Acetaminophen toxicity is a result of the formation of a reactive intermediate N-acetyl-p-benzoquinonimine (NAPQI), the product of a minor pathway involved in the metabolism of acetaminophen. At therapeutic doses, the majority of acetaminophen metabolism occurs via glucuronidation and sulfation to nontoxic metabolites. In overdose, the nontoxic routes of metabolism become saturated and the metabolism of acetaminophen to NAPQI becomes a major metabolic pathway. The formation of NAPQI occurs primarily via oxidation by hepatic CYP2E1 and, to a lesser extent, by CYP3A4, CYP2A6, and CYP1A2. A fraction of the total NAPQI may be a result of renal CYP2E1 metabolism.
At therapeutic doses, NAPQI is detoxified rapidly by glutathione which combines with NAPQI to form nontoxic compounds that are eliminated in the urine as mercapturic acid; however, in overdose, the production of NAPQI increases disproportionately to the dose ingested. Toxicity occurs when glutathione utilization surpasses the rate of glutathione formation, resulting in free, unbound NAPQI that rapidly binds to cellular components (eg, hepatocytes). The covalent binding of NAPQI to cellular components results in apoptosis and/or direct cellular necrosis.
Glutathione depletion may occur as a result of a single acute overdose of acetaminophen, repeated supratherapeutic acetaminophen ingestions, decreased glutathione stores (eg, alcoholism, malnutrition), and/or increased production of NAPQI (eg, secondary to drug interactions) (Zenger 2004). Drugs that induce CYP2E1 and the other CYP enzymes involved in acetaminophen metabolism may increase the ability to produce NAPQI; ethanol (chronic ingestion) and isoniazid are among the enzyme inducers that have been theorized to increase the risk of acetaminophen toxicity following prolonged excessive use of acetaminophen (Brackett 2000). Chronic ethanol ingestion, in combination with chronically poor diet, may also decrease glutathione stores. Conversely, acute coingestion of ethanol with acetaminophen may be temporarily hepatoprotective; in theory, ethanol acts as a competitive inhibitor of CYP2E1 due to enzyme occupancy, thus preventing the conversion of acetaminophen to NAPQI until ethanol has been metabolized (Rumack 2002; Thummel 2000).
“Off-label” drug use puts patients at risk for serious side effects, especially when scientific evidence is lacking, a new study finds.
Physicians prescribe “off-label” when they recommend drugs for uses that have not been approved by the U.S. Food and Drug Administration. It’s a common and legal practice.
It’s also hard to track, because U.S. doctors aren’t required to document the reason for prescribing a treatment.
But in what may be the most extensive review of the practice to date, a Canadian-U.S. research team found reason for concern.
Patients prescribed off-label drugs without strong scientific evidence were 54 percent more likely to experience an adverse event, such as a drug reaction, drug interaction or allergic response, forcing them to stop taking the drugs, the study found.
“We are not saying that off-label is bad,” said Dr. Tewodros Eguale, who led a research team at McGill University in Montreal. “But when it’s off-label and there’s no strong scientific evidence, we showed that there’s a high risk of adverse drug events.”
Among drugs commonly prescribed off-label, the researchers found hallucinations were linked to the antidepressant trazodone (Oleptro), often ordered to treat insomnia. And weight gain was associated with the schizophrenia drug Zyprexa (olanzapine), which is frequently prescribed off-label for depression.
Off-label drug use should be part of the discussion between patients and their physicians, he said.
The study was published online Nov. 2 in the journal JAMA Internal Medicine.
Doctors have many reasons to prescribe off-label. The arsenal of medications to treat a condition may be limited, patients may have exhausted other drug options or medicines with good evidence may not have gone through the FDA process.
“Off-label use is higher than it should be, in part because the FDA does less than physicians and the public thinks it does,” said Dr. Randall Stafford, director of the Program on Prevention Outcomes and Practices at Stanford University in Palo Alto, Calif.
He said the FDA judges a drug’s safety and effectiveness for a single clinical condition.
“Unfortunately, many physicians think of FDA approval as a blanket endorsement,” Stafford said. “This leads to use of drugs for clinical conditions that have not been evaluated.”
Amitriptyline (Elavil), approved solely to treat depression, is frequently prescribed off-label. Preventing migraine is one such use, for example.
Almost half of amitriptyline’s off-label uses are backed by strong scientific evidence, said Eguale, now an associate professor at the Massachusetts College of Pharmacy and Health Sciences in Boston and an adjunct professor at McGill.
