Twelve-month, open-label assessment of long-term safety and abuse potential of hydrocodone extended-release formulated with abuse-deterrence technology in patients with chronic pain

2015 ◽  
Vol 11 (5) ◽  
pp. 425 ◽  
Author(s):  
Martin E. Hale, MD ◽  
Thomas R. Zimmerman, Jr, MD ◽  
Yuju Ma, MS ◽  
Richard Malamut, MD
Keyword(s):  
Chronic Pain ◽  
Extended Release ◽  
Vital Signs ◽  
Study Drug ◽  
Abuse Potential ◽  
Open Label ◽  
Drug Loss ◽  
Analgesic Dose ◽  
Safety Assessments

Objective: To evaluate long-term safety of hydrocodone extended-release (ER) formulated with CIMA® Abuse-Deterrence Technology platform. Design: Phase 3, open-label study.Setting: Sixty-one US study centers.Patients: Patients with chronic pain newly enrolled or rolled over from a 12-week, placebo-controlled hydrocodone ER study; 330 patients enrolled, 329 patients received study drug, and 189 completed the study.Intervention: After titrating to an analgesic dose (15-90 mg every 12 hours), patients received ≤52 weeks of open-label treatment.Main outcome measures: Safety: adverse events (AEs), vital signs, laboratory values, electrocardiograms, and audiometry. Abuse potential: drug loss and diversion, Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), Addiction Behaviors Checklist (ABC), Current Opioid Misuse Measure (COMM) questionnaires, and Patient Global Assessment (PGA) of pain control.Results: Of 329 patients who received ≥1 hydrocodone ER dose, 284 (86 percent) reported ≥1 AE and 27 (8 percent) experienced ≥1 serious AE. Sixty-two (19 percent) patients withdrew because of AEs, and two AEs leading to death were reported. No serious AEs or AEs leading to death were considered treatment related by the investigator. There were no clinically meaningful trends in other safety assessments. SOAPP-R, ABC, and COMM scores demonstrated low risk of aberrant drug-related behavior. Good/excellent PGA responses were reported by 20 percent of patients at baseline and 75 percent at endpoint. The incidence of drug loss (11 percent) and diversion (2 percent) was low.Conclusions: Hydrocodone ER demonstrated acceptable safety when administered for ≤12 months in patients with chronic pain. Low occurrence of aberrant drug-related behavior may support the abuse-deterrence properties of hydrocodone ER.

Efficacy and safety of a hydrocodone extended-release tablet formulated with abuse-deterrence technology in patients with moderate-to-severe chronic low back pain

2015 ◽  
Vol 11 (6) ◽  
pp. 507 ◽  
Author(s):  
Martin E. Hale, MD ◽  
Thomas R. Zimmerman, MD ◽  
Eli Eyal, MSc ◽  
Richard Malamut, MD
Keyword(s):  
Low Back Pain ◽  
Back Pain ◽  
Extended Release ◽  
Study Drug ◽  
Low Back ◽  
Efficacy And Safety ◽  
Open Label ◽  
Double Blind ◽  
Drug Loss ◽  
Efficacy Measure

