British Columbia CA – Jeffrey Baglot developed a large ulcer that eventually perforated and required surgery to be repaired, following the use of the powerful anti-inflammatory drug. He was prescribed Ketorolac by Dr. Clasina Fourie (Abbotsford Regional Hospital, BC) during a flareup of his Crohn’s disease in 2011.

Within days, he developed an ulcer at the beginning of his small intestine. The two-centimetre ulcer ultimately ruptured and needed to be surgically repaired. Baglot ended up in another hospital for more than two months.

Baglot, now 33, thought he was going to die.

“My body was shutting down,” he testified in B.C. Supreme Court last year.

Baglot initiated the lawsuit against Dr. Fourie and won. She was ordered to pay nearly $900,000 in damages on Jan. 31.

Justice Diane Cheryl MacDonald said Fourie’s “negligence has had a devastating impact on Mr. Baglot’s life.”

“Today Mr. Baglot is totally disabled, homebound and isolated. Without the prescribing error, I find that it is more likely than not that Mr. Baglot would have continued to have Crohn’s disease but that he would have worked and been a contributing member of society,” MacDonald said.

Review of SAFETY considerations when prescribing Ketorolac

Concern over the high incidence of reported adverse effects with ketorolac trometamol has led to its withdrawal in some countries while in others its permitted dosage and maximum duration of treatment have been reduced. The recommended maximum duration for parenteral therapy is 2 days in the UK; if required, patients should be transferred to oral therapy with another analgesic. In the USA it is recommended that the maximum combined duration of use of parenteral and oral ketorolac should not exceed 5 days. Complications associated with Ketorolac misuse include potential kidney failure, liver damage and gastrointestinal bleeding. There’s also increased risk of heart attack and stroke.

WARNING

Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following IV or IM dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days.

Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.

GASTROINTESTINAL RISK

Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events.

CARDIOVASCULAR THROMBOTIC EVENTS

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

Ketorolac tromethamine is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

RENAL RISK

Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion.

RISK OF BLEEDING

Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding.

Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery.

HYPERSENSITIVITY

Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac tromethamine injection.

Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).

INTRATHECAL OR EPIDURAL ADMINISTRATION

Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content.

RISK DURING LABOR AND DELIVERY

The use of ketorolac tromethamine in labour and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions.

CONCOMITANT USE WITH NSAIDs

Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.

SPECIAL POPULATIONS

Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs.) of body weight and for patients with moderately elevated serum creatinine. Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients.

DOSAGE AND ADMINISTRATION

Ketorolac Tromethamine Tablets:

Ketorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine injection, and the combined duration of use of ketorolac tromethamine injection and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events.

The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine injection (maximum 120 mg).

Excerpts:

1. CBC News
2. MARTINDALE – The Complete Drug Reference
3. DailyMed – FDA-approved label information

January 21, 2019: The Ghanaian Food and Drugs Authority (FDA) has issued a public safety alert for cosmetic products with undeclared steroids, hydroquinone and mercury. The agency is warning the public about the potential health hazards associated with the use of these cosmetic products. Investigations by the agency revealed that these cosmetic products on the market contain harmful substances which are not declared on the product labels.

The agency has directed the companies whose products contain these substances (mercury, hydroquinone and steroids) to initiate an immediate recall of the affected products from the market. It stated that these substances are not permitted in cosmetic products due to their potential for severe adverse reactions, especially with prolonged use. Some of the adverse effects associated with these noxious substances include:

• Permanent neurological damage in children (prenatal and neonatal) exposed to mercury during pregnancy and/or lactation
• Kidney toxicity
• Fertility problems
• Birth defects
• Gastrointestinal toxicity
• Liver toxicity
• Skin infections
• Skin cancer
• Hyperpigmentation/Ochronosis

The FDA is advising the general public:

1. Not to purchase any of these cosmetic products as indicated
2. Immediately discontinue the use and return all such products to the retail shops from where they were purchased or to the FDA
3. Report to the FDA any adverse effects arising from the use of any cosmetic product through the FDA’s Safety Monitoring System

The list of companies and products that contain the substances that are not permitted in cosmetic products are:

DIMD Limited

1. Perfect White Beauty Lotion (Clobetasol, Hydroquinone)
2. Day By Day Men Perfect Body Lotion (Betamethasone)

Banare Limited

1. Ahoofe Foundation Body Cream (Mercury, Hydroquinone)

France Mod Limited

1. Fair & White So White Skin Perfecter Brightening and Moisturizing Body Milk (Hydroquinone)

IVO Ghana Limited

1. Zoe Peau Sublime Beauty Lotion (BN:AF50.04000002.09:15) (Mercury, Betamethasone, Hydroquinone)
2. Zoe Peau Sublime Beauty Lotion (BN: not stated) (Mercury, Betamethasone, Hydroquinone)
3. Body Clear Lightening Lotion (BN: not stated) (Mercury, Hydroquinone)
4. Zoe Peau Sublime Face Corrective Cream (BN: not stated) (Mercury, Clobetasol, Betamethasone)
5. Body Fashion Body Milk (BN: not stated) (Mercury, Hydroquinone)
6. HT7 Hyprogel Body Lotion (BN: not stated) (Betamethasone)
7. Beauty Clinic Whitening Lotion (BN: AF51.0500 0001) (Mercury, Hydroquinone)

