THE NATIONAL PHARMACOVIGILANCE CENTER

SPECIAL POINTS OF INTEREST: 1. 2. 3. 4. 5. 6. Public Health Risk with Herbal Medicines Fluoroquinolones Drug Interactions Understanding CYP450 Glutathione Paracetamol in children

ALERTO
Volume 1 Issue 2

SIGNALS

December 2011

INSIDE THIS ISSUE: Simvastatin Avastin Drospirenone Pioglitazone Dabigatran

2 2 2 3 4

Public Health Risk with Herbal Medicines

any plants are potent or toxic. Indeed, many pharmaceutical medicines, ranging from aspirin to digoxin, have their origins in the isolation of active chemical constituents in particular plants. In considering issues of safety it is essential not make the common mistake of confusing herbal medicine with homoeopathy. Homeopathy is defined as A system of therapy based on the concept that disease can be treated with drugs (in minute doses) thought capable of producing the same symptoms in healthy people as the disease itself. There may be an erroneous perception in some quarters that the practice of herbal medicines poses few safety issues. In fact, given that in some practitioners, who may be inexpert, are supplying potentially powerful unlicensed herbal medicinal products, the range of opportunities for things to go wrong is significantly greater than is the case with many other complementary and alternative medicine therapies. It is important to note that use of herbal medicine is not restricted to the worried well or to use by people with minor or transient conditions. Studies show that complementary and alternative medicine (CAM) use in patients with cancer is high and this usage is increasing. It has been reported that over 40% of breast cancer patients and over 20% of the patients with lung cancer in Europe use CAM. In all of these surveys herbal medicine was the commonly used form of CAM. There is clear evidence, e.g.from clinic leaflets and websites, that many practitioner treat patients with serious medical conditions including heart disease, cancer, diabetes and asthma. Some practitioners treat particularly vulnerable groups, such as babies and children, or the terminally ill. A substantial area of usage of herbal medicines is to treat or relieve the symptoms of chronic, difficult-to-treat conditions, for example eczema.

Fluoroquinolones
The flouroquinolones have become an increasingly popular class of antibiotics for use in a variety of infections. Newer drugs in this class have been developed with a broader spectrum of activity including better coverage of gram-positive organisms and, in one, case, even anaerobes. However, toxicities have been associated with some of these newer agents. Gatifloxacin was withdrawn because of an increased frequency of hypoglycemia and hyperglycemia compared to other marketed flouroquinolones. Trovafloxacin was withdrawn because of the risk of hepatic toxicity.

This will often occur in cases where patients have not been satisfied with the results of conventional medication (e.g. they dont like the side effects) and therefore in some cases there may be long term usage of herbal medicine. Surveys show that the use of herbal medicines by older patients is increasing and that typically more than one herbal product is used at a time, often concomitantly with prescription medicines. Older patients are often reluctant to tell their doctor that they are taking herbal products and so are at risk of potential drug-herb interactions. The main areas of risk with herbal medicines include: Delay in effective treatment Interference with vital treatment Exploitation of vulnerable groups such as children and the seriously ill Overloading patient with multiple medications Unexpected rare but serious liver toxicity of plants Toxic plants used Side effects Interactions Wrong, toxic, plant used Adulteration with pharmaceutical substances. Addition of analogues of pharmaceutical substances Addition of heavy metals/toxic elements as ingredients Contamination Confusion over standards Weak of missing information, and Communications
CONTINUED ON PAGE 2

Flouroquinolones are associated with an increased risk of tendinitis and tendon rupture. This is risk is further increase in those over age 60, in kidney, heart, and lung transplant patients and with use of concomitant steroid therapy. Physicians should advise patients, at the first sign of tendon pain, swelling, or inflammation to stop taking the drug. These drugs should only be used for the treatment/prevention of infections proven or strongly suspected to be caused by bacteria. Patients with a rare condition known as myasthenia gravis who take a flouroquinolone antibiotic may risk a worsening of their symptoms, including muscle weakness or breathing problems. The risk of this happening is considered rare, but serious. Use of this antibiotic with myasthenia gravis should be avoided.

