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FDA Rejects ADHD Drug NDA Citing Want for Extra Information

Posted in News on 1st September 2018
The treatment was studied in approximately 2500 children and adults with ADHD.

The treatment was studied in approximately 2500 children and adults with ADHD.

Sunovion announced that the Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for dasotraline, an investigational treatment for attention-deficit hyperactivity disorder (ADHD). 

Dasotraline, a novel dual-acting dopamine and norepinephrine reuptake inhibitor (DNRI), was studied in approximately 2500 children and adults with ADHD. The drug has an extended half-life with 47-77 hours in adults and 58-84 hours in children; this allows for stable plasma concentrations and a sustained clinical effect over 24 hours. 

The NDA for dasotraline, submitted in August 2017, included data from a clinical program that included 4 placebo-controlled safety and efficacy studies, as well as two long-term studies assessing the safety of dasotraline in patients with ADHD for up to one year. The FDA stated that the dasotraline NDA cannot be approved in its current form and is requiring additional data to further assess the efficacy and tolerability of the drug. Sunovion EVP, CEO, Antony Loebel, MD, said, “We plan to discuss next steps for the dasotraline ADHD program with the FDA as soon as possible.”

Dasotraline is also being evaluated as a treatment of moderate to severe binge eating disorder (BED) in adults. Findings from 2 pivotal studies will be included in the application submission to the FDA in fiscal year 2018.

Which Opioids Are Extra More likely to Induce QT Interval Prolongation?

Posted in News on 8th August 2018

August 07, 2018

Concomitant use of methadone-interacting drugs was also found to increase the risk of QT prolongation and TdP

Concomitant use of methadone-interacting medication was additionally discovered to extend the danger of QT prolongation and TdP

Amongst opioids, methadone seems to hold the very best threat for inducing QT interval prolongation and arrhythmia even at low doses, based on a examine revealed within the journal Medical Rules and Practices.

To evaluate the influence of opioid use on exercise of the center, researchers searched papers revealed as much as 2017 utilizing 20 opioid names together with key phrases akin to ‘QTc’, ‘QT interval’, ‘QT prolongation’, ‘ventricular arrhythmias’, ‘atrial arrhythmias’ ‘hERG’, ‘torsades de pointes (TdP)’ and ‘different associated phrases’.

A 2016 examine (Romero et al.) discovered that methadone was the main reason for TdP amongst 2735 sufferers with extended QT interval who have been taking prescribed drugs. Concomitant use of methadone-interacting medication was additionally discovered to extend the danger of QT prolongation and TdP.  One other examine (Butler et al. 2011) of 14,500 sufferers on methadone upkeep remedy (MMT) discovered that the prime cause for cardiac arrhythmia-related dying was taking different interacting prescribed drugs.

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Research evaluating MMT to buprenorphine upkeep remedy (BMT) over 5-years discovered buprenorphine to be a safer drug for opioid upkeep remedy because it had no important impact on QT prolongation. Increased doses of methadone, Pearson (2005) and Value (2014) concluded, have been ‘seemingly’ to contribute to the magnitude of QT prolongation. Nonetheless, different research (Chowdhury et al. 2015) couldn’t discover a correlation between dose and better prevalence of QT prolongation. Ehret et al. (2006) discovered that TdP occurred in a affected person on a methadone dose as little as 40mg/day.

Oxycodone doses of ≥100mg have been associated to longer QT intervals, main the authors to deem it an ‘intermediate’ threat for arrhythmia, nevertheless they acknowledged that extra analysis was wanted to verify these findings. Restricted research of tramadol point out that it might considerably improve the QT interval however additional analysis can also be wanted to verify this. Morphine was discovered to be ‘low-risk’ at routine doses and research of fentanyl confirmed contradictory outcomes.

The authors concluded that “To scale back arrhythmogenic threat, excessive doses of opioids should be used cautiously with periodic monitoring of electrocardiogram in high-risk customers akin to sufferers below opioid upkeep remedy.”

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OnabotulinumtoxinA Safer, Extra Efficient for Headache Prevention Than Topiramate

Posted in News on 2nd July 2018

June 29, 2018

This text initially appeared on Neurology Advisor.

Forty percent of patients in the onabotulinumtoxinA group saw a reduction of ≤50% in headache days by 32 weeks.

Forty % of sufferers within the onabotulinumtoxinA group noticed a discount of ≤50% in headache days by 32 weeks.

SAN FRANCISCO — OnabotulinumtoxinA was discovered to be extra tolerable than topiramate for stopping headache, in keeping with analysis introduced on the American Headache Society’s 60th Annual Scientific Assembly, held June 28–July 1, 2018, in San Francisco, California. This randomized, open-label research examined participant reported outcomes, security, and tolerability of onabotulinumtoxinA and topiramate in adults with persistent migraines.