Magic Dodo Ltd

1. Dodo Beauty Lightening Lotion (BN: 006114) (Mercury, Hydroquinone)
2. Marie France Skin Care (BN: 006045) (Mercury, Betamethasone, Hydroquinone)

Nouvelle Parfumrie Gandour Ghana Limited

1. Tiatio Concentrated Serum (Betamethasone, Clobetasol, Hydroquinone)
2. Bravia Unifying Body Cream (BN: 1006618) (Hydroquinone)
3. Bronze Tone Cocoa Butter and Honey Extracts (Hydroquinone)
4. Passionella Complexion Unifying Serum (Hydroquinone)
5. Passionella Brightening Cream (BN:241540) (Hydroquinone)
6. Fluo Pommade a Huile de Ricin (Betamethasone)
7. Bravia Lotion (Mercury, Clobetasol, Hydroquinone)
8. Doctoress Creme (Clobetasol)
9. Pure Skin Vanishing Care Body Cream (Clobetasol, Hydroquinone)
10. Senophine Creme (Clobetasol)
11. Abana Facial Creme (Mercury, Clobetasol, Hydroquinone)
12. Bronze Tone Maxi Tone Cocoa Butter & Honey Extract Lotion (Hydroquinone)
13. Maxilight Lightening & Purifying Body Lotion (Clobetasol, Hydroquinone)
14. G&G Body Cream (Mercury, Clobetasol, Hydroquinone)

Paradise Cosmetics Limited

1. Bioskin Lightening Body Lotion (BN: 750) (Hydroquinone, Clobetasol)
2. Bioskin Lightening Body Lotion (BN: 847) (Clobetasol, Hydroquinone)
3. Clair-Liss Genial Lightening Body Cream (BN: B9834) (Clobetasol, Hydroquinone)
4. Clair-Liss Genial Lightening Body Cream (9816) (Clobetasol, Hydroquinone)
5. Sivoclair Lightening Body Lotion (BN-3560) (Clobetasol, Hydroquinone)
6. Goldskin Clarifying Body Lotion with Argan Oil (BN: 740) (Clobetasol, Hydroquinone)
7. Goldskin Fast Action Cream with Argan Oil (BN: G07025) (Clobetasol)
8. Peau Claire Lightening Body Cream (BN: 3926) (Clobetasol, Hydroquinone)
9. Biocarrot Lightening Body Lotion (BN: 167) (Clobetasol, Hydroquinone)

Stopover JRA Enterprise

1. RA Foundation Body Cream (Mercury, Hydroquinone)

Universal Basic Company Limited

1. Tendrina Special Hand and Body Complexion Lotion (BN: 139) (Betamethasone)
2. Tendrina Complexion Cream (BN: CT 4003) (Betamethasone)
3. Tendrina Hand and Body Complexion Lotion (BN: not legible) (Betamethasone)
4. TC 35 Clear Complexion Milk (BN: 14352) (Betamethasone)

 

Source: Ghana Food and Drugs Authority (FDA). Press Release; 2019 Jan 21. Available here: https://fdaghana.gov.gh/images/stories/pdfs/Press%20release/PRESS%20RELEASE%202.pdf

The FDA’s Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee held a joint meeting on January 11, 2019, to discuss the “Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES)” trial results and the benefit-risk assessment of febuxostat. Members of the committees voted 19 to 2, with 1 abstention, that based on available data, there are patient populations in which the benefit-risk profile for febuxostat is favourable for the treatment of hyperuricemia in patients with gout. The committees held a widely varied discussion about the appropriate patient populations and potential regulatory actions.

The outcome of the FDA joint committee review was announced by Takeda, makers of Uloric® (brand of febuxostat). Febuxostat is available in Nigeria under the brand name Febo-G®, marketed by Getz Pharma Ltd

“Many believe that gout is a condition that comes and goes for patients, but it is a chronic disease that can be severe and potentially debilitating, and many patients require pharmacologic treatment options to manage their disease,” said Lawrence Edwards, MD, rheumatologist, University of Florida Health. “Today’s vote from the Advisory Committees reflects the continued importance of having treatment options available for patients with gout.”

Laurel A. Habel, MPH, PhD (voted yes), an epidemiologist, said that at the very least febuxostat’s label should “include the CARES results, even though they’re not definitive.” This might come in the form of a BLACK-BOX WARNING or some other phrasing to “result in more restrictive use and encourage it as second-line therapy,” she commented. Further, professional societies should also frame febuxostat as second-line therapy, Habel asserted, though there shouldn’t be barriers that make the drug hard to obtain for patients who really need it to treat debilitating gout.

Martin Kulldorff, PhD voted against febuxostat having a favourable risk-benefit balance. He cited the argument that “there is evidence that the drug causes death in some people.” Moreover, it isn’t known whether patients who are unable to take allopurinol would, in fact, do well on febuxostat, he said. “I think we basically don’t know. I think the future of this drug for the moment is to withdraw it from the market and encourage prospective clinical trials to study the drug among those who do not tolerate allopurinol.”

In the CARES trial, febuxostat met the primary endpoint, demonstrating that the rate of major adverse CV events (MACE: CV death, non-fatal myocardial infarction (MI), non-fatal stroke, and unstable angina with urgent coronary revascularization) in patients treated with febuxostat was non-inferior to that of allopurinol. When analyzing the individual components of MACE as secondary endpoints, the individual rates for MI, stroke, and unstable angina with urgent coronary revascularization were similar with febuxostat compared to allopurinol. However, the rate of CV death was higher among patients assigned to febuxostat compared to allopurinol, which also contributed to a higher rate of death from all causes. Based on analyses conducted to date, a reason for this finding has not been identified. There were no significant differences in rates of other serious CV events such as hospitalization for heart failure or arrhythmias.

