Category: Drugs and Disease

Major implicated agents include anabolic steroids, green tea, multi-ingredient nutritional supplements

Herbal and dietary supplement (HDS)-induced liver injury accounts for 20 percent of cases of hepatotoxicity in the United States, according to research published online Sept. 27 inHepatology.

Victor Navarro, M.D., from Einstein Healthcare Network in Philadelphia, and colleagues examine the current challenges in the diagnosis and management of HDS-induced liver injury.

The researchers note that HDS-induced liver injury accounts for one in five cases of hepatotoxicity in the United States. Anabolic steroids, green tea extract, and multi-ingredient nutritional supplements (MINS) are the major implicated agents. Anabolic steroids, which are marketed as bodybuilding supplements, tend to induce a prolonged cholestatic, self-limiting liver injury, characterized by a distinctive biochemical and histological phenotype. In contrast, green tea extracts and other products cause an acute hepatitis-like injury. MINS account for most cases of HDS-associated liver injury; the causative agent is usually unknown or can only be suspected.

“The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists,” the authors write. “The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety.”

The US Food and Drug Administration (FDA) has approved a new version of a recombinant, egg-free influenza vaccine called Flublok (Protein Sciences) that will protect against four strains of the virus, the manufacturer announced today.

The current version of Flublok, available during the 2016-2017 flu season, is designed for three strains: an A/California/7/2009 (H1N1)-like virus, an A/Hong Kong /4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-like virus (B/Victoria lineage). The new formulation, Flublok Quadrivalent, protects against these as well as the B/Phuket/3073/2013-like virus (B/Yamagata lineage). Both are injectables.

A company spokesperson told Medscape Medical News that  Flublok Quadrivalent would be available for the 2017-2018 flu. Like its trivalent predecessor, Flublok Quadrivalent is indicated for adults 18 years of age and older.

Approved in 2013, trivalent Flublok is the only influenza vaccine on the market fashioned through recombinant DNA technology. The manufacturer isolates a hemagglutinin (HA) protein found on the surface of a naturally occurring flu virus that, as an antigen, triggers an immune response. These HA proteins are combined with portions of another virus, and the mix is grown in insect cells. The HA protein is then harvested and purified.

The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommended trivalent Flublok in 2013 as a vaccine alternative for individuals who have an egg allergy. The two other current ways of making flu vaccines involve eggs. In egg-based manufacturing, inactivated or live attenuated vaccine viruses are grown in eggs. In the cell-based process, vaccine viruses first are grown in eggs and then combined with mammalian cells to replicate. Vaccine antigen is purified from this mix.

In a news release, Protein Sciences called Flublok Quadrivalent a “good choice” for seniors and individuals with compromised immune systems because it contains three times more active ingredient than other quadrivalent flu vaccines, compensating for a weaker immune response.

A clinical study of 9000 adults 50 years of age and older showed that individuals who received Flublok Quadrivalent were more than 40% less likely to come down with a confirmed case of influenza than those who received Fluarix Quadrivalent (Glaxo SmithKline), according to the manufacturer.

Injection-site tenderness and pain, headache, and fatigue are among the most common adverse events associated with Flublok Quadrivalent.

Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), can significantly disrupt sleep architecture in elderly patients and may contribute to early signs of neurodegeneration that can progress to dementia, new research shows.

“We take into account other side effects of antidepressants, including weight gain and sexual side effects, but we are less concerned about sleep, especially when we use the SSRIs,” Muhammad Tahir, MD, psychiatry resident, SUNY Upstate Medical University, Syracuse, New York, told Medscape Medical News.

“But the SSRIs increase sleep latency in the elderly and decrease REM [rapid eye movement] sleep duration and are also associated with REM sleep behavioral disorders, including nightmares,” he added.

“So our literature review suggests that we should be careful about using SSRIs in the elderly population and not underestimate the effectiveness of psychotherapy and other holistic care approaches for the elderly,” Dr Tahir said.

The study was presented here at the Institute of Psychiatric Services (IPS): The Mental Health Services 2016 Conference.

The literature review included 10 studies published within the past 5 years. The studies included systemic reviews, retrospective studies, and prospective studies, and patients had to be at least 50 years of age and receiving an antidepressant, largely an SSRI, for the treatment of depression.

Analyses revealed that not only did the SSRIs in particular change sleep architecture in older patients, they also appeared to increase the risk for REM behavioral disorders.

REM sleep behavioral disorders are characterized by normal brain activity, but the body is agitated and is not sleeping. This may be an early sign of neurodegeneration, said Dr Tahir.

Changes in the sleep architecture brought on by antidepressant therapy may result in agitation, Dr Tahir noted, which may prompt further treatment with further side effects.

Unfortunately, there is little evidence to support the use of any treatment other than the SSRIs for depression in the elderly.

