ZUBSOLV®: Proven clinically comparable to Suboxone® sublingual film, but with the added benefit of patient-preferred attributes1

The largest combination buprenorphine/naloxone opioid dependence trial ever conducted in the United States.

Stabilization, Adherence and Retention Trial (OX219-006)1


  • A randomized, noninferiority study to assess early treatment efficacy of ZUBSOLV versus Suboxone film and to explore switching between treatments
  • Opioid dependent adult male or female subjects ≥18 to 65 years of age
  • 758 subjects randomized
  • Stabilization doses were titrated to a maximal daily dose of 17.1/4.2 mg and 24/6 mg for ZUBSOLV and Suboxone, respectively, based upon clinical symptoms
methodology2

Study Design

  • On Day 3, subjects on buprenorphine were switched to Suboxone film
  • On Day 15, all subjects on Suboxone were switched to ZUBSOLV and all subjects on ZUBSOLV were switched to Suboxone

PRIMARY OBJECTIVES:

Retention in treatment at Day 15

 


SECONDARY OBJECTIVES:

Assessment of treatment effects on:

  • Opioid withdrawal symptoms (COWS, SOWS)

  • Opioid cravings (Craving VAS)

  • Illicit drug use (UDS, SRSU)

  • Addiction severity (CGI-S, CGI-I, PGI-I)



Formulation acceptability and preference of Zubsolv compared to Suboxone film

Switching between Suboxone film and ZUBSOLV
Safety and tolerability of ZUBSOLV


COWS (Clinical Opiate Withdrawal Scale)
SOWS (Subjective Opiate Withdrawal Scale)
VAS (Visual Analogue Scale)
UDS (Urine Drug Screen)


SRSU (Self Report of Substance Use)
CGI-S (Clinical Global Impression-Severity)
CGI-I (Clinical Global Impression-Improvement)
PGI-I (Patient’s Global Impression-Improvement)


Patient Demographics

Patients

  • 758 adult patients

  • Aged 18 to 65 years (mean 35.6 years)

  • Meeting DSM-IV-TR® criteria for opioid dependence

  • Mean duration of opioid dependence: 10.6 years

59.6%

Male

40.4%

Female


ZUBSOLV showed comparable retention at Day 15 vs Suboxone film (74.9% vs 74.4%)1


ZUBSOLV showed comparable retention at Day 15 vs Suboxone film

ZUBSOLV
0%
Suboxone film
0%

Note: Percentages were rounded to the nearest whole number.


ZUBSOLV demonstrated comparable clinical efficacy in patients who were changed from Suboxone film


One week after changing to ZUBSOLV from Suboxone film (Day 22), 93.9% of ZUBSOLV patients remained on treatment

ZUBSOLV
0%
Suboxone film
0%

Note: Percentages were rounded to the nearest whole number.


ZUBSOLV showed no increased rate of withdrawal symptoms or opioid cravings compared to Suboxone film


Withdrawal Symptoms Day 15 (COWS)

ZUBSOLV
0 %
Suboxone film
0 %

COWS=Clinical Opiate Withdrawal Scale. COWS is measured on a scale of 0-48 where a lower score is favorable. Note: Numbers are due to rounding.

Opioid Cravings Day 15 (VAS)

ZUBSOLV
0 &
Suboxone film
0 %

VAS=Visual Analogue Scale VAS is measured on a scale of 0-100 where a lower score is favorable. Note: Numbers are due to rounding.



More than 70% of patients preferred ZUBSOLV’S attributes to Suboxone film


Significantly more patients preferred ZUBSOLV to Suboxone film based on overall preference, taste, mouthfeel, and ease of administration


Overall Preference (n=493)
ZUBSOLV
0%
Suboxone film
0%

Note: Percentages were rounded to the nearest whole number.

Taste (n=493)
ZUBSOLV
0%
Suboxone film
0%

Note: Percentages were rounded to the nearest whole number.

Mouthfeel (n=493)
ZUBSOLV
0%
Suboxone film
0%

Note: Percentages were rounded to the nearest whole number.

Ease of Administration (n=491)
ZUBSOLV
0%
Suboxone film
0%

Note: Percentages were rounded to the nearest whole number.

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Adverse events were similar across treatments1

Treatment-related, treatment-emergent adverse events (TEAEs) in ≥2% of patients Day 3 through Day 15 by system organ class (safety population)


System Organ Class

  • Patients with any TEAEs
  • Gastrointestinal disorders
  • Constipation
  • Nervous system disorder
  • Headache

ZUBSOLV

  • 42 (11.8%)
  • 22 (6.2%)
  • 10 (2.8%)
  • 12 (3.4%)
  • 5 (1.4%)

Suboxone film

  • 37 (10.8%)
  • 18 (5.2%)
  • 12 (3.5%)
  • 12 (3.5%)
  • 7 (2.0%)