Objective: To evaluate efficacy and safety of hydrocodone bitartrate extended-release (ER) tablets developed with CIMA® Abuse-Deterrence Technology (ADT) versus placebo in alleviating moderate-to-severe pain in patients with chronic low back pain.Design: Phase 3, randomized, double-blind study consisting of a screening period (7-14 days), open-label titration period (≤6 weeks), and double-blind treatment period (≤12 weeks).Setting: Seventy-eight US centers.Main outcome measures: Changes from baseline at week 12 in weekly average of daily worst pain intensity (WPI; primary efficacy measure), weekly average pain intensity (API; secondary efficacy measure), adverse events (AEs), and study drug loss and diversion.Results: Patients (N = 625) who entered open-label dose titration and identified the analgesic hydrocodone ER dose (30-90 mg every 12 h) providing optimal pain relief with minimal AEs were randomized to hydrocodone ER (n = 191) or placebo (n = 180) for double-blind treatment at the identified dose; 297 patients completed the study. Least squares means [SE] changes from baseline were significantly greater (worsening pain; 11-point scale) with placebo than hydrocodone ER in weekly average of daily WPI (0.74 [0.15] vs 0.11 [0.14]; p < 0.001) and weekly API (0.55 [0.14] vs −0.03 [0.12]; p < 0.001). The most common AEs with hydrocodone ER were constipation (14 percent) and nausea (10 percent). Study drug loss (≤4 percent) and diversion (≤2 percent) rates were low.Conclusions: Hydrocodone ER formulated with ADT was significantly more effective than placebo in alleviating chronic low back pain and demonstrated a safety profile consistent with that of opioids, with a low occurrence of study drug loss and diversion.

Long-Term Safety and Effectiveness of Mixed Amphetamine Salts Extended Release in Adults With ADHD

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S20) ◽  
pp. 16-25 ◽  
Author(s):  
Joseph Biederman ◽  
Thomas J. Spencer ◽  
Timothy E. Wilens ◽  
Richard H. Weisler ◽  
Stephanie C. Read ◽  
...  
Keyword(s):  
Adverse Events ◽  
Adult Adhd ◽  
Extended Release ◽  
Rating Scale ◽  
Vital Signs ◽  
Therapeutic Effects ◽  
Open Label ◽  
Dose Escalation Study ◽  
Double Blind

AbstractObjective: Assess the long-term safety and effectiveness of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype.Methods: A 24-month, open-label extension of a 4-week, multicenter, double-blind, placebo-controlled, parallel-group, forced–dose-escalation study of MAS XR in adults (≥ 18 years of age) with ADHD. The 223 enrolled subjects started treatment at 20 mgl day for 1 week, with subsequent titration up to 60 mgl day for optimal therapeutic effects. At monthly visits, efficacy was assessed based on the ADHD Rating Scale IV (ADHD-RS-N). Safety assessments included spontaneously reported adverse events, laboratory assessments, and monitoring of vital signs.Findings: ADHD symptoms significantly improved for all subjects as measured by change from baseline in mean ADHD-RS-IV total scores (-7.2±13.04 unit points; P<.001); this was sustained for up to 24 months. The most common treatment-related adverse events were dry mouth (43% of subjects reporting at least one occurrence), infection (33%), insomnia (32%), anorexia/decreased appetite (32%), headache (30%), and nervousness (26%). Most adverse events were mild to moderate in intensity.Conclusion: Treatment with MAS XR 20–60 mgl day for adult ADHD was generally well tolerated and was associated with sustained symptomatic improvement for up to 24 months.

Efficacy and Tolerability of Long-Term, Open-Label, Mixed Amphetamine Salts Extended Release in Adolescents With ADHD

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S15) ◽  
pp. 14-21 ◽  
Author(s):  
Thomas J. Spencer ◽  
Joseph Biederman ◽  
Timothy E. Wilens
Keyword(s):  
Adverse Events ◽  
Extended Release ◽  
Rating Scale ◽  
Controlled Trial ◽  
Vital Signs ◽  
Adhd Symptoms ◽  
Open Label ◽  
End Point ◽  
Term Tolerability

