Warning : This Drug May Kill You

Health experts discuss opioids and the dangerous role they play in treating pain

Told from the perspectives of four families devastated by opioid addiction, Warning: This Drug May Kill You offers a harrowing, unflinching look at the deadly epidemic currently facing the United States.

FDA’s new drug approvals : is there evidence that the public is happy to sacrifice safety for speed ?

Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study

Most drugs today qualify for one of the FDA’s expedited pathways. But what is the evidence that the public is on board with the notion of sacrificing safety for speed?

What is already known on this topic
  • Recent legislation in America opens the possibility for the expansion and increased use of FDA expedited drug development and review pathways designed to respond to public health priorities
  • Evidence on whether drugs approved through expedited regulatory pathways carry higher levels of safety risks that are unknown at the time of approval is conflicting
  • Some studies suggest that the review process does not impact the quality of the safety assessment, whereas others show a difference
What this study adds
  • In this analysis concerning more than 15 years of comprehensive data, expedited pathway drugs had a 38% higher rate of safety related label changes than drugs approved through non-expedited pathways
  • As policymakers continue to expand expedited regulatory pathways, physicians and patients should be aware of the potential safety trade-offs involved in these pathways

2017 Study Abstract

Objective
To determine if drugs approved through the Food and Drug Administration’s expedited development and review pathways have different rates of safety related label changes after approval compared with drugs approved through standard non-expedited pathways.

Design
Retrospective cohort study.

Setting
FDA public records, January 1997 to April 2016.

Participants
382 FDA approved drugs.

Main outcome measures
The number of times a particular safety section of a label (boxed warning, contraindication, warning, precaution, or adverse reaction) was changed during a drug’s time on the market. The relative rate of safety related label changes per year for expedited pathway and non-expedited pathway drugs was compared by forming matched pairs of drugs in the same therapeutic class that were approved within three years of each other.

Results
Among the 382 eligible new drugs, 135 (35%) were associated with an expedited development or review pathway, and matches were available for 96 (71%). The matched pairs were associated with a total of 1710 safety related label changes during the study period. Expedited pathway drugs were characterized by a rate of 0.94 safety related label changes for each drug per year, compared with 0.68 safety related label changes per year for non-expedited pathway drugs (rate ratio 1.38, 95% confidence interval 1.25 to 1.52). Compared with non-expedited pathway drugs, expedited pathway drugs had a 48% higher rate of changes to boxed warnings and contraindications, the two most clinically important categories of safety warnings (1.48, 95% confidence interval 1.07 to 2.06). A qualitative review of changes to the boxed warning sections revealed that less than 5% (3/67) were changed to describe reduced risks for patients.

Conclusions
Expedited development and regulatory review pathways can accelerate the availability of new drugs, but drugs approved through these pathways are associated with increased safety related label changes after approval, particularly for the types of changes representing the highest risk warnings. To inform appropriate policy interventions, additional research should explore the causal factors contributing to these different rates.

More Information

  • Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study, BMJ 2017;358:j3837, 07 September 2017.
  • Speed vs safety in the FDA’s new drug approvals—speed wins, again, blogs.bmj, September 12, 2017.
  • Featured image credit stickergiant.

EDCs : evidence that co-exposures should be considered when evaluating the risk of a single chemical

Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants

2017 Study Abstract

BACKGROUND
Numerous chemicals are capable of disrupting androgen production, but the possibility that they might act together to produce effects greater than those of the most effective component in the mixture has not been studied directly in human tissues. Suppression of androgen synthesis in fetal life has been associated with testis maldescent, malformations of the genitalia at birth, and poor semen quality later in life.

OBJECTIVES
Our aim was to investigate whether chemicals can act together to disrupt androgen production in human fetal testis explants and to evaluate the importance of mixture effects when characterizing the hazard of individual chemicals.

METHODS
We used an organotypic culture system of human fetal testes explants called FEtal Gonad Assay (FEGA) with tissue obtained at 10 and 12 gestational wk (GW 10–12), to screen 27 chemicals individually for their possible anti-androgenic effect. Based on the results of the screen, we selected 11 compounds and tested them as mixtures.

RESULTS
We evaluated mixtures composed of four and eight antiandrogens that contained the pharmaceuticals ketoconazole and theophylline and several previously untested chemicals, such as the pesticides imazalil and propiconazole. Mixtures of antiandrogens can suppress testosterone synthesis in human fetal testicular explants to an extent greater than that seen with individual chemicals. This revealed itself as a shift towards lower doses in the dose–response curves of individual antiandrogens that became more pronounced as the number of components increased from four to eight.

CONCLUSIONS
Our results with the FEGA provide the foundations of a predictive human mixture risk assessment approach for anti-androgenic exposures in fetal life.