Febuxostat was approved in 2009 and allopurinol in 1966. The two drugs are the only xanthine oxidase inhibitors (XOIs) on the market for the treatment of gout. Since approval, the Prescribing Information for febuxostat has included a warning and precaution that a higher rate of adverse CV events was observed in patients treated with febuxostat when compared with allopurinol in clinical trials.

Febuxostat is the only first-line alternative for patients who cannot take allopurinol, due to being genetically predisposed to a hypersensitivity reaction, having chronic kidney disease, or developing a skin reaction or other side effects on the drug.

The outcome of the Advisory Committee meeting is non-binding and will be taken into consideration by the FDA.

Uses of Febuxostat:

Febuxostat is a prescription medicine used to lower blood uric acid levels in adults with gout. Febuxostat is not for the treatment of high uric acid without a history of gout.

Important Safety Information:

Do not take febuxostat if you are taking azathioprine or mercaptopurine.

Febuxostat may cause serious side effects, including:

Gout Flares: Gout flares can happen when you first start taking febuxostat. Your healthcare provider may give you other medicines to help prevent your gout flares.

Heart Problems: People who take febuxostat can have serious heart problems including heart attacks, strokes and heart-related deaths. It is not known that febuxostat caused these problems. Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms: chest pain, shortness of breath, dizziness, numbness or weakness on one side of your body, trouble talking or a headache.

Liver Problems: Liver problems can happen in people who take febuxostat. Your healthcare provider may do blood tests to check how well your liver is working before and during your treatment with febuxostat.

Severe Skin and Allergic Reactions: Serious skin and allergic reactions that may affect different parts of the body such as your liver, kidneys, heart or lungs, can happen in people who take febuxostat. Call your healthcare provider right away or get emergency medical help if you have any of the following symptoms: rash, red and painful skin, severe skin blisters, peeling skin, sores around the lips, eyes or mouth, swollen face, lips, mouth, tongue or throat, or flu-like symptoms.

The most common side effects of febuxostat include liver problems, nausea, gout flares, joint pain, and rash. Tell your healthcare provider if you have any side effect that bothers you, or that does not go away.

About Gouty Arthritis:

Gout is caused by a buildup of uric acid in the body. Uric acid forms crystals in the joints, which can lead to the inflammation and pain of a gout attack. As the uric acid level rises, so does the chance for gout and gout attacks. Over time, these attacks, or flares, can involve more joints, last longer, and happen more often.

An estimated 8.3 million Americans have gout, which may be increasing. Half of the gout patients have three or more attacks per year; a typical gout attack can last at least 4 days.

References:

1. Takeda Announces Outcome of Uloric FDA Advisory Committee Meeting [Internet]. [cited 2019 Jan 16]. Available from: https://www.takeda.com/en-us/newsroom/news-releases/2019/takeda-announces-outcome-of-uloric-fda-advisory-committee-meeting/
2. Febuxostat Emerges Relatively Unscathed After FDA Advisory Committee Review [Internet]. TCTMD.com. [cited 2019 Jan 16]. Available from: https://www.tctmd.com/news/febuxostat-emerges-relatively-unscathed-after-fda-advisory-committee-review
3. FDA Advisers Back Febuxostat for Gout Despite Possible CV Risk [Internet]. Medscape. [cited 2019 Jan 16]. Available from: http://www.medscape.com/viewarticle/907633

Excerpts from: Cohen PA. Probiotic Safety—No Guarantees. JAMA Intern Med. 2018;178(12):1577–1578

Isolated live bugs are being promoted for their purported beneficial or “probiotic” properties. Claims such as these are all too common: “boosts digestive health”; “supports the immune system”; “friendly bacteria that benefit your skin, health & beauty”.

Do probiotics really work? Are there safety concerns we should be worried about?

Creative marketing and a general fascination for gut bacteria have combined to create a huge market for probiotics. Perhaps surprisingly, to sell a product that contains live microorganisms there is no legal requirement to provide evidence that it works or, importantly, that it is safe.

What is a probiotic?

The World Health Organization defines probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”

The state of the evidence

Certain live microorganisms do have well-defined health benefits, and emerging literature supports the use of select strains of bacteria and yeast to treat specific medical conditions. The yeast Saccharomyces boulardii, for example, reduces the rates of antibiotic-associated diarrhea in children and can decrease rates of recurrent Clostridium difficile infections in adults, when combined with antibiotics. Most microorganisms used in the production of food, however, do not have proven health benefits, and their safety, when sold as probiotic supplements, has not been fully established.

Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings, such as preventing C. difficile and antibiotic-associated diarrhea, widespread use, particularly among people who are healthy, has greatly outpaced the science.

Probiotics are promoted to assist healthy adults, adolescents, and children to maintain normal intestinal function and to sustain cardiovascular, respiratory, immunologic, reproductive, and even psychological health. Despite the advertised indications, there are no large, long-term clinical trials proving that probiotics offer clinical benefits for people who are already healthy.