Both the tricyclic antidepressants and the monoamine oxidase inhibitors are associated with too many side effects, especially in the elderly, and are generally not used in older patients.

Benzodiazepines in turn are associated with an increased risk for falls and again are inappropriate for use in the elderly.

Dr Tahir suggested that psychiatrists screen their elderly patients for any signs and symptoms of neurodegenerative disorders and, if an SSRI is prescribed, ask detailed questions about sleep quality on all follow-up visits.

SSRI Dosing Important

Commenting on the findings for Medscape Medical News, Peter Yellowlees, MD, professor of psychiatry, University of California, Davis, said the analysis, though interesting, does not include information on the doses of the SSRIs used in the studies that were included for review.

“In the elderly, these doses should be a maximum of half of the usual dose prescribed for younger patients,” Dr Yellowlees observed.

As for the possible association between SSRI use and neurodegenerative disease, Dr Yellowlees also noted that SSRIs are not necessarily causative.

“Rather, it may simply be that in the early stages of these diseases, depression and agitation are more common, and hence antidepressants are more commonly prescribed,” he noted.

In fact, the same association has been reported between the benzodiazepines and neurodegenerative disease that has been reported in the new study with respect to SSRIs, Dr Yellowlees pointed out.

“The jury is definitely out on the connection between degenerative disorders and medications, but in my view, there is not a lot of evidence to suggest that there is a causative link, although there does seem to be an association,” Dr Yellowlees suggested.

“The key issue here is that depression in the elderly is common and can be debilitating and is very treatable with both medications in lower doses than usually prescribed in younger patients along with behavioral interventions.”

U.S. Food and Drug Administration (FDA) has approved Stelara (ustekinumab) for the treatment of moderately to severely active Crohn’s disease in adults (18 years or older) who have failed or were intolerant to treatment with immunomodulators or corticosteroids but never failed treatment with a tumor necrosis factor (TNF) blocker, or who failed or were intolerant to treatment with one or more TNF blockers. Stelara is the first biologic therapy for Crohn’s disease targeting interleukin (IL)-12 and IL-23 cytokines, which play a key role in inflammatory and immune responses.

“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient,” said William J. Sandborn, MD, Chief, Division of Gastroenterology, and Professor of Medicine, UC San Diego School of Medicine, and study investigator. “The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time. Based on the results of the clinical development program, Stelara has the potential to benefit many adults living with Crohn’s disease.”

In clinical studies of patients who were either new to, experienced with, or failed biologic therapy (TNF blockers), between 34% (UNITI-1 study) and 56% (UNITI-2 study) of patients experienced relief from their Crohn’s disease symptoms in just six weeks after receiving the one-time intravenous (IV) infusion of Stelara. Noticeable improvement was observed as early as three weeks. Additionally, the majority of those who responded to induction dosing and continued treatment with Stelara subcutaneous maintenance doses every 8 weeks were in remission at the end of 44 weeks (52 weeks from initiation of the induction dose).

Stelara is the only treatment for Crohn’s disease that starts with a weight-based, one-time intravenous (IV) infusion induction dose (260 mg [55 kg or less], 390 mg [more than 55 kg to 85 kg], or 520 mg [more than 85 kg]) to help reduce symptoms, followed by 90 mg subcutaneous maintenance injections every 8 weeks to help keep the symptoms under control. The first dose of Stelara is an induction dose, administered intravenously, under the supervision of a healthcare professional. Subsequent maintenance doses are administered as a subcutaneous injection every 8 weeks, either by a healthcare professional or self-injected by the patient after proper training.

About Crohn’s Disease

Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract that affects approximately 700,000 Americans. Symptoms of Crohn’s disease can vary but often include abdominal pain and tenderness, frequent diarrhea, rectal bleeding, weight loss, and fever. Hospitalization is at times required for severe disease, to treat certain complications, and for surgery. There is currently no cure for Crohn’s disease.¹

About Stelara (ustekinumab)

Stelara is a prescription medicine used to treat moderately to severely active Crohn’s disease in adult patients (18 years and older) who have already taken other medicine that did not work well enough or they could not tolerate it.

SOURCE Janssen Biotech, Inc.

September 23, 2016 — The U.S. Food and Drug Administration today approved Amjevita (adalimumab-atto) as a biosimilar to Humira (adalimumab) for multiple inflammatory diseases. Amjevita is approved for the following indications in adult patients:

• moderately to severely active rheumatoid arthritis;
• active psoriatic arthritis;
• active ankylosing spondylitis (an arthritis that affects the spine);
• moderately to severely active Crohn’s disease;
• moderately to severely active ulcerative colitis; and
• moderate to severe plaque psoriasis.

Amjevita is also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.