AbstractObjectiveAssess long-term tolerability and efficacy of once-daily mixed amphetamine salts extended release (MAS XR) for attention-deficit/hyperactivity disorder (ADHD) in adolescents (13–17 years of age).MethodsEfficacy of MAS XR (10–60 mg/day) in 138 adolescents with ADHD was assessed in a 6-month, openlabel, extension study following participation in a 4-week, randomized, placebo-controlled trial of MAS XR. Efficacy was based on ADHD Rating Scale-IV (ADHD-RS-IV) scores and Clinical Global Impressions-Improvement (CGI-I) ratings at end point. Tolerability was based on reported adverse events, physical and laboratory examintions, vital signs, and electrocardiographic measures.FindingsPatients exhibited sustained improvement in ADHD symptoms in this 6-month, open-label study of MAS XR 10–60 mg/day. End point ADHD-RS-IV total score was significantly decreased from baseline (-7.9; P<.0001); similar decreases were seen for hyperactivity/impulsivity (-4.0; P<.0001) and indttentiveness (-3.8; P<.0001). Based on CGI-I ratings, 60.9% of patients were very much/much improved, 33.3% were unchanged, 5.8% were much worse, and 0% were very much worse. The most common adverse events related to MAS XR were anorexia (24.6%), weight loss (24.6%), headache (14.5%), and nervousness (13.0%).ConclusionLong-term MAS XR therapy is generally well tolerated and exerts sustained control of ADHD symptoms in otherwise healthy adolescents.

scholarly journals A long-term, open-label safety study of single-entity hydrocodone bitartrate extended release for the treatment of moderate to severe chronic pain

2014 ◽  
pp. 669 ◽  
Author(s):  
Srinivas Nalamachu ◽  
Richard L. Rauck ◽  
Martin E. Hale ◽  
Orlando G. Florete, Jr. ◽  
Cynthia Robinson ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Extended Release ◽  
Open Label ◽  
Safety Study ◽  
Single Entity ◽  
Severe Chronic Pain ◽  
Hydrocodone Bitartrate

scholarly journals Long-Term Efficacy and Safety of Deutetrabenazine for Chorea in Huntington’s Disease: Results From the ARC-HD Open-label Study

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 164-165
Author(s):  
Samuel Frank ◽  
Claudia M. Testa ◽  
David Stamler ◽  
Elise Kayson ◽  
David Oakes ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Study Drug ◽  
Motor Dysfunction ◽  
Open Label ◽  
Entire Treatment Period ◽  
End Of Treatment ◽  
Pharmaceutical Industries

AbstractBackgroundChorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.MethodsPatients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.ResultsOf 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119 [48] weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.ConclusionsThe type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Short- and Long-Term Cardiovascular Effects of Mixed Amphetamine Salts Extended-Release in Adolescents With ADHD

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S15) ◽  
pp. 22-30 ◽  
Author(s):  
Timothy E. Wilens ◽  
Thomas J. Spencer ◽  
Joseph Biederman
Keyword(s):  
Extended Release ◽  
Cardiovascular Effects ◽  
Dose Titration ◽  
Open Label ◽  
Double Blind ◽  
Once Daily ◽  
Open Label Extension ◽  
Short And Long Term ◽  
Clinically Significant

AbstractObjectiveAssess cardiovascular effects of once-daily mixed amphetamine salts extended release (MAS XR) in adolescents (13–17 years of age) with attention-deficit/hyperactivity disorder (ADHD).MethodsBlood pressure (BP), pulse, and electrocardiograms were assessed in 327 healthy subjects during a 4-week, randomized, double-blind, placebo-controlled, forced dose-titration study. Placebo (n=69) or once-daily MAS XR(10, 20, 30, or 40 mg) was administered to subjects ≤75 kg (n=233); 50- and 60-mg MAS XR was administered to subjects >75 kg (n=25). One hundred thirty-eight subjects participated in a 6-month, open-label extension study.FindingsChanges in BP and QTcB (Bazett's formula) intervals at 4 weeks with MAS XR were not significantly different from the placebo group. Pulse increased by 5.0 and 8.5 bpm after 3 weeks with MAS XR 20 and 50 mg/day, respectively (P≤.002). After 6 months of open-label MAS XR treatment, mean increases in systolic BP (1.7 mm Hg; P=.0252) and pulse (4.4 bpm; P<.0001) were statistically, but not clinically, significant diastolic BP was not significantly changed (0.6 mm Hg) A decrease in QTcB interval (-4.6±19.9 msec) was statistically (P=.009), but not clinically, significant. There were no serious cardiovascular adverse events.ConclusionCardiovascular effects of short- and long-term MAS XR treatment (≤60 mg/day) were minimal in otherwise healthy adolescents with ADHD.