For instance, a comprehensive review of relevant literature published earlier this year concluded that “the feasibility of probiotics consumption to provide benefits in healthy adults requires further investigation.” In other words, there may be benefits, but the evidence simply does not exist to definitively say either way.

What are the possible dangers?

Over the years, dozens of case reports have underscored the potential hazards of probiotic supplementation. Risks include fungemia and bacteremia — the presence of fungi or bacteria in the blood, respectively. Individuals with compromised immune systems are most at risk, including the very young and old. These organisms have evolved to infect, after all. Because many probiotic trials do not report adverse events sufficiently, the exact scope of this problem is not known. Aside from the risk of opportunistic infections sparked by probiotic consumption, there is the potential threat of low quality and contaminated products.

Take-home message

Consumers and physicians should not assume that the label on probiotic supplements provides adequate information to determine if consuming the live microorganism is worth the risk

Poor oral hygiene is the #1 risk factor for bad breath. In most cases, the cause can be traced to the mouth. The smell is mainly caused by volatile sulfur compounds (VSC) produced by bacteria.

The patient is often unaware of the problem and it can be worsened by mouth breathing. Transient oral malodour on awakening is a natural phenomenon.

Halitosis may cause significant social impairment, fear of social situations and social withdrawal. For most patients, halitosis may be more of a social vs medical problem.

Management of halitosis usually involves identifying and treating the specific cause. Oral hygiene should be recommended to every patient. Stimulation of salivary flow and use of refreshing mouthwashes or gargles may benefit certain patients

Causes of bad breath

Poor oral hygiene, dental caries, periodontal diseases, and difficulty in cleaning prostheses.

Reduced salivation and drying of the mouth often associated with Sjögren’s syndrome, Radiotherapy and post-operative conditions, Anticholinergic drugs

Bad-smelling nutrients, drugs, and stimulants and their degradation products e.g. Garlic, Tobacco, Alcohol, Isosorbide nitrate, Disulfiram

Infection and putrefaction involving salivary glands, tongue, ulcers and lesions of the oral mucosa

Infection of the tonsils, adenoids or lingual tonsil

Tonsillary plugs: whitish or yellowish foul-smelling grainy mass is accumulated in the tonsillary crypts and is shed by pressure on the crypt.

Retropharyngeal or nasopharyngeal accumulation of mucus and pus, adenoids (cause mouth breathing, particularly in children), maxillary sinusitis

Nasal tumours, foreign bodies, other causes increasing mouth breathing

Atrophic rhinitis and ozaena

Oesophageal diverticles, achalasia, reflux disease

Bronchitis, bronchiectasis, pulmonary empyema

Some systemic diseases namely diabetes, renal and hepatic failure

If no outside person has reported on the patient having oral malodour, the patient may suffer from a disturbance of the sense of smell or from olfactory hallucinations.

Treatment

Treatment is aetiology-specific. Severe tonsil-associated malodour problem may warrant tonsillectomy.

When no specific treatable cause is found, the management consists of attempts to increase salivary secretion, to decrease the amount of bacteria in the mouth and to mask the odour:

• Good oral hygiene, tongue brushing or scraping
• Stimulation of salivation using chewing gum or lozenges; artificial saliva
• Non-alcoholic antimicrobial mouthwashes and gargles. Mouthwashes and toothpastes containing e.g. chlorhexidine, cetylpyridinium or triclosan temporarily decrease the amount of odour-producing bacteria. Disadvantages of chlorhexidine include unpleasant taste and staining of teeth.
• Lozenges, mouthwashes and sprays intended for masking the odour have a momentary effect only.

A U.S. Food and Drug Administration (FDA) review found that fluoroquinolone antibiotics can increase the occurrence of rare but serious events of ruptures or tears in the main artery of the body, called the aorta.  These tears, called aortic dissections, or ruptures of an aortic aneurysm can lead to dangerous bleeding or even death.  They can occur with fluoroquinolones for systemic use given by mouth or through an injection.

Fluoroquinolones should not be used in patients at increased risk unless there are no other treatment options available.  People at increased risk include those with a history of blockages or aneurysms (abnormal bulges) of the aorta or other blood vessels, high blood pressure, certain genetic disorders that involve blood vessel changes, and the elderly.  We are requiring that a new warning about this risk be added to the prescribing information and patient Medication Guide for all fluoroquinolones.

Fluoroquinolone antibiotics are approved to treat certain bacterial infections and have been used for more than 30 years.  They work by killing or stopping the growth of bacteria that can cause illness.  Without treatment, some infections can spread and lead to serious health problems (see List of Currently Available FDA-Approved Systemic Fluoroquinolones).

Health care professionals should avoid prescribing fluoroquinolone antibiotics to patients who have an aortic aneurysm or are at risk for an aortic aneurysm, such as patients with peripheral atherosclerotic vascular diseases, hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and elderly patients.  Prescribe fluoroquinolones to these patients only when no other treatment options are available.  Advise all patients to seek immediate medical treatment for any symptoms associated with aortic aneurysm.  Stop fluoroquinolone treatment immediately if a patient reports side effects suggestive of aortic aneurysm or dissection.