Simvastatin
The US FDA has issued an advisory regarding the use of high dose simvastatin, a well known cholesterol lowering medication. The FDA recommends that theuse of drugs containing 80 mg simvastatin the highest approved dose should be sharply curtailed because of the risk of muscle injury. According to FDA, this dose should only be used by patients who have been taking the drug for 12 months or longer without ill effects. All statins, despite their proven benefit in lowering the risk of heart attacks and strokes, carry some risk of an injury called myopathy, characterized by unexplained muscle weakness or pain. But the risk is greater for patients who take the 80 mg doses of simvastatin, especially in the first year of treatment. The muscle damage is often the result of certain medicines, and is frequently associated with a genetic predisposition toward simvastatin-related myopathy. Patients with myopathy generally have muscle pain, tenderness or weakness, and an elevation of a muscle enzyme in the blood (creatine kinase, or CK). The most serious form of myopathy, called rhabdomyolysis occurs in 4.9 people out of every 100,000 people exposed to simvastatin for one full year (the average incidence for hospitalized rhabdomyolysis for atorvastatin, pravastatin, or simvastatin is 4.4 people out of every 100,000 people exposed to the drugs for one full year. Simvastatin 80 mg should not be started in new patients, including patients already taking lower dose of the drugs The labels for simvastatin has been revised to include the new dosing restriction for the 80 mg dose.
Drug Safety Communication, FDA 2011

Cont. HERBAL MEDICINES

1. Perception that natural equates safe and therefore many herbal medicine users would not realize that a herbal remedy may be responsible for symptoms they have experienced. 2. Reluctance of patients to tell their doctor about a herbal remedy they are taking so the doctor never suspects that their patients symptoms might be linked to the herbal product. 3. Herbal practitioners are largely supplying unlicensed products on a private basis; there may therefore be an inbuilt disincentive for less responsible practitioners to report patient side effects lest this affects adversely on them personally.
MHRA Overview of Public Health Risk with Herbal Medicines

Bevacizumab (Avastin)
Ms. Margaret Hamburg, USFDA Commissioner recently issued a decision to revoke the agencys accelerated approval of the breast cancer indication for Bevacizumab (Avastin), manufactured by Genentech. Based on post market clinical studies following FDA review, it was concluded that the drug has not shown to provide a benefit, particularly delay in the growth of tumors, that justifies its serious and potentially life-threatening risks. Further, the studies did not provide evidence that the use of Avastin will either help women with breast cancer live longer or improve their quality of life. The decision involved Avastin used in combination with the cancer drug paclitaxel for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative. This indication must now be removed from Avastinns product labeling. Meanwhile, in another development, a recently published study NSAPBP-CO8, found that the incidence of new cases of ovarian failure (defined as amenorrhea lasting 3 or more months, FSH level 30 mIU/mL and a negative serum -HCG pregnancy test) is higher in pre-menopausal women treated with Avastin. In a prospectively designed sub study of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared with the control arm (2%) After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin treated patients. Avastin will still remain in the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (gliblastome multiforme). USFDA/ Medwatch

Drospirenone
Health Canada has completed a safety review of drospirenone-containing oral contraceptives (marketed under the brand names Yasmin and Yaz) with respect to the risk of blood clots (venous thromboembolism, or VTE). The review determined that drospirenone-containing birth control pills may be associated with a risk of blood clots that is 1.5 to 3 times higher than other birth control pills. Blood clots are a rare but well known side effect associated with all birth control pills. Patients should talk to their healthcare professional about their risk for blood clots before deciding which birth control pill to use. Known risk factors that increase the risk of a blood clot include smoking, being overweight (obesity), and family history of blood clots, in addition to other factors that contraindicate use of birth control pills. Doctors must consider the risks and benefits of drospirenone-containing combination oral contraceptives before prescribing to their patients.

a cheerful heart is good medicine.