The percentages of patients with treatment-related TEAEs were similar between the 2 treatments (post Day 3 through Day 15, 11.8% versus 10.8% for ZUBSOLV and Suboxone film, respectively)

  • Gastrointestinal effects were minimal with constipation reported in <5% of patients in the study. Similar improvements were demonstrated in constipation symptoms from baseline to Day 15 in both groups.
  • Nervous system disorders were similar between groups, all were mild to moderate in severity with headache being the most commonly reported event

97% of treatment-related TEAEs were of mild or moderate severity

No deaths occurred during the study

1. Data on file. Orexo US, Inc.

Conclusions

ZUBSOLV patients demonstrated comparable clinical efficacy vs Suboxone film and when changed from Suboxone film, with no increased rate of withdrawal symptoms, opioid cravings, or treatment discontinuation observed

After experiencing both ZUBSOLV and Suboxone film, more than 70% of patients preferred the attributes of ZUBSOLV overall (P <0.0001)

Treatment-related adverse events were similar for ZUBSOLV and Suboxone film

In an open-label, comparative bioavailability study in 60 healthy volunteers:

ZUBSOLV offers a highly efficient delivery system to support your patients on their journey to recovery2


ZUBSOLV delivered comparable blood concentration to other buprenorphine / naloxone tablets, but with less drug2

  • ZUBSOLV has a concentrated formulation, which contains less buprenorphine than other buprenorphine/naloxone-containing sublingual tablets to achieve equivalent systemic exposure

*Study design: Open-label, fasting, randomized, 2-period, crossover, comparative bioavailability study in 60 healthy volunteers. Subjects received either ZUBSOLV sublingual tablet or Suboxone sublingual tablet under naltrexone block according to a 2-sequence randomization schedule. Blood samples were collected at predose and at intervals over 72 hours after dosing each period. Pharmacokinetics, tolerability, safety, and dissolve time were assessed and acceptability and subject preference of drug product were evaluated by specific questioning.
Exposure is the concentration of buprenorphine detectable in the plasma evaluated after dosing.

Reference:

  1. Data on file. Orexo US, Inc.
  2. Fischer A, Jönsson M, Hjelmström P. Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers. Drug Dev Ind Pharm. 2013;1-6. DOI: 10.3109/03639045.2013.846365.

Indication

ZUBSOLV® (buprenorphine and naloxone) sublingual tablet (CIII) is indicated for the treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and psychosocial support.

Treatment should be initiated under the direction of physicians who are certified under the Drug Addiction Treatment Act of 2000, and who have been assigned a unique identification number (“X” number).

IMPORTANT SAFETY INFORMATION

Contraindications

  • ZUBSOLV sublingual tablet should not be used by patients hypersensitive to buprenorphine or naloxone, as serious adverse reactions, including anaphylactic shock, have been reported.

Warnings and Precautions

  • ZUBSOLV sublingual tablet can be abused in a manner similar to other opioids, legal or illicit. 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.

  • ZUBSOLV sublingual tablet can cause serious, life-threatening, respiratory depression and death, particularly when taken by the intravenous (IV) route in combination with benzodiazepines or other central nervous system (CNS) depressants (e.g., sedatives, tranquilizers, or alcohol). Patients should be warned against self-administration or misuse of these combinations.

  • ZUBSOLV sublingual tablet is not recommended in patients with severe hepatic impairment.

  • Not recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy.

  • Dose reduction of CNS depressants, ZUBSOLV sublingual tablet, or both should be considered in situations of concomitant prescriptions, as patients may exhibit increased CNS depression.

  • Store ZUBSOLV safely out of the sight and reach of children. Buprenorphine can cause severe, possibly fatal respiratory depression in children.

  • Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit.

  • Intravenous misuse or taking ZUBSOLV sublingual tablet before the effects of full-agonist opioids (e.g., heroin, hydrocodone, methadone, morphine, oxycodone) have subsided is likely to cause opioid withdrawal syndrome.

  • Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

  • ZUBSOLV sublingual tablet is not appropriate as an analgesic. There have been reported deaths of opioid-naïve individuals who received a 2-mg sublingual dose of buprenorphine.

Use in Specific Populations

  • Pregnancy: Based on animal data, buprenorphine may cause fetal harm. Use of ZUBSOLV sublingual tablet in pregnant women or during breastfeeding should only be considered if the potential benefit justifies the potential risk.

  • Nursing mothers: Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

  • Not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment.

Adverse Reactions

  • Adverse events commonly observed with the sublingual administration of buprenorphine/naloxone sublingual tablets during clinical trials and post-marketing experience are headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, pain, and 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.

  • Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.

This is not a complete list of potential adverse events associated with buprenorphine/naloxone sublingual tablets. Please see full Prescribing Information for a complete list.

To report an adverse event associated with taking ZUBSOLV sublingual tablet, please call 1-888-ZUBSOLV (1-888-982-7658). You are encouraged to report adverse events of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see accompanying full Prescribing Information and Medication Guide.