Topics within the onabotulinumtoxinA arm (n=140) acquired a set dose each 12 weeks for 36 weeks, whereas topics within the topiramate arm (n=142) acquired 50 to 100 mg per day as much as 36 weeks. The efficacy finish level, a discount of at the very least 50% in headache days by 32 weeks, was better within the onabotulinumtoxinA arm than the topiramate arm (40% vs 12%).

Security and tolerability have been assessed by opposed occasion stories, a cognitive verbal fluency take a look at, and a depressive symptom questionnaire at baseline, 12, 24, and 36 weeks. Antagonistic occasions have been greater within the topiramate arm (76.eight%) vs onabotulinumtoxinA arm (45.5%), and drop out charges have been greater within the topiramate arm (80.three%) vs the onabotulinumtoxinA arm (14.three%). Nervous system problems have been the most typical purpose for discontinuation within the topiramate arm and cognitive adjustments have been famous on the verbal fluency take a look at as early as 12 weeks. No new security considerations have been famous within the onabotulinumtoxinA arm, and contributors handled with onabotulinumtoxinA even confirmed slight enhancements in cognitive perform and depressive signs.

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The researchers concluded that, “[onabotulinumtoxinA] had a superior tolerability profile versus topiramate based mostly on treatment-related [adverse events] and general discontinuations.”


Blumenfeld A, Patel AT, Zhao X, Adams AM, Rothrock JF. A multicenter, potential, randomized, open-label research to check onabotulinumtoxinA and topiramate for headache prevention in adults with persistent migraine: Affected person reported outcomes from the FORWARD Examine. Introduced at: 2018 American Headache Society Annual Scientific Assembly. June 28-July 1, 2018; San Francisco, CA. Summary 448961.

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Larger doses of rifampin kill extra TB micro organism in sputum with out rising hostile results

Posted in News on 30th June 2018

Larger every day doses of rifampin, a cornerstone of tuberculosis remedy, killed extra TB micro organism in sputum cultures, and the upper doses did so with out rising the hostile results of remedy, in response to a randomized managed trial revealed on-line within the American Thoracic Society’s American Journal of Respiratory and Essential Care Drugs.

In “Efficacy and Security of Excessive-Dose Rifampin in Pulmonary Tuberculosis: A Randomized Managed Trial,” Gustavo E. Velásquez, MD, MPH, affiliate doctor within the Division of Infectious Illnesses at Brigham and Girls’s Hospital in Boston, and co-authors report on a section 2 trial performed in Lima, Peru, with 180 adults with new, drug-susceptible TB.

Earlier research taking a look at whether or not intermittent supply of upper doses of rifampin had been efficient in killing the TB bacterium discovered intermittent greater doses had been extra poisonous than decrease doses.The authors of the present trial stated that the findings had been notably encouraging as a result of they counsel that at a excessive sufficient dose of every day rifampin, a remedy interval of lower than the usual six months could also be doable.”

Six months of remedy with 4 drugs-;usually delivered with help and supervision-;represents a considerable burden on the well being care system, in addition to on the affected person,” Dr. Velásquez stated. “Sufferers who can not full the complete routine might not be cured, which allows ongoing transmission and the event of drug-resistant TB.”

The authors wrote that optimization of rifampin dosing is a precedence as a result of it has probably the most potent sterilizing impact of the 4 first-line brokers, is accessible all through the world, and prices solely pennies per capsule.Trial members had been randomized equally to obtain an ordinary dose of 10 mg/kg/day of rifampin or greater doses of 15 and 20 mg/kg/day, together with customary doses of the opposite first-line anti-TB medicine (isoniazid, pyrazinamide, ethambutol), throughout the first eight weeks of intensive remedy. After that, members in all three trial arms acquired customary doses of rifampin and isoniazid throughout 4 months of continuation remedy.

The trial discovered that every 5 mg/kg/day enhance in rifampin elevated the elimination fee of TB micro organism from sputum. The trial additionally checked out rifampin concentrations in plasma and located that elimination charges of TB micro organism had been considerably associated to greater rifampin concentrations.All findings had been true even after adjusting for age, intercourse and extent of illness.

Importantly, the elevated efficacy of upper doses didn’t seem to lead to extra grade two or greater rifampin-related hostile occasions. Two generally reported hostile occasions of rifampin are liver toxicity and flu-like syndrome. Flu-like syndrome was not noticed on this trial.The trial didn’t discover that charges of tradition conversion, a milestone in TB remedy indicating that micro organism are not detectable in tradition, differed among the many three trial arms after the eight-week intensive remedy section. The authors stated the trial was not powered to make that willpower.