Discussion

Concerns that the traditional focus of chemical risk assessment on single chemical exposures might underestimate the risks associated with adverse effects of multiple chemicals have been expressed earlier (Kortenkamp 2014), but the impact on risk estimates has been proven difficult to define. This is partly due to incomplete information about the complexity of combined human exposures and to a lack of clarity about the approaches and methods that should be used for mixture risk assessment. Our study provides important advances in improving the scientific basis for human mixture risk assessment. To our knowledge, we demonstrate for the first time that the mixture assessment concept of dose addition is applicable to human tissues. This not only enabled us to avoid certain uncertainties associated with animal-to-human extrapolations, but also enabled us to use a predictive approach. Rather than studying every conceivable combination of chemicals within a mixture, the joint effects of anti-androgenic chemicals in the FEGA can now be approximated on the basis of the effects of each single component by using dose addition as the default assumption.

To utilize the FEGA in multi-component mixture studies required making a leap from qualitative studies to quantitative dose–response analyses. Due to the inhomogeneity of the material and the variations inevitably introduced through the age differences of the fetal testes, the assay outcome (fetal testosterone production) shows high variability, which we had to deal with by rigorously controlling experimental conditions. We achieved good reproducibility, which was essential for realizing our goal of analyzing whether the combined effects of multiple chemicals can be predicted accurately on the basis of the effects of individual mixture components and of assessing the impact of co-exposures on the dose–response curves of single chemicals.

A difficulty in using the FEGA as a screening method for the identification of chemicals with endocrine disruptive properties is the limited availability of human fetal tissue. An additional challenge is in the requirement of collecting tissues of comparable age.

Our study provides direct evidence that co-exposures should be considered when evaluating the risk of a single chemical. We show that effects of a single chemical are underestimated when co-exposure to related chemicals are not considered, and that this underestimation is driven by the number, type, and potency of co-occurring chemicals. In this study, overlooking co-exposures to only seven chemicals led to an underestimation of the potency of BPA by a factor of 10. A corollary of the principles of dose addition is that co-exposure to a larger number of chemicals will drive up the extent of such underestimations if these chemicals are present at levels equipotent with the components we used in our experiments. Alternatively, replacement of some components with larger numbers of other chemicals, but at lower levels, may lead to similar underestimations. More studies using the FEGA are needed to establish these assumptions.

Based on our findings, we suggest that the impact of mixture effects on male sexual differentiation during the first trimester of pregnancy may be considerable. However, although in this study the selection of chemicals was empirically based on the results obtained in our dose–response study, analysis of individual chemicals, assessment of the extent of adverse effects in human fetuses will require more knowledge about the spectrum of chemicals capable of suppressing testosterone synthesis. Future FEGA studies will help close this knowledge gap, especially if based on companion studies that identify all of the exogenous chemicals found in maternal and fetal tissues.

Full Study
  • Featured image : predicted and observed testosterone secretion in human fetal testis by four chemical mixtures. Experimental data are shown as mean ± SEM (blue) of at least four independent experiments. Testosterone production is represented as relative to the first day of culture (D0) production and the control level, see text for more details. The mixture effects were predicted according to dose addition (DA) (thick red curve), with dashed curves the respective 95% confidence intervals (CIs) (dotted orange lines) credit ehp.
  • Endocrine Disruption in Human Fetal Testis Explants by Individual and Combined Exposures to Selected Pharmaceuticals, Pesticides, and Environmental Pollutants, Environmental Health Perspectives, DOI:10.1289/EHP1014, AUGUST 2017 | VOLUME 125 | ISSUE 8. Full PDF.
Endocrine Disruptors

Reporting side effects of medicines

EU Medicines Agency‏ survey on safety of medications and reporting of adverse drug reactions

This EU Medicines Agency survey, will take approximately 5 to 10 minutes of your time to complete. It will help understand the awareness of patients/consumers and healthcare professionals regarding the need and the way they can report adverse drug reactions (side effects). The results will be analysed by the European Medicines Agency and a report containing summary information will be provided to the European Commission (DG SANTE) and will be further disseminated publicly.

EMA launches survey to assess whether patients and doctors are aware of the arrangements for reporting of side effects – European Medicines Agency, the European Union agency responsible for the evaluation and supervision of medicinesEMA_News/status/905720311445893120, 7 sept. 2017.