Patients should seek medical attention immediately by going to an emergency room or calling 911 if you experience sudden, severe, and constant pain in the stomach, chest or back.  Be aware that symptoms of an aortic aneurysm often do not show up until the aneurysm becomes large or bursts, so report any unusual side effects from taking fluoroquinolones to your health care professional immediately.  Before starting an antibiotic prescription, inform your health care professional if you have a history of aneurysms, blockages or hardening of the arteries, high blood pressure, or genetic conditions such as Marfan syndrome or Ehlers-Danlos syndrome.  If you have been prescribed a fluoroquinolone to treat an infection, do not stop the antibiotic without first talking to your health care professional.

We reviewed cases reported to FDA* and four published observational studies1,2,3,4 that showed an increased risk of aortic aneurysm or dissection associated with fluoroquinolone use (see Data Summary).  How some of the studies were designed or carried out, and the ways the data were analyzed could affect the study findings; however, taken together, the results of all four studies provide consistent evidence of an association between fluoroquinolone use and aortic aneurysm or dissection.  The underlying mechanism for this risk cannot be determined from these studies, and the background risk of aortic aneurysm can vary depending on the population.  The background risk has been estimated from nine aortic aneurysm events per 100,000 people per year in the general population to 300 aortic aneurysm events per 100,000 people per year in individuals at highest risk.  Because multiple studies showed higher rates of about twice the risk of aortic aneurysm rupture and dissection in those taking fluoroquinolones, FDA determined the warnings were warranted to alert health care professionals and patients.

We communicated safety information associated with fluoroquinolones in July 2018 (significant decreases in blood sugar and certain mental health side effects), July 2016 (disabling side effects of the tendons, muscles, joints, nerves, and central nervous system), May 2016 (restricting use for certain uncomplicated infections), August 2013 (peripheral neuropathy), and July 2008 (tendinitis and tendon rupture)

Further reading: FDA Drug Safety Communication, December 20, 2018

A refresher for every clinician

Contrast media (contrast agents or dyes) are widely used as adjuncts to diagnostic visualisation techniques such as radiography (X-ray), magnetic resonance imaging (MRI), and ultrasound imaging. These agents are broadly classified based on WHO’s ATC system as shown below:

1) Radiocontrast media, Iodinated e.g., Diatrizoic acid (Amidotrizoate or Diatrizoate), Iohexol, Iopamidol, Iopromide, Iotroxic acid (or Meglumine iotroxate)

2) Radiocontrast media, Non-iodinated e.g., Barium sulfate

3) Magnetic resonance imaging (MRI) contrast media e.g., Gadobutrol, Gadopentetic acid

4) Ultrasound contrast media e.g., Optison® (GE Healthcare) – contains an albumin shell and octafluoropropane gas core

RADIOGRAPHIC OR X-RAY CONTRAST MEDIA (RADIOCONTRAST MEDIA)

Radiocontrast media are needed for delineating soft tissue structures such as blood vessels, stomach, bowel loops, and body cavities that are not otherwise visualized by standard X-ray examination. The contrast media in this group, which all contain heavy atoms (metal or iodine), absorb a significantly different amount of X-rays than the surrounding soft tissue, thereby making the exposed structures visible on radiographs.

The radiocontrast media are subdivided into iodinated (iodine-containing) and non-iodinated (metal-containing) compounds.

Radiocontrast media, Non-iodinated

Barium sulfate is a metal salt which is chiefly used for gastrointestinal imaging. It is not absorbed by the body and does not interfere with stomach or bowel secretion or produce misleading radiographic artefacts. Barium sulfate may be used in either single- or double-contrast techniques or computer-assisted axial tomography.

Single-contrast technique can be positive or negative. Positive contrast imaging is achieved by introducing a contrast medium (i.e., barium sulfate) into the GI tract to increase the density and enhance absorption of the X-rays. In negative contrast imaging, a gas (air, oxygen, or carbon dioxide) may be used to allow the X-rays to penetrate more easily. In double contrast examinations, both gas and contrast medium are used together. The gas is introduced into the GI tract by using suspensions of barium sulfate-containing carbon dioxide or by using separate gas-producing preparations based on sodium bicarbonate. Air administered through a GI tube can be used as an alternative to carbon dioxide to achieve a double-contrast effect.

Radiocontrast media, Iodinated

Iodinated contrast media all have a common functional group – tri-iodinated benzene ring. The 3 iodine atoms covalently bonded to benzene are essential for absorbing X-rays and help reduce the risk of toxic effects from free iodide. Based on the benzene ring structure and the presence (ionic) or absence (non-ionic) of carboxylate ion (-COO^–), these agents are classified into 4 categories:

• Ionic high-osmolarity monomers: one tri-iodinated benzene ring plus carboxylate ion. These agents are water-soluble, nephrotropic, high-osmolar radiocontrast media e.g., Meglumine amidotrizoate, Sodium amidotrizoate
• Ionic low-osmolality dimers: two tri-iodinated benzene rings plus carboxylate ion. These agents are water-soluble, hepatotropic, low-osmolar radiocontrast media e.g., Meglumine iotroxate
• Non-ionic low-osmolality monomers: one tri-iodinated benzene ring without carboxylate ion. These agents are water-soluble, nephrotropic, low-osmolar radiocontrast media e.g., Iohexol, Iopamidol, Iopromide
• Non-ionic iso-osmolar dimers: two tri-iodinated benzene ring without carboxylate ion. These agents are water-soluble, nephrotropic, iso-osmolar, high-viscosity radiocontrast media e.g., Iodixanol

The ionic agents have negative charge conferred by the carboxylate ion and are usually available in salt forms e.g., as sodium or meglumine salts of tri-iodinated benzoic acid.