The malaria drug quinine is often prescribed for leg cramps and restless leg syndrome, although regulators have warned against its off-label use due to risks of serious bleeding.
“It’s not the biggest offender [in terms of adverse events], but its off-label prescribing rate is very high. Close to 99.4 percent of the time, it’s used for an off-label condition,” Eguale said.
All of the off-label uses of quetiapine (Seroquel), risperidone (Risperdal) and Zyprexa — three powerful antipsychotic drugs — lack strong scientific evidence, he said.
For the study, researchers scoured electronic health record data on roughly 46,000 adults patients who received more than 151,000 prescriptions from primary care clinics in Quebec from 2005 through 2009.
Physicians using that data system must enter the reason for each new prescription, change in dosage or discontinuation. They must also include specifics on any adverse drug events.
More than one in 10 prescriptions in the study were for an off-label use. Of those, more than 80 percent were for off-label uses lacking strong scientific evidence, the researchers said.
Rates of adverse events involving on-label use and off-label use with strong scientific evidence were about the same, the study found.
In all, the study authors identified 3,484 adverse drug events. However, they acknowledged that the study might not capture all medication-related events, that doctors can miss symptoms and patients may fail to mention all of their symptoms.
The average cost per adverse event, considering possible emergency room visits and hospitalizations, ranges from $759 to $1,214, the study authors estimated.
In a related journal commentary, doctors at the Veterans Affairs Pittsburgh Healthcare System highlighted a recent U.S. federal court ruling against an FDA ban on off-label drug promotion.
This study provides “compelling evidence” that the FDA and courts must carefully consider before relaxing the ban, they concluded.
The FDA has issued a Safety Alert restricting the use of codeine and tramadol in children. Children under 12 years and some adolescents younger than 18 years (especially those with certain genetic factors, obesity, or obstructive sleep apnea and other breathing problems) should not use medicines containing these drugs because of increased medical risks, including slowed or difficult breathing and death. The FDA is also recommending against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants, including excess sleepiness, serious breathing problems, or death.
The FDA is requiring several labeling changes to all prescription medicines containing these drugs. Health care professionals should be aware that tramadol and single-ingredient codeine medicines are FDA-approved only for use in adults, and should consider recommending OTC or other FDA-approved prescription medicines for cough and pain management in children younger than 12 years and in adolescents younger than 18 years. The FDA also reminds health care professionals that cough is often secondary to infection and not serious, usually resolving on its own and not requiring treatment.
FDA is restricting the use of codeine and tramadol medicines in children. These medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children. These medicines should also be limited in some older children. Single-ingredient codeine and all tramadol-containing products are FDA-approved only for use in adults. FDA is also recommending against the use of codeine and tramadol medicines in breastfeeding mothers due to possible harm to their infants.
As a result, FDA is requiring several changes to the labels of all prescription medicines containing these drugs. These new actions further limit the use of these medicines beyond the 2013 FDA restriction of codeine use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids. FDA is now adding:
FDA’s strongest warning, called a Contraindication, to the drug labels of codeine and tramadol alerting that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12 years.
A new Contraindication to the tramadol label warning against its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.
A new Warning to the drug labels of codeine and tramadol to recommend against their use in adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease, which may increase the risk of serious breathing problems.
A strengthened Warning to mothers that breastfeeding is not recommended when taking codeine or tramadol medicines due to the risk of serious adverse reactions in breastfed infants. These can include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.
An elderly female was on a maintenance opioid regimen of Morphine ER 15 mg BID, with breakthrough Norco 10/325mg QID PRN. Needless to say, I was fairly shocked to see a prescription come in for her calling for Fentanyl 100 mcg/hr patches W 72 hours and breakthrough Dilaudid 2 mg Q 2 hours. This is an increase from approximately 70 mg morphine equivalent to 450 mg morphine equivalent. I called the prescriber and they informed me that the patient was on the 100 mcg patch in the hospital with them along with a PCA pump for 2 days and that she had tolerated it fine. “The doctor is not worried about this dose at all” the nurse said to me on the phone. I then spoke with the patients husband when he came to pick up the prescription for fentanyl and I inquired about how she was doing. He then informed me that she had been home for three days, used none of her breakthrough medication and was still very sedated with limited ability to communicate.