Antidepressant use during pregnancy and psychiatric disorders in offspring

Danish nationwide register based cohort study, 2017

What is already known on this topic

  • Several studies have linked selective serotonin reuptake inhibitor use during pregnancy to autism spectrum disorder in offspring, although results have been conflicting
  • The potential explanation for this association is that selective serotonin reuptake inhibitors cross the placental barrier and affect the development of the fetal brain
  • If this holds true, in utero exposure to selective serotonin reuptake inhibitor and other classes of antidepressants may increase risk for various psychiatric disorders besides autism spectrum disorder

What this study adds

  • Antidepressant use during pregnancy was associated with increased risk for various diagnostic groups of psychiatric disorders in offspring
  • The observed associations may be attributable to the severity of underlying maternal psychiatric disorders in combination with in utero antidepressant exposure

Study Abstract

Objective
To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders.

Design
Population based cohort study.

Setting
Danish national registers.

Participants
905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk.

Exposures for observational studies
Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy).

Main outcome measure
First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models.

Results
Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group.

Conclusions
In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.

  • Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study, BMJ 2017;358:j3668, 06 September 2017.
  • Characteristics of study population according to maternal antidepressant use before and during pregnancy. Values are numbers (percentages) unless stated otherwise, featured image credit bmj.

We should recognise the impact Primodos has had on women who took it, said Theresa May

MP Mims Davies asked PM about Primodos scandal in PMQs

Mims Davies, MP for the Eastleigh Constituency, questioned the Prime Minister about Primodos : “Should there be a public enquiry?

Sky News’ hour-long documentary Primodos: The Secret Drug Scandal – presented by senior political correspondent Jason Farrell, who investigating it for six years – revealed how documents were destroyed and information withheld about a drug that may have deformed and killed babies in the womb.

More Information

Opioids Kill More Than Pain

Know The Risks, 2017

What starts as a prescription all too often ends in an addiction. Learn the risk factors associated with opioid prescriptions and share your knowledge with others.

  • The “Know the Risks” campaign was created established by the Cuyahoga County Opioid Marketing Task Force to educate about the dangers of opioid prescriptions before a script is ever filled – with the ultimate goal of reducing the number of opioid-related deaths.
  • Watch more Meds: prescription drugs side effects videos on our YouTube channel.

Selective Uptake and Bioaccumulation of Antidepressants in Fish

How antidepressants are ending up in Great Lakes fish

Antidepressant drugs, making their way through an increasing number of people’s bodies, getting excreted in small amounts into their toilets, and moving through the wastewater treatment process to lakes and rivers, are being found in multiple Great Lakes fish species’ brains.

2017 Study Abstract

The continuous release of pharmaceuticals and personal care products (PPCPs) into freshwater systems impacts the health of aquatic organisms.

This study evaluates the concentrations and bioaccumulation of PPCPs and the selective uptake of antidepressants in fish from the Niagara River, which connects two of the North American Great lakes (Erie and Ontario).

The Niagara River receives PPCPs from different wastewater treatment plants (WWTPs) situated along the river and Lake Erie. Of the 22 targeted PPCPs, 11 were found at part-per-billion levels in WWTP effluents and at part-per-trillion levels in river water samples.

The major pollutants observed were the antidepressants (citalopram, paroxetine, sertraline, venlafaxine, and bupropion, and their metabolites norfluoxetine and norsertraline) and the antihistamine diphenhydramine. These PPCPs accumulate in various fish organs, with norsertraline exhibiting the highest bioaccumulation factor (up to about 3000) in the liver of rudd (Scardinius erythrophthalmus), which is an invasive species to the Great Lakes.

The antidepressants were selectively taken up by various fish species at different trophic levels, and were further metabolized once inside the organism. The highest bioaccumulation was found in the brain, followed by liver, muscle, and gonads, and can be attributed to direct exposure to WWTP effluent.

  • How antidepressants are ending up in Great Lakes fish, Detroit Free Press, Sept. 1, 2017.
  • Selective Uptake and Bioaccumulation of Antidepressants in Fish from Effluent-Impacted Niagara River, ACS Journal, Environ. Sci. Technol., DOI: 10.1021/acs.est.7b02912, August 16, 2017.

Why Some Prescription Drugs are More Dangerous than Illegal Drugs

Adam Ruins Everything – November 2016

Adam Conover explains that some doctors prescribe medicine drugs just as addictive and dangerous as street drugs.

Hitrol

Diethylstilbestrol Injection via Hitech Pharmaceuticals, India.

DES use for livestock “growth”, weight-gain …

DES was/is still sold under many names including Distilbène®, Stilbetin®, Stilboestrol-Borne®, Benzestrol®, Chlorotrianisene®, Estrobene® and Estrosyn® to name just a few.

Many different companies manufactured and marketed this drug under more than 200 different brand names.

This Hitrol Diethylstilbestrol Injection U.S.P. is sold by Hitech Pharmaceuticals, S.B. Nagar, Dayal Bagh, Agra, India.

DES Drugs Pictures
DES DiEthylStilbestrol Resources