The first-generation agents are the ionic monomeric media e.g., Amidotrizoates; available as Meglumine amidotrizoate and Sodium amidotrizoate. Although both salts have been used alone in diagnostic radiography (including computer-assisted axial tomography), a mixture of both is often preferred so as to minimize adverse effects and to improve the quality of the examination. Amidotrizoates are used in a wide range of procedures including urography, and examination of the gallbladder, biliary ducts, and spleen. Owing to their high osmolality, they are associated with a high incidence of adverse effects.

The osmolality for a given radiodensity which depends on iodine concentration, can be reduced by using an ionic dimeric medium such as Meglumine iotroxate, which contains twice the number of iodine atoms in a molecule, or by using a non-ionic monomeric media such as Iohexol, Iopamidol or Iopromide. Low osmolality radiocontrast media such as iohexol are associated with a reduction in some adverse effects (see below), but they are generally more expensive. Iohexol is used for a wide range of diagnostic procedures including urography, angiography and arthrography, and also in computer-assisted axial tomography. Meglumine iotroxate is excreted into the bile after intravenous administration and is used for cholecystography and cholangiography.

Non-ionic dimeric media (e.g., Iodixanol) have the best ratio of radiodensity to osmolality but they tend to be more viscous. Increased viscosity can make intravascular injection more difficult, especially at high flow rates. This may be less an issue for nonvascular administration. More viscous contrast media are routinely warmed to 37°C so that adequate flow rates can be attained during intravenous injection.

MAGNETIC RESONANCE IMAGING (MRI) CONTRAST MEDIA

Contrast media may be used to enhance magnetic resonance images. MR contrast agents are subdivided based on magnetic properties:

(a) Paramagnetic contrast media e.g., Gadobutrol, Gadopentetic acid, Ferric ammonium citrate

(b) Superparamagnetic contrast media e.g., Ferumoxsil, Iron oxide (nanoparticles)

Paramagnetic compounds contain gadolinium or manganese and are used as complexes or chelates to reduce their toxicity. Example of gadolinium-based contrast media is gadopentetic acid. Superparamagnetic contrast media contain coated particles of iron compounds.

ULTRASOUND CONTRAST MEDIA

Contrast agents used to enhance ultrasound imaging consist of gas-filled microbubbles which provide a gas-liquid interface that reflects sound more effectively than blood alone, allowing blood flow to be more easily detected. The microbubbles consist of air or another inert gas and an outer shell (e.g., albumin, galactose). Example of commercially available microbubble contrast agent is Optison® by GE Healthcare. It has an albumin shell and octafluoropropane gas core.

ADVERSE EFFECTS OF CONTRAST MEDIA & THEIR MANAGEMENT

Excerpts from ESUR (European Society of Urogenital Radiology) Guidelines on Contrast Media

Contrast media generally have similar adverse effect profiles, but the incidence tends to be higher with the high-osmolality agents. Osmolality depends on the iodine concentration and for a given iodine content, this is highest for the ionic monomers and lowest for non-ionic dimers.

The adverse reactions are broadly classified as non-renal and renal.

Non-renal adverse reactions

Acute adverse reactions occur within 1 hour of contrast medium injection; usually mild to moderate. Common minor adverse reactions include rash, pain at the injection site, nausea, vomiting, and minor hemodynamic changes, which are all usually self-limiting. Acute severe reactions are usually anaphylactic or anaphylactoid and the risk is usually greatest in patients with asthma, atopy, or a previous reaction to an iodinated contrast agent.

Delayed adverse reaction to intravascular iodine-based contrast medium is defined as a reaction which occurs 1 h to 1 week after contrast medium injection. Late skin reactions similar in type to other drug-induced eruptions. Maculopapular rashes, erythema, swelling and pruritus are most common. Most skin reactions are mild to moderate and self-limiting. Management is similar to other drug-induced skin reactions e.g. antihistamines, topical steroids and emollients

Very late adverse reactions usually occur more than 1 week after contrast medium injection. They may include thyrotoxicosis (due to iodine-based contrast media) and nephrogenic systemic fibrosis (or NSF, due to gadolinium-based contrast media).

NOTE: The risk of an acute reaction to a gadolinium-based MRI contrast agent is lower than the risk with an iodine-based contrast agent, but severe reactions to gadolinium-based contrast media may occur.

Delayed skin reactions of the type which occur after iodine-based contrast media have not been described after gadolinium-based and ultrasound contrast media.

Factors predisposing to nonrenal adverse reactions to contrast media

• Previous adverse reactions
• History of asthma or bronchospasm
• History of allergy or atopy
• Risk of acute reactions usually greater with high-osmolality ionic contrast media; risk of delayed reactions is higher with the non-ionic dimers.
• Cardiac disease
• Dehydration
• Haematological and metabolic conditions (sickle cell anaemia, patients with thrombotic tendency, e.g. polycythaemia, myelomatosis or phaeochromocytoma)
• Renal disease
• Neonates, very old and infirm patients
• Anxiety and apprehension
• Sun exposure may increase the risk of developing delayed cutaneous reaction
• Medications (beta-blockers, interleukin 2 (a potent stimulator of the immune system), aspirin, NSAIDs)

Guidelines for first-line treatment of acute nonrenal reactions to all contrast media

The same reactions are seen after iodine- and gadolinium-based contrast agents and after ultrasound contrast agents. The incidence is highest after iodine-based contrast agents and lowest after ultrasound agents.