Less than 50% of the U.S. population obtains the seasonal influenza vaccine, and the vaccine does not confer perfect immunity. There are three types of influenza, plus numerous variations. Practitioners should be confident in the use of antiviral agents in patients with influenza. The most recent guidelines recommend the use of nonpharmacologic management and neuraminidase inhibitors to either prevent the transmission of influenza or treat the infection. Pharmacotherapy is based on an understanding of which
Nonpharmacologic Treatment: Nonpharmacologic recommendations for influenza are bed rest, avoidance of other persons, and hydration. Fluids should be consumed throughout the illness to prevent complications from dehydration. Acetaminophen or ibuprofen may be used to relieve fever, headache, and muscle aches. However, some patients may benefit from antiviral treatment (see Pharmacotherapy Considerations section).17-19
Pharmacologic Agents: Antiviral medications with activity against influenza viruses are an important adjunct to vaccination for control of the influenza virus. Oseltamivir (Tamiflu), inhaled zanamivir (Relenza), and IV peramivir (Rapivab) are the currently recommended agents for influenza.20-22 These drugs, which are neuraminidase inhibitors with activity against both influenza A and influenza B, work by selectively inhibiting the neuraminidase enzyme, thereby preventing the release of viral particles from infected cells. These medications may be used for treatment, but only oseltamivir and zanamivir may be used for treatment and chemoprophylaxis. The chemoprophylaxis dosages for these drugs are lower than the treatment dosages; however, the therapy duration is longer (TABLE 1).20-23 Oseltamivir and zanamivir are indicated for use in adults and children; peramivir has not been FDA-approved for use in children.19,23
Summary of currently available antiviral agents
Besides the neuraminidase inhibitors, two other products are available: amantadine (Symmetrel) and rimantadine (Flumadine), both of which are adamantane antiviral agents with activity against influenza A viruses. These agents exert an inhibitory effect on influenza A subtypes (H1N1, H2N2, and H3N2) early in the viral replicative cycle. However, they are no longer recommended for treatment and prevention of influenza because of the increased rates of resistance (>99%) in influenza A types H3N2 and H1N1.19,23
Early treatment with the previously mentioned antivirals can shorten the duration of influenza symptoms by 1/2 day to 3 days and may reduce the risk of complications.24 The greatest clinical benefit is seen when antiviral treatment is initiated within 48 hours of illness onset. It is also important to correctly identify patients who meet parameters for either chemoprophylaxis or treatment so that they receive the correct dosage and duration of therapy.19
Chemoprophylaxis should be considered in adults and children aged 1 year and older who are at high risk for developing influenza complications and for whom influenza vaccination is contraindicated, unavailable, or expected to have low effectiveness (e.g., significantly immunocompromised persons).18,19 Chemoprophylaxis should also be considered in this population when the vaccination has not yet been administered and influenza has been detected within the community. Unvaccinated adults—including healthcare workers—and children aged ≥1 year who are in close contact with persons at high risk for developing influenza complications during periods of influenza activity should be considered for chemoprophylaxis, as should all vaccinated and unvaccinated persons in institutions experiencing influenza outbreaks.19
Antiviral treatment should be initiated in all persons with laboratory-confirmed or highly suspected influenza virus infection, including those at high risk for developing complications (TABLE 2).19 Patients who require hospitalization for influenza regardless of vaccination status or underlying illness should also receive treatment. Outpatients at high risk for complications whose illness is not improving and who have a positive influenza test result may be candidates for influenza treatment. The same is true for outpatients who are not at increased risk, but wish to shorten the duration of illness or are in close contact with someone at high risk for complications secondary to influenza infection.19
high rist for Influenza complications
When the appropriate drug for chemoprophylaxis or treatment is being selected, local patterns of influenza circulation in the community throughout the influenza season should be considered. Oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab) were the antivirals recommended for the 2016–2017 influenza season.19 A generic oseltamivir was approved by the FDA in August 2016, giving patients a less expensive option.25
In patients who are mechanically ventilated or critically ill, oseltamivir may be administered via nasogastric or orogastric (NG/OG) tube. The powder from capsules should be dissolved in 20 mL of Sterile Water and injected down the NG/OG tube, followed by a 10-mL Sterile Water flush.20
– See more at: https://www.uspharmacist.com/article/antiviral-therapy-in-patients-with-influenza#sthash.5hPEtMHF.dpuf
Despite advances in preventive care, infection with the influenza virus sometimes occurs. In such cases, practitioners must be able to quickly identify patients at high risk for developing complications in order to lessen the morbidity and mortality associated with the influenza virus. Some patients may require chemoprophylaxis to prevent infection. The agents for treatment and chemoprophylaxis are the same, and pharmacists should play an active role in ensuring that the correct dosage is used for the correct indication.
1. Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol. 2008;3:499-522.
2. CDC. CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States. www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm. Accessed December 29, 2016.
3. CDC. Weekly US influenza surveillance report: 2016-2017 season, week 51 ending December 24, 2016. www.cdc.gov/flu/weekly/weeklyarchives2016-2017/Week51.htm. Accessed March 8, 2017.
4. Santibanez TA, Kahn KE, Zhai Y, et al. Flu vaccination coverage, United States, 2015–2016 influenza season. www.cdc.gov/flu/fluvaxview/coverage-1516estimates.htm. Accessed March 3, 2017.
5. Luo M. Influenza virus entry. Adv Exp Med Biol. 2012;726:201-221.
6. Lakadamyali M, Rust MJ, Zhuang X. Endocytosis of influenza viruses. Microbes Infect. 2004;6:929-936.
7. CDC. Influenza (flu): information for schools. www.cdc.gov/flu/school/qa.htm. Accessed December 30, 2016.
8. CDC. Types of influenza viruses. www.cdc.gov/flu/about/viruses/types.htm. Accessed January 14, 2017.
9. CDC. How the flu virus can change: “drift” and “shift.” www.cdc.gov/flu/about/viruses/change.htm. Accessed December 30, 2016.
10. Hunt R. Vaccines: past successes and future prospects. Virology. www.microbiologybook.org/lecture/vaccines.htm. Accessed January 14, 2017.
11. Sedova ES, Shcherbinin DN, Migunov AI, et al. Recombinant influenza vaccines. Acta Naturae. 2012;4:17-27.
12. CDC. Selecting viruses for the seasonal influenza vaccine. www.cdc.gov/flu/about/season/vaccine-selection.htm. Accessed January 14, 2017.
13. Thompson WW, Comanor L, Shay DK. Epidemiology of seasonal influenza: use of surveillance data and statistical models to estimate the burden of disease. J Infect Dis. 2006;194(suppl 2):S82-S91.
14. Montalto NJ. An office-based approach to influenza: clinical diagnosis and laboratory testing. Am Fam Physician. 2003;67:111-118.
15. CDC. Influenza signs and symptoms and the role of laboratory diagnostics. www.cdc.gov/flu/professionals/diagnosis/labrolesprocedures.htm. Accessed January 14, 2017.
16. Vemula SV, Zhao J, Liu J, et al. Current approaches for diagnosis of influenza virus infections in humans. Viruses. 2016;8:96.
17. CDC. Influenza (flu) treatment. www.cdc.gov/flu/consumer/treatment.htm. Accessed December 22, 2016.
18. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1-24.
19. Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:1003-1032.
20. Oseltamivir. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed December 9, 2016.
21. Zanamivir. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed December 9, 2016.
22. Peramivir. Lexi-Comp Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed December 9, 2016.
23. CDC. Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Accessed March 8, 2017.
24. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomized controlled trials. BMJ. 2003;326:1235.
25. The FDA approves first generic version of widely used influenza drug, Tamiflu. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm514854.htm. Accessed January 13, 2017.
26. CDC. Antiviral emergency use authorization. www.cdc.gov/flu/professionals/antivirals/antiviral-emergency-use.htm. Accessed December 17, 2016.
The reviewers point to other limitations, including that all studies were short-term, lasting less than 6 months, and that all studies on effective drugs had more than 9% of participants drop out due to adverse effects.
With more than 9% of the United States population having diabetes and an estimated half of those having some form of diabetic peripheral neuropathy, even if symptomless, identifying the optimal treatment is a high priority for neurologists and other clinicians.
Making that especially critical is the fact that, in some cases of severe neuropathy, amputation is the only real option.
New research published online recently in the journal Neurology and in publications of the Agency for Healthcare Research and Quality (AHRQ) suggests that certain antidepressants and antiseizure drugs are among medications that can effectively treat diabetic nerve pain.
“Providing pain relief for neuropathy is crucial to managing this complicated disease,” explained systematic review author Julie Waldfogel, PharmD, of The Johns Hopkins Hospital. “Unfortunately, more research is still needed, as the current treatments have substantial risk of side effects, and few studies have been done on the long-term effects of these drugs.”
Overall, 106 studies were included in the systematic review of trials conducted after release of the American Academy of Neurology’s 2011 guideline “Treatment of Painful Diabetic Neuropathy.”