“The distinction was too modest on the examined doses for profitable remedy shortening,” Dr. Velásquez stated. “Nevertheless, these outcomes, trial taken along with different not too long ago revealed experiences, help efforts to extend doses of rifampin to 35 mg/kg/day and presumably greater till the utmost tolerable dose is recognized.”​


Canakinumab reduces gout charge by greater than half in atherosclerosis sufferers, examine exhibits

Posted in News on 27th June 2018

The outcomes of a examine introduced in the present day on the Annual European Congress of Rheumatology (EULAR 2018) show that canakinumab considerably lowered the speed of gout by greater than half in comparison with placebo, no matter baseline serum urate stage.

“These are vital outcomes as they add to the proof base demonstrating a possible preventative position for canakinumab in sufferers with gout,” stated Professor Robert Landewé, Chairperson of the Scientific Programme Committee, EULAR. “They may even contribute to our understanding of the interplay between gout, uric acid and heart problems.”

Gout is a quite common situation. It’s attributable to deposits of crystals of a substance referred to as uric acid (often known as urate) within the joints, which results in irritation. Durations of time when gout signs happen are referred to as flares. Flares may be unpredictable and debilitating, creating over just a few hours and inflicting extreme ache within the joints.

Canakinumab is a monoclonal antibody that blocks an inflammatory pathway mediated by interleukin-1β. It’s licensed for the remedy of a number of uncommon auto-inflammatory issues though it may also be used to deal with flares in sure sufferers with gout who’ve contraindications to straightforward therapies. There have been some studies so far of efficacy in stopping flares, nevertheless canakinumab is at present not accepted for this indication.

“Our outcomes show a placing impact of canakinumab on decreasing the danger of gout assaults in atherosclerosis sufferers,” stated Daniel Solomon, Professor of Medication, Harvard Medical Faculty and Brigham and Ladies’s Hospital. “Furthermore, these information illustrate serum urate as a danger marker for each gout and cardiovascular occasions, although canakinumab has no impact on serum urate ranges on account of its mechanism of motion.”

This report is a secondary evaluation of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Examine) trial which studied the impression of canakinumab within the secondary prevention of cardiovascular (CV) occasions. For this evaluation, all individuals have been divided into three teams based mostly on their serum urate stage at baseline; low (<6.9mg/dl), medium (6.9-Eight.9mg/dl), and excessive (?9.Zero mg/dL). Canakinumab (pooled doses) considerably lowered the speed of flares of gout by greater than half in comparison with placebo, throughout all baseline serum urate teams. The hazard ratio (95% confidence interval) was Zero.40 (Zero.22-Zero.73), Zero.48 (Zero.31-Zero.74), and Zero.45 (Zero.28-Zero.72) for the low, medium and excessive baseline serum urate teams respectively. The serum urate ranges weren’t affected by canakinumab over time, though it did cut back excessive sensitivity C-reactive protein (hsCRP).

By finding out the charges of flares of gout and main CV occasions between the baseline serum urate teams, investigators demonstrated a correlation confirming it as a danger marker for each these circumstances. Charges per 100-person years for the low, medium, and excessive baseline serum urate teams have been Zero.28, 1.36, and 5.94 respectively for gout-flares, and four.1, 5.three, 5.6 respectively for main hostile CV occasions.

The examine included 10,Zero61 sufferers with secure atherosclerosis (prior coronary heart assault) and a hsCRP?2mg/L which signifies an elevated danger of CV illness. Sufferers have been randomly assigned to obtain placebo or considered one of three doses of canakinumab (50mg, 150mg, or 300mg) as soon as each three months. The teams have been nicely balanced with respect to their baseline traits with a median follow-up time of three.7 years. Median age was 61 years, 74% have been male, median BMI was 29.8kg/m2, median serum urate stage at baseline was 6.1 mg/dl.

Serum urate and hsCRP have been examined at baseline and each three months for the primary 12 months after which yearly. A doctor identified historical past of gout was ascertained at baseline and subsequent assaults have been assessed throughout follow-up as a part of the systematic hostile occasion reporting. The charges of gout assaults and main hostile CV occasions (coronary heart assault, stroke, re-vascularisation, and CV dying) have been in contrast throughout completely different baseline serum urate ranges and by randomized remedy project.

Within the outcomes from the unique trial, neutropenia was extra frequent amongst sufferers who have been assigned to obtain canakinumab than amongst these within the placebo group, and considerably extra deaths have been attributed to an infection or sepsis within the pooled canakinumab teams than within the placebo group (incidence charge Zero.31 vs. Zero.18 occasions per 100 person-years; P=Zero.02). Thrombocytopenia was extra frequent amongst sufferers who have been assigned to obtain canakinumab than amongst these within the placebo group, however no vital distinction within the incidence of hemorrhage was noticed.