication, including pain relief or feelings of well-being that can lead to opioid abuse.

Buprenorphine and naloxone is a combination medicine used to treat narcotic (opiate) addiction. Buprenorphine and naloxone is not for use as a pain medication.

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

This medicine can slow or stop your breathing. Never use this medicine in larger amounts, or for longer than prescribed. Buprenorphine and naloxone may also 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 medicine 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.

You should not use this medicine if you are allergic to buprenorphine or naloxone (Narcan).

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

• any type of breathing problem or lung disease;
• enlarged prostate, urination problems;
• liver or kidney disease;
• curvature of the spine that affects breathing;
• problems with your gallbladder, adrenal gland, or thyroid;
• a history of drug abuse, alcohol addiction, or mental illness; or
• a history of head injury, brain tumor, or seizures.

It is not known whether this medicine will harm an unborn baby. If you use buprenorphine and naloxone 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.

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

Zubsolv is a prescription medication used to treat adults who are addicted to opioid drugs (either prescription or illegal) as part of a complete treatment program that also includes counseling and behavioral therapy.

Zubsolv comes in tablets to be dissolved under the tongue, once daily. Do not cut, chew, or swallow Zubsolv tablets. 

Common side effects include headache, drug withdrawal syndrome, nausea, and decrease in sleep.

Zubsolv can also cause blurred vision, drowsiness, and dizziness. Do not drive or operate heavy machinery until you know how Zubsolv affects you.

• Orexo US, Inc.

Serious side effects have been reported with Zubsolv. See the “Zubsolv Precautions” section.

Common side effects of Zubsolv include the following:

• headache
• nausea
• vomiting
• excessive sweating
• constipation
• opioid withdrawal symptoms
• insomnia
• pain
• mouth numbness
• tongue pain
• lightheadedness
• irregular heartbeat
• fainting

This is not a complete list of Zubsolv side effects. Ask your doctor or pharmacist for more information.

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

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

Serious side effects have been reported with Zubsolv including the following:

• Respiratory problems. You have a higher risk of death and coma from respiratory problems if you take Zubsolv with other medicines that cause respiratory problems, such as benzodiazepines including diazepam (Valium), alprazolam (Xanax), clonazepam (Klonopin), lorazepam (Ativan), and zolpidem (Ambien).
• Sleepiness, dizziness, and problems with coordination
• Decreased blood pressure. You may feel dizzy if you get up too fast from sitting or lying down.
• Dependency or abuse
• Liver problems. Tell your doctor right away if you have any of the following signs or symptoms of liver problems:
  • Yellowing of the skin or eyes
  • Dark urine
  • Light colored stools
  • Decreased appetite
  • Stomach pain
• Allergic reaction. Tell your doctor right away if you have any of the following signs or symptoms of an allergic reaction:
  • Rash
  • Hives
  • Swelling of the face
  • Wheezing
  • Decreased blood pressure
  • Loss of consciousness
• Opioid withdrawal. Symptoms of opioid withdrawal may include:
  • Shaking
  • Excessive sweating
  • Feeling hot or cold more than normal
  • Runny nose
  • Watery eyes
  • Goose bumps
  • Diarrhea
  • Vomiting
  • Muscle aches

Zubsolv can also cause blurred vision, drowsiness, and dizziness. Do not drive or operate heavy machinery until you know how Zubsolv affects you.

Do not take Zubsolv if you:

• are allergic to Zubsolv or to any of the ingredients in the combination product

If you take too much Zubsolv, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Zubsolv is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Cough or hoarseness
• feeling faint, dizzy, or lightheaded
• feeling of warmth or heat
• fever or chills
• flushing or redness of the skin, especially on the face and neck
• headache
• lower back or side pain
• painful or difficult urination
• sweating

• Bloating or swelling of the face, arms, hands, lower legs, or feet
• rapid weight gain
• tingling of the hands or feet
• unusual weight gain or loss

Get emergency help immediately if any of the following symptoms of overdose occur:

• Blurred vision
• confusion
• difficult or troubled breathing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drowsiness
• irregular, fast, slow, or shallow breathing
• pale or blue lips, fingernails, or skin
• pinpoint pupils
• relaxed and calm feeling
• sleepiness
• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain
• difficulty having a bowel movement (stool)
• lack or loss of strength
• nausea
• pain
• trouble sleeping
• vomiting

• Back pain
• diarrhea
• runny nose
• sneezing
• stuffy nose

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

Zubsolv sublingual tablet is indicated for treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and psychosocial support.

Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this product in the treatment of opioid dependence is limited to physicians who meet certain qualifying requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent to prescribe this product for the treatment of opioid dependence and have been assigned a unique identification number that must be included on every prescription.

The induction of buprenorphine therapy with Zubsolv was evaluated in two blinded randomized, non-inferiority studies. The identical blinded induction phase component of the studies was designed to assess the tolerability of Zubsolv versus generic buprenorphine tablets when used as initial treatment, as measured by retention in treatment. The studies included opioid dependent (DSM-IV criteria) male and female patients 18 to 65 years of age. Induction doses for generic buprenorphine tablets were 8 mg for day 1 and 8 mg or 16 mg for day 2. The induction doses for Zubsolv were 5.7 mg/1.4 mg for day 1 and 5.7 mg/1.4 mg or 11.4 mg/2.8 mg for day 2. In the first study, 758 patients were randomized. In the second study, 310 patients were randomized. 

Both protocols stipulated that first Day 1 dose would be given under supervision, with an initial dose of buprenorphine 2 mg or Zubsolv 1.4 mg. Subsequently, investigators were provided an option to give buprenorphine 6 mg or Zubsolv 4.2 mg as a single dose 1.5 hours after the second dose, or to divide the second dose of study medication into 3 separate dosing occasions of Zubsolv 1.4 mg/0.36 mg or generic buprenorphine 2 mg each, 1 to 2 hours between doses, if there was precipitated withdrawal after the first dose, as assessed by the investigator. The option to divide the second dose was used at the discretion of the investigators only rarely in Study 2 (5%), compared to more frequent use in Study 1 (22%).

Results for Day 3 retention rate from each study are presented in Table 6. The lower rate of retention on Day 3 observed for Zubsolv in comparison to generic buprenorphine in Study 2 may be attributable to the infrequent use of divided dosing.