Health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

“This is the fourth FDA-approved biosimilar. The biosimilar pathway is still a new frontier and one that we expect will enhance access to treatment for patients with serious medical conditions,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

Biological products are generally derived from a living organism and can come from many sources, including humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Amjevita is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Amjevita is biosimilar to Humira. It has been approved as a biosimilar, not as an interchangeable product.

The most serious known side effects with Amjevita are infections and malignancies. The most common expected adverse reactions with Amjevita are infections and injection site reactions.

Like Humira, the labeling for Amjevita contains a Boxed Warning to alert health care professionals and patients about an increased risk of serious infections leading to hospitalization or death. The Boxed Warning also notes that lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor blockers, including adalimumab products. The drug must be dispensed with a patient Medication Guide that describes important information about its uses and risks.

Amjevita is manufactured by Amgen, Inc., of Thousand Oaks, California. Humira was approved in December 2002 and is manufactured by AbbVie Inc. of North Chicago, Illinois.

September 21, 2016 – Janssen Pharmaceuticals, Inc. (Janssen) announced today the U.S. Food and Drug Administration (FDA) has approved Invokamet XR – a once-daily, fixed-dose combination therapy of canagliflozin and metformin hydrochloride extended-release (XR)—for first-line use as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes when treatment with the two medications is appropriate.[1] Invokamet XR combines Invokana (canagliflozin), the most prescribed sodium glucose co-transporter 2 (SGLT2) inhibitor, with more than 9 million U.S. prescriptions since launch,[2] and an XR formulation of metformin. Metformin is commonly prescribed as an initial therapy for the treatment of type 2 diabetes.

“Invokamet XR offers the convenience of once-daily dosing and provides physicians needed flexibility for tailoring treatment to the needs of type 2 diabetes patients, especially those with higher A1C levels,” said John Anderson, M.D.,* Frist Clinic, Nashville, Tenn. “As with Invokamet, physicians can prescribe the XR formulation to adults when they are first diagnosed with type 2 diabetes or as additional therapy for people whose A1C levels are not well controlled with either agent alone.”

Phase 3 studies have shown the combination of Invokana and metformin reduces A1C significantly more than metformin alone, sitagliptin plus metformin, or glimepiride plus metformin. Treatment with Invokana as an add-on to metformin also demonstrated greater reductions in the secondary endpoints of body weight and systolic blood pressure.

The approved indication for Invokamet XR aligns with current type 2 diabetes treatment guidelines from the American Association of Clinical Endocrinologists and American College of Endocrinology and from the American Diabetes Association, which recommend dual therapy for patients with higher A1C levels.[3],[4] Specifically, guidelines recommend dual therapy for patients who have an initial A1C level of 7.5 percent or higher[3] and for those who have an initial level below 7.5 percent and do not achieve an A1C treatment goal after about three months on single therapy, often metformin.4 In addition, dual or triple therapy is recommended as first-line therapy in asymptomatic patients with an initial A1C level above 9 percent.[3]

A1C is a measure of average blood glucose over the past two to three months; the American Diabetes Association recommends most adults with type 2 diabetes maintain A1C levels of 7 percent or less.[5]

“The approval of Invokamet XR is further evidence of our ongoing commitment to provide new treatment options for people with type 2 diabetes,” said Paul Burton, M.D., Ph.D., Vice President, Medical Affairs, Janssen. “Our Invokana portfolio now offers physicians even more choices for helping patients improve control of A1C levels and other important health measures, with numerous dosing options for monotherapy and for combination therapy with both metformin and metformin XR.”

Invokamet XR is available in four dosages, in tablets containing canagliflozin 50 milligrams (mg) or 150 mg, and metformin XR 500 mg or 1000 mg. The recommended dosing is two tablets once daily with the morning meal. The prescribing information for Invokamet XR also contains a boxed warning for lactic acidosis, a rare but serious complication that can occur due to metformin accumulation.[1]

Studies in healthy adults have demonstrated that administration of Invokamet XR results in the same levels of canagliflozin and metformin XR in the body as when corresponding dosages of the two medicines are administered as separate tablets. Canagliflozin works with the kidneys to help adults with type 2 diabetes lose some sugar through the process of urination, and metformin decreases the production of glucose in the liver and improves the body’s response to insulin. Invokamet XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.[1]

Invokamet, the first combination of an SGLT2 inhibitor and an immediate-release formulation of metformin available in the United States, was initially approved by FDA in August 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes not adequately controlled with metformin or canagliflozin, or who are already being treated with both medications separately. In May 2016, FDA expanded the Invokamet indication to include adults with type 2 diabetes who are not already being treated with canagliflozin or metformin and may benefit from dual therapy.

High and high-normal thyroid function is associated with increased risk of dementia, experts say.

Data analysis was done within the Rotterdam Study. A total of 9,446 subjects with a mean age of 65 years were included in the evaluation of the link between thyroid-stimulating hormone (TSH) and free thyroxine with dementia, cognition, and subclinical vascular brain disease by MRI. The subjects were followed-up for a mean duration of 8 years. During this period, 601 subjects developed dementia.