Moderate-strength evidence suggested that duloxetine and venlafaxine, which act as serotonin-norepinephrine reuptake inhibitors, were effective in reducing neuropathy-related pain. Only weak evidence was identified, however, for the effectiveness of the botulinum toxin, the antiseizure drugs pregabalin and oxcarbazepine, tricyclic antidepressants, and atypical opioids.
Waldfogel emphasized that the long-term use of opioids is not recommended for chronic neuropathic pain, adding that the guidance was bolstered by the lack of evidence of long-term benefit, as well as growing concerns about the risk of abuse, misuse, and overdose.
Overall, the reviewers said, “For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo.”
Some of the evidence was contrary to the 2011 AAN guideline, however. For example, researchers note that pregabalin works in the same way as gabapentin, which was found to be no more effective than placebo in the recent review. The previous guideline said the drug was probably effective.
In addition, the seizure drug valproate and topical capsaicin cream, which were recommended as probably effective in the 2011 AAN guideline, were deemed ineffective in this meta-analysis.
“Unfortunately, there was not enough evidence available to determine if these treatments had an impact on quality of life,” Waldfogel said. “Future studies are needed to assess this.”
The thought of having to pull out an inhaler in the middle of school might stop some kids with asthma from breathing better, a study of British schoolchildren suggests.
An online survey of almost 700 students with asthma showed that nearly 50 percent reported poor asthma control.
With asthma, the lungs and airways become inflamed when exposed to triggers that can include pollen, catching a cold or having a respiratory infection. Childhood asthma can interfere with play, sports, school and sleep. Unmanaged asthma can cause dangerous asthma attacks.
Inhalers that contain short- and long-acting medications can help keep those attacks from happening, the study authors noted.
But the survey found that more than 42 percent of schoolchildren with a short-acting beta agonist inhaler said they didn’t feel comfortable using it at school. In addition, more than 29 percent said they did not use it when they had wheezing.
Just over half (56 percent) of those with regular inhaled corticosteroids did not take them as prescribed. And nearly 42 percent did not know what the inhaler was for, according to the researchers from Queen Mary University of London.
“This study is the first to measure asthma control in U.K. schools, and highlights an under-reporting of asthmatics in schools, as well as high rates of poor asthma control,” corresponding study author Katherine Harris said in a university news release.
“These findings will inform the development of a school-based intervention, aimed at improving adherence to medication, knowledge and control,” she added.
Jonathan Grigg, from the university’s Blizard Institute, added: “The aim of inhaled therapy of asthma in children is to completely suppress symptoms, but we found that many children with regular asthma symptoms did not realize what good control should feel like.”
The United Kingdom has among the highest rates of asthma symptoms in children worldwide. On average, there are three children with asthma in every U.K. classroom, and a child is admitted to a hospital every 20 minutes because of an asthma attack, the study authors said.
In the United States, 8.4 percent of children under 18 have asthma — a total of 6.2 million kids, according to the U.S. Centers for Disease Control and Prevention.
The British study was published online recently in the Journal of Asthma.
Medicines play an important role in treating many conditions and diseases and when they are no longer needed it is important to dispose of them properly to help reduce harm from accidental exposure or intentional misuse. Below, we list some options and special instructions for you to consider when disposing of expired, unwanted, or unused medicines.
Transfer Unused Medicine to Authorized Collectors for Disposal
Consumers and caregivers should remove expired, unwanted, or unused medicines from their home as quickly as possible to help reduce the chance that others may accidentally take or intentionally misuse the unneeded medicine.
Medicine take-back programs are a good way to safely dispose of most types of unneeded medicines. The U.S. Drug Enforcement Administration (DEA) periodically hosts National Prescription Drug Take-Back events where collection sites are set up in communities nationwide for safe disposal of prescription drugs. Local law enforcement agencies may also sponsor medicine take-back programs in your community. Likewise, consumers can contact their local waste management authorities to learn about medication disposal options and guidelines for their area.
Another option for consumers and long-term care facilities, like nursing homes, to dispose of unneeded medicines is to transfer unused medicines to collectors registered with the DEA. DEA-authorized collectors safely and securely collect and dispose of pharmaceuticals containing controlled substances and other medicines. In your community, authorized collection sites may be retail pharmacies, hospital or clinic pharmacies, and law enforcement locations. Some authorized collection sites may also offer mail-back programs or collection receptacles, sometimes called “drop-boxes,” to assist consumers in safely disposing of their unused medicines.