Prov.17:22

Avoiding Drug Interactions

Everyone responds to drugs differently. The way a person responds to a drug is affected by many factors, including genetic makeup, age, body size, the use of other drugs and dietary supplements (such as medicinal herb. The consumption of food (including beverages), the presence of diseases (such as kidney or liver disease), storage of the drug (whether the drug was stored too long or in the wrong environment), and the development of tolerance and resistance. The effect a drug has on a person may be different than expected because that interacts with, 1) another drug the person is taking (drug-drug interaction); 2) Food, beverages, or supplements the person is consuming (drug-nutrient interaction) or 3) another disease the person has (drug-disease interaction). The effects of drug interactions are usually unwanted and sometimes harmful. Interactions may increase or decrease the actions of one or more drugs, resulting in adverse effects or failed treatment. Some tips to reduce the risk of interactions are: 1. 2. 3. 4. 5. Consult the doctor before taking new drugs, including over-the-counter, supplements or herbals. Always read drug labels carefully. Learn about the warnings for all the drugs you take. Keep medications in their original containers for easy identification. Ask your doctor what you need to avoid when you are prescribed a new medication. 6. 7. 8. Ask about food, beverages, dietary supplements, and other drugs. Use one pharmacy for all your drug needs. Keep a list of all drug (OTC, prescription, herbals, supplements) that you take. Report to the doctor or pharmacist any symptom that might related to the use of the drug.

The rate of adverse drug reactions increases dramatically with four or more medications. Be informed about the warnings for your medications to lower risk of possible food-drug, drug-drug inter-actions. Drug Interactions Merck Manual

Pioglitazone
The European Medicines Agency (EMA), following its review of antidiabetic pioglitazone-containing medicines and the occurrence of bladder cancer, has confirmed that there is small increased risk of bladder cancer in patients taking these medicines. The small increased risk could be reduced by appropriate patient selection and exclusion, including a requirement for periodic review of the efficacy and safety of the individual patients treatment. Nevertheless, these medicines remain a valid treatment option for certain patients with type 2 diabetes. The increased risk for bladder cancer was noted among patients with the longest exposure to pioglitazone, and in those exposed to the highest cumulative dose of the drug. Prescribers are advised not to use these medicines in patients with current or a history of bladder cancer or inpatients with uninvestigated macroscopic hematuria. Risk factors for bladder cancer should be assessed before inititating pioglitazone treatment. In light of age-related risks, the balance of benefits and risks should be considered carefully both before initiating and during treatment in the elderly. Prescribers should review the treatment of patients on pioglitazone after three six months (and regularly afterwards) to ensure that only patients who are deriving sufficient benefit continue the treatment.

EMA Press release USFDA Safety Announcment

Understanding an Enzyme:
Cytochrome P450 3A4 (abbreviated CYP3A4), a member of the cytochrome P450 mixedfunction oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in the largest quantity of all the CYPs in the liver. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene.[1] This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. It has been estimated that CYP3A4 metabolizes about half of all drugs on the market. Because many other commonly used drugs are moderateto-potent inhibitors of CYP3A4, it is not surprising that drug toxicity of CYP3A4 substrates due to inhibition of CYP3A4 is relatively common. CYP3A4 also is sensitive to enzyme induction, and a number of drugs are known to be CYP3A4 inducers. CYP3A4 inducers tend to lower plasma concentrations of CYP3A4 substrates, resulting in reduced efficacy of the substrate. This type of drug interaction is probably more frequent than commonly realized, because reduced drug effect may simply be attributed to lack of patient response. Many drugs that are CYP3A4 substrates, inhibitors, and inducers are also substrates, inhibitors, or inducers of the ABC transport protein known as P-glycoprotein. Many drug interactions, therefore, involve additive effects of both CYP3A4 and P-glycoprotein.

CYP3A4 Substrates
Drugs metabolized by CYP3A4 are called CYP3A4 substrates. Keep in mind that many drugs are metabolized by more than one CYP450 enzyme, and CYP3A4 may represent only one pathway. Unfortunately, many CYP3A4 substrates have substantial toxicity, and some patients may develop severe toxicity when CYP3A4 inhibitors are taken concurrently. A selected list of such interactions appears in the Table. 1
See INSERT

Horn & Hansten pharmacytimes.com

DOH-FDA Advisory
No. 2011-004 Subject: Safety on the Off-label Use of Glutathione Solution for Injection (IV)