Nausea/Vomiting
Transient: Supportive treatment
Severe, protracted: Appropriate antiemetic drugs should be considered.

Urticaria
Scattered, transient: Supportive treatment including observation.
Scattered, protracted: Appropriate H1-antihistamine intramuscularly or intravenously should be considered. Drowsiness and/or hypotension may occur.
Generalized: Appropriate H1-antihistamine intramuscularly or intravenously should be given. Drowsiness and/or hypotension may occur. Consider Adrenaline 1:1,000, 0.1-0.3 mL (0.1-0.3 mg) intramuscularly in adults, 50% of adult dose to pediatric patients between 6 and 12 years old and 25% of adult dose to pediatric patients below 6 years old. Repeat as needed.

Bronchospasm

1. Oxygen by mask (6-10 L/min)
2. β-2-agonist metered-dose inhaler (2-3 deep inhalations)
3. Adrenaline

Normal blood pressure
Intramuscular: 1:1,000, 0.1-0.3 mL (0.1-0.3 mg) [use smaller dose in a patient with coronary artery disease or elderly patient]
In pediatric patients: 50% of adult dose to pediatric patients between 6 and 12 years old and 25% of adult dose to pediatric patients below 6 years old. Repeat as needed.

Decreased blood pressure
Intramuscular: 1:1,000, 0.5 mL (0.5 mg),
In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intramuscularly

Laryngeal edema

1. Oxygen by mask (6 – 10 L/min)
2. Intramuscular adrenaline (1:1,000), 0.5 mL (0.5 mg) for adults, repeat as needed.

In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intra

Hypotension
Isolated hypotension

1. Elevate patient’s legs
2. Oxygen by mask (6-10 L/min)
3. Intravenous fluid: rapidly, normal saline or Ringer’s solution
4. If unresponsive: Adrenaline: 1:1,000, 0.5 mL (0.5 mg) intramuscularly, repeat as needed
   In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intramuscularly

Vagal reaction (hypotension and bradycardia)

1. Elevate patient’s legs
2. Oxygen by mask (6-10 L/min)
3. Atropine 0.6-1.0 mg intravenously, repeat if necessary after 3-5 min, to 3 mg total (0.04 mg/kg) in adults.
   In pediatric patients give 0.02 mg/kg intravenously (max. 0.6 mg per dose), repeat if necessary to 2 mg total.
4. Intravenous fluids: rapidly, normal saline or Ringer’s solution

Generalized anaphylactoid reaction

1. Ensure patent airway as needed
2. Elevate patient’s legs if hypotensive
3. Oxygen by mask (6–10 L/min)
4. Intramuscular Adrenaline (1:1,000), 0.5 mL (0.5 mg) in adults. Repeat as needed.
   In pediatric patients: 6-12 years: 0.3 mL (0.3 mg) intramuscularly; <6 years: 0.15 mL (0.15 mg) intramuscularly
5. Intravenous fluids (e.g. normal saline, Ringer’s solution).
6. H1-blocker e.g. Diphenhydramine 25-50 mg intravenously

Renal adverse reactions

Contrast-induced nephropathy (CIN) is a condition in which a decrease in renal function occurs within 3 days of the intravascular administration of a CM in the absence of an alternative aetiology. An increase in serum creatinine by more than 25% or 44 μmol/L (0.5 mg/dL) indicates CIN.

NOTE: The risk of nephrotoxicity is very low when gadolinium-based contrast media are used in approved doses.

Risk Factors for Contrast Medium-Induced Nephropathy

• Pre‐existing renal dysfunction, particularly when the reduction in renal function is secondary to diabetic nephropathy
• Conditions associated with reduced renal perfusion e.g., dehydration, CHF, myocardial infarction.
• Age over 70 due to the reduction in renal mass, function and perfusion which occurs with age
• Concurrent use of nephrotoxic drugs e.g., NSAIDs and aminoglycosides, potentiates the nephrotoxic effects of contrast media
• Intra-arterial administration of contrast medium. Intrarenal concentration of contrast media is much higher immediately after intra‐arterial injection than after intravenous administration
• High osmolality agents
• Large doses of contrast medium
• Multiple contrast medium administrations within a few days

DRUG INTERACTIONS

Co-administration of Iodine-based contrast media with Metformin

Metformin and iodine-based contrast media are eliminated via the kidneys. Administration of contrast agents in patients receiving Metformin can precipitate lactic acidosis, especially in patients with abnormal renal function. Symptoms of lactic acidosis include vomiting, somnolence, nausea, epigastric pain, anorexia, hyperpnoea, lethargy, diarrhoea and thirst.

Below is an outline of ESUR guideline recommendations for the use of iodinated contrast agents in patients receiving Metformin:

• Patients (eGFR ≥60 mL/min/1.73m²): Continue Metformin normally
• Patients receiving intravenous contrast medium (eGFR ≥45 mL/min/1.73 m²): Continue Metformin normally
• Patients receiving intra-arterial or intravenous contrast medium (eGFR 30-44 mL/min/1.73 m²): Stop Metformin 48 h before contrast medium and only restart Metformin 48 h after contrast medium if renal function has not deteriorated
• Patients (eGFR <30 mL/min/1.73 m² or with an intercurrent illness causing reduced liver function or hypoxia): Metformin is contra-indicated and iodine-based contrast media should be avoided.
• Emergency patients: Metformin should be stopped from the time of contrast medium administration. After the procedure, the patient should be monitored for signs of lactic acidosis. Metformin should be restarted 48 h after contrast medium if serum creatinine/eGFR is unchanged from the pre-imaging level.