In both full and normal ranges of thyroid function, high TSH function was associated with dementia risk, independent of cardiovascular risk factors.

Subjects with higher free thyroxine were at greater risk of developing dementia. High TSH in older women was associated with decreased absolute 10-year dementia risk.

An association was seen between higher TSH and better global cognitive scores while thyroid function was not linked with to subclinical vascular brain disease.

The authors concluded that high and high-normal thyroid function may increase the risk of developing dementia.

September 19, 2016 — The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age, and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

Exondys 51 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (how a patient feels or functions or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

Sept. 20, 2016 — New research seems to confirm that stress lowers a woman’s chances of becoming pregnant, particularly stress that occurs around the time of ovulation.

“If you are feeling more stress than you usually do [around ovulation time], you are 40 percent less likely to get pregnant that month,” said study author Kira Taylor. She is an assistant professor of epidemiology and population health at the University of Louisville School of Public Health and Information Sciences.

Taylor believes her team’s study is the first to look at stress at different time periods in a woman’s monthly cycle, to determine if there are different effects at different points.

In the study, the researchers evaluated 400 women, aged 40 and younger. All were sexually active and not using contraception.

“Only about a third were actively trying to get pregnant, but all were having unprotected sex, without birth control,” Taylor said.

On a daily basis, the women recorded their stress levels, from one (lowest) to four (highest). They did so for up to 20 cycles, or until pregnancy occurred. On average, the women recorded their stress for eight cycles.

Over the study period, 139 women became pregnant. There was a 46 percent reduction in conception for each one-unit rise in stress during the ovulation window, the researchers found. Day 14 of the cycle was estimated as the time of ovulation.

The impact on conceiving held even after the investigators took into account other factors, such as age, body mass index (a measurement based on weight and height), alcohol use and how often sex occurred.

The researchers looked at other times in the cycle as well, but “we did not find an effect of stress on implantation,” Taylor said. “Implantation generally occurs six to 10 days after ovulation, if you have conceived.”

While the study found a connection between stress and conception, it didn’t prove cause and effect.

In another finding, “women who did get pregnant had much higher levels [of stress] around the end of their cycle.” Taylor said that may be due to hormone levels, with increasing levels of estrogen and progesterone causing mood swings at that time.

Dr. Tomer Singer, director of reproductive endocrinology and infertility at Lenox Hill Hospital in New York City, said the new research pinpoints the time period most affected by stress.

“They were able to focus a light on the important time of being stress-free, and this is the first half of the [cycle],” he said.

Taylor’s team did not look at why stress affected conception at the time of ovulation. But, she speculated that “stress disrupts the signaling between the brain and the ovaries, and reduces the chances of ovulation.”

Singer agreed. He said when a woman has a high stress level, hormones responsible for ovulation can be disrupted.

This hormonal disruption can hamper the process, Taylor said, so “it could be nature’s way of saying ‘Don’t have a baby right now.’ ”

Singer suggested that women can reduce their stress levels by practicing yoga or mindfulness meditation, among other ways.

Moderate exercise, five times a week for 30 minutes, can also reduce stress, Taylor said. But exercising to extremes can reduce the likelihood of conceiving, she said.

She also suggested that using talk therapy and time-management skills could lower stress levels.

The study was published online recently in the Annals of Epidemiology.

The use of tenofovir disoproxil fumarate (TDF) during pregnancy resulted in lower rate of mother-to-child transmission of hepatitis B virus (HBV) compared with those who received usual care without antiviral therapy, a recent study finds.

To assess the efficacy of TDF use during pregnancy for the prevention of HBV transmission from mother to child, researchers randomized 197 mothers who were positive for hepatitis B e antigen (HBeAg) and who had an HBV DNA level higher than 200,000 IU per millilitre to receive usual care without antiviral therapy (n=100) or TDF (n=97; 300 mg/day) from 30 to 32 weeks of gestation until postpartum week 4. The participants were followed until postpartum week 28. All the infants received immunoprophylaxis.

The primary outcomes were the rates of mother-to-child transmission and birth defects. The secondary outcomes were the safety of TDF, the percentage of mothers with an HBV DNA level of less than 200,000 IU per milliliter at delivery, and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28.

At delivery, 68 percent of the mothers in the TDF group, as compared with 2 percent in the control group (2 of 100), had an HBV DNA level of less than 200,000 IU per milliliter (p<0.001). At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (5 vs 18 percent; p=0.007) and the per-protocol analysis (0 vs 7 percent; p=0.01).

The maternal and infant safety profiles were similar in the TDF group and the control group, including birth-defect rates (2 and 1 percent, respectively; p=1), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45 vs 30 percent; p=0.03). The maternal HBV serologic outcomes did not differ significantly between the groups.