Dabigatran and the risk of bleeding

Warning to the Public:
Dabigatran is a potent short-acting anticoagulant for which there is no antidote or reversal agent. As with warfarin, bleeding events can occur. Clinicans are urged to give careful consideration to the suitability of their patients for dabigatran particularly with regar to recognized risk of bleeding. Dabigatran, a potent oral anticoagulant, is a direct thrombin inhibitor that inhibits free and clot-bound thrombin. It has a mean half-life of 1 2-17 hours. It is excreted by the kidneys and the rate of elimination is related to renal function. There is a close correlation between plasma dabigatran levels and anticoagulant effect. Dabigatran may be considered an alternative to warfarin and it carries similar risks of bleeding. In clinical trails the risk of bleeding per year of treatment with dabigatran was 16.6% (1 in 6 patients) when taking 150 mg twice daily, and 14.&% (1 in 6.8 patients) taking 110 mg twice daily compared with 18.4% (1 in 5.4 patients) for warfarin. The most common site of serious bleeding for dabigatran is the gastro-intestinal tract. The risk factors for bleeding are: Age 75 years Moderate renal impairment (30-50mL/min) - severe renal impairment is a contraindication Concomitant use of aspirin (approximately twice the risk), clopidogrel (approximately twice the risk), nonsteroidal anti-inflammatory drugs including COX-2 inhibitors. Inform your doctor if patients on this drug develop any signs or symptoms of bleeding such as: Unusual bleeding from gums, frequent nose bleeds, pink of brown urine, bruises without a known cause, red or black stools. Medicines Safety Update Vol.2 No. 6 Dec. 2011

The use of glutathione IV as a skin whitener is not approved by the FDA. The public is strongly warned to refrain from using glutathione for this purpose in light of potential harm associated with such use. The alarming increase in the unapproved use of glutathione administered intravenously as a skin-whitening agent at very high doses is unsafe and may result in serious consequences to the health of the users. There is inadequate safety documentation on the use of high doses of glutathione administered at 6000 mg to 1.2 grams once weekly and even up to twice weekly. The only approved indication of the intravenous format of glutathione is as adjunctive treatment to reduce neurotoxicity associated with Cisplatin chemotherapy. Adverse drug reactions resulting from the use of glutathione IV for skin whitening have been reported and include the following: 1. 2. 3. 4. 5. Reports of adverse drug reactions ranging from skin rashes to the serious and potentially fatal Stevens Johnson Syndrome and Toxic Epidermal Necrolysis. Derangements in the thyroid function. Suspected kidney dysfunction potential resulting in kidney failure. Severe abdominal pain in a patient receiving twice-weekly glutathione administered intravenously have been reported. Incorrect technique in intravenous administration especially in association with administration by untrained persons can result in the following: introduction of harmful micro-organisms injection of air leading to embolus, transmission of hepatitis and even HIV with unsafe needles. Counterfeiting of glutathione has been reported and may lead to non-sterile preparations which could lead to serious infections.

6.

Giving paracetamol in children linked to asthma

A new study conducted in New Zealand has now found that young children given paracetamol may be at greater risk of asthma and allergies. Julian Crane, a professor at Otago University in Wellington and author of the report, said: The problem is that paracetamol is given quite liberally to young children. The research, published in the journal Clinical and Experimental Allergy tracked almost 1500 children as part of the cohort study. The major finding is that children who used paracetamol before the age of 15 months (90%) were more than 3x likely to become sensitised to allergens and 2x as likely to develop symptoms of asthma at six years old than children not using paracetamol. The current WHO recommendations for the management of fever in children include the use of paracetamol for children with fever of 39 C . The Telegraph Nov. 2010

Adverse Drug ReactionBANTAYAN I-REPORT AGAD SA FDA PARA MAAKSYONAN!

All suspected reactions to drugs especially drugs of curent interest * All suspected drug interactions * Reactions to drugs suspected to significantly affect patients management including reactions suspected of causing: Death Danger to life Admission to hospital or prolonged stay Absence from productive activity Increased investigational or treatment costs Birth defects

For your REPORTS, comments/suggestions, write , call or e-mail: Phone: Fax:: (632) 807-07-00 (632) 807-07-51 (DIRECTORs office) cynchdiza@yahoo.com

What needs reporting?

E-mail:

Download ADR Form from FDA website: www.fda.gov.ph

Blessed are those whose ways are blameless, who walk according to the law of the Lord.. Psalm 119:1