NOTE: No special precautions are necessary when diabetic patients on metformin are given gadolinium-based contrast medium

Interaction with other drugs

• Nephrotoxic drugs: Cyclosporine, Cisplatin, Aminoglycosides, NSAIDs
• Beta-blockers: β-blockers may impair the management of bronchospasm and the response to adrenaline
• Do not mix contrast media with other drugs in tubes and syringes

References:

1. Pasternak JJ, Williamson EE. Clinical Pharmacology, Uses, and Adverse Reactions of Iodinated Contrast Agents: A Primer for the Non-radiologist. Mayo Clin Proc. 2012 Apr;87(4):390–402.
2. European Society of Urogenital Radiology [Internet]. [cited 2018 Nov 16]. Available from: http://www.esur.org/guidelines/
3. Thomsen HS, Morcos SK. Radiographic contrast media: Radiographic Contrast Media. BJU Int. 2002 Jan 2;86:1–10

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.

Aemcolo is rifamycin SV engineered with the MMX® technology which allows the antibiotic to be delivered directly into the colon, avoiding unwanted effects on the beneficial bacterial flora living in the upper portions of the gastrointestinal tract. The specific dissolution profile of Aemcolo tablets is thought to increase the colonic disposition of the antibiotic so that an optimized intestinal concentration is achieved thus abating its systemic absorption in the small intestine.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.

The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.

The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP) designation. QIDP designation is given to antibacterial and antifungal drug products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame

The study funded by Canadian Institutes of Health Research showed that a pharmacist-led educational intervention resulted in greater discontinuation of inappropriate prescriptions compared with usual care after 6 months.

Key Points

Question: Can a consumer-targeted, pharmacist-led educational intervention reduce prescriptions for inappropriate medication among community-dwelling older adults?

Findings: In this cluster randomized trial that included 489 older adults, the percentage achieving discontinuation of a targeted inappropriate prescription at 6 months was 43% among patients receiving the intervention vs 12% receiving usual care, which represents a significant difference.

Meaning: A pharmacist-led intervention has the potential to reduce prescriptions for inappropriate medication in older adults.

Introduction

Inappropriate prescriptions continue to be frequently dispensed to older adults. It has been estimated that 29.0% of Medicare beneficiaries aged 65 years and older in the United States in 2015 and 31.1% of older adults in Canada in 2016 filled a prescription for at least 1 medication included in the 2015 American Geriatrics Society Beers Criteria list of drugs to avoid in older adults. Labelled as inappropriate because of the risk of harm and availability of safer treatments, inappropriate prescriptions can lead to adverse drug events, falls, cognitive impairment, and emergency hospitalizations.

Deprescribing is the act of reducing or stopping medication that is no longer necessary or that may cause harm. Primary care physicians express a lack of time, poor awareness of the harms of medications, and fear of withdrawal symptoms or patient criticism as barriers to deprescribing. Pharmacists can assist physicians in optimizing medication management in older adults. Medication reviews by a pharmacist followed by direct communication to the prescribing physician have been shown to result in safer prescribing practices. Patients can also initiate the deprescribing process. In a randomized clinical trial of 303 long-term users of benzodiazepine medications, providing education about the risks of benzodiazepine use compared with providing usual care resulted in an additional 23% of patients discontinuing their medication within 6 months. Patients who elected not to taper their medication cited physician or pharmacist discouragement as the major impediment. Streamlining communication and deprescribing efforts among patients, physicians, and pharmacists may augment shared accountability for safer prescribing while maintaining patient trust.

The objective of the D-PRESCRIBE (Developing Pharmacist-led Research to Educate and Sensitize Community Residents to the Inappropriate Prescriptions Burden in the Elderly) cluster randomized trial was to determine the effectiveness of a pharmacist-led intervention to educate older adults and their physicians about reducing inappropriate prescriptions.

Access to the full article available on JAMA Network

Sandoz Inc. Issues Voluntary Nationwide Recall of One Lot of Losartan Potassium and Hydrochlorothiazide Due to the Detection of Trace Amounts of NDEA (N-Nitrosodiethylamine) Impurity Found in the Active Pharmaceutical Ingredient (API)

FDA is alerting patients and health care professionals to Sandoz’s voluntary recall of one lot – JB8912 – of losartan potassium and hydrochlorothiazide 100mg/25mg tablets, that contain losartan, an angiotensin II receptor blocker (ARB), and hydrochlorothiazide, a diuretic, used in combination for the treatment of hypertension. Sandoz’s product was made using an active pharmaceutical ingredient (API) that has tested positive for NDEA. The API was manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd, which is on import alert.

Sandoz’s losartan drug products make up less than 1% of the total losartan drug products in the U.S. market.

FDA continues to investigate the presence of NDEA and NDMA, which are probable human carcinogens, in ARBs and is taking swift action when it identifies unacceptable impurities in API and finished drug products.

FDA reminds patients taking this medication or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDEA or NDMA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition

Full text of the company announcement available here