ABPM Comparison of the Anti-Hypertensive Profiles of Telmisartan and Enalapril in Patients with Mild-to-Moderate Essential Hypertension

2002 ◽  
Vol 30 (6) ◽  
pp. 543-552 ◽  
Author(s):  
J Amerena ◽  
S Pappas ◽  
J-P Ouellet ◽  
L Williams ◽  
D O'Shaughnessy
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Blood Pressure Monitoring ◽  
Study Drug ◽  
Pressure Control ◽  
Moderate Essential Hypertension ◽  
Open Label ◽  
Night Time ◽  
Once Daily

In this multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE) study, the efficacy of 12 weeks' treatment with once-daily telmisartan 40–80 mg and enalapril 10–20 mg was evaluated using ambulatory blood pressure monitoring (ABPM) in 522 patients with mild-to-moderate essential hypertension. Patients were titrated to the higher dose of study drug at week 6 if mean seated diastolic blood pressure (DBP) was ≥ 90 mmHg. The primary endpoint was the change from baseline in ambulatory DBP in the last 6 h of the 24-h dosing interval after 12 weeks' treatment. Telmisartan and enalapril produced similar reductions from baseline in DBP and systolic blood pressure (SBP) over all ABPM periods evaluated (last 6 h, 24-h, daytime and night-time). Telmisartan produced a significantly greater reduction in mean seated trough DBP, measured unblinded with an automated ABPM device in the clinic, amounting to a difference of −2.02 mmHg ( P < 0.01). A significantly greater proportion of patients achieved a seated diastolic response with telmisartan than enalapril (59% versus 50%; P < 0.05), also measured with the same ABPM device. Both treatments were well tolerated. Compared with telmisartan, enalapril was associated with a higher incidence of cough (8.9% versus 0.8%) and hypotension (3.9% versus 1.1%). Therefore, telmisartan may provide better long-term compliance and, consequently, better blood pressure control than enalapril.

scholarly journals Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study

2020 ◽  
Vol 10 ◽  
pp. 204512532092247 ◽  
Author(s):  
Paul Glue ◽  
Natalie J. Medlicott ◽  
Shona Neehoff ◽  
Peter Surman ◽  
Fred Lam ◽  
...  
Keyword(s):  
Extended Release ◽  
Vital Signs ◽  
Oral Formulation ◽  
Depression And Anxiety ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Open Label ◽  
Oral Ketamine ◽  
Tolerability Data ◽  
Resistant Depression

Background: Ketamine’s defining side effects are dissociation and increased blood pressure/heart rate. An oral formulation with delayed absorption could minimize these effects. We recently reported safety and tolerability data for an extended release ketamine tablet in healthy volunteers. Methods: To assess safety, tolerability, efficacy, and pharmacokinetics of an extended release oral ketamine tablet in patients with treatment-resistant depression/anxiety. This was a multiple dose open-label flexible dose uncontrolled study in seven patients with treatment-resistant depression/anxiety, who had all previously demonstrated mood improvement to subcutaneous ketamine. Assessments included ratings of anxiety, depression and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and brain-derived neurotrophic factor (BDNF) concentrations. Results: Improvements in anxiety and depression ratings occurred gradually over 96 h; all patients had >50% improvements in mood ratings. Ketamine was safe and well tolerated, with no changes in vital signs, and a single brief report of dissociation. Ketamine may induce its own metabolism, as the ratio of norketamine to ketamine increased out to 96 h. Serum BDNF concentrations did not change during the study. Conclusion: Ketamine’s safety/tolerability may be improved with an extended release oral formulation. Onset of mood improvement is slightly delayed compared with parenteral dosing. These data support the further development of extended release ketamine tablets for treatment of resistant depression and anxiety disorders.

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