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Safety Assessment & Monitoring of Marketed Medicine including Cosmetics and Herbal Drugs Professor : S.S.Agrawal Professor S.S.Agrawal (Delhi Pharmaceutical.

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Presentation on theme: "Safety Assessment & Monitoring of Marketed Medicine including Cosmetics and Herbal Drugs Professor : S.S.Agrawal Professor S.S.Agrawal (Delhi Pharmaceutical."— Presentation transcript:

1 Safety Assessment & Monitoring of Marketed Medicine including Cosmetics and Herbal Drugs
Professor : S.S.Agrawal Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

2 A- Definition & Concept
Safety Assessment/Monitoring of Marketed Medicine:(SAMMM) is defined as ‘ a formal Investigation conducted for the purpose of assessing the clinical Safety of Marketed Medicine(s) in clinical Practice. Pharmacovigilance: The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. It deals with Quality, Safety and Efficacy of the Drugs- including monitoring and Reporting. Pharmacovigilance Quality Safety Efficacy Reporting Monitoring of ADR Adverse Drug Reaction: A response which is noxious an unintended and which occurs at doses normally used in humans for prophylaxis , diagnosis or therapy of disease, or for the modification of physiological function (WHO, 1972). Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

3 Need to broaden the scope of Pharmacovigilance
ADRs due to adulterations in Herbal drugs should be included in the Pharmacovigilance and should be termed as HERBOVIGILANCE. ADRs due to adulterations of Heavy metals in Cosmetics should be included in the pharmacovigilance and should be termed as COSMETOVIGILANCE - As Cosmetics are covered under Drugs And Cosmetics Act , moreover Cosmetics are consumed even by Healthy People whereas Drugs are consumed only by Patients. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University)

4 Need to Carry out SAMM At the time of Approval –information about the safety is limited. Due to Short duration of study. Limited Number of People in Trials. Such Studies increase variety of Database as: It may include patients with Co-morbidity Concomitant illness Chronic illness. After Marketing New Safety Information's will be Available through Such Studies: New ADRs Pregnant , elderly Off label Indication Compliance Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

5 Need To carry out SAMM contd.
ACTUAL Effect is observed during Clinical Trials BUT SAFETY is observed During Post Marketing Surviellance (PMS) . Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University)

6 List of Drugs Withdrawn from the market as a consequence of SAMM
Thalidomide(1950s–1960s)Withdrawn because of risk of teratogenicity; returned to market for use in leprosy and multiple myeloma under FDA orphan drug rules Lysergic acid diethylamide (LSD)(1950s–1960s) Marketed as a psychiatric cure-all; withdrawn after it became widely used recreationally Diethylstilbestrol(1970s) Withdrawn because of risk of teratogenicity Methaqualone (1984)Withdrawn because of risk of addiction and overdose Phenformin and Buformin(1978) Withdrawn because of risk of lactic acidosis Phenacetin(1983) An ingredient in "A.P.C." tablet; withdrawn because of risk of cancer and kidney disease Triazolam(1991W0ithdrawn in the United Kingdom because of risk of psychiatric adverse drug reactions. This drug continues to be available in the U.S. Temafloxacin(1992)Withdrawn in the United States because of allergic reactions and cases of hemolytic anemia, leading to three patient deaths. Alpidem (Ananxyl)(1996) Withdrawn because of rare but serious hepatotoxicity. Terfenadine (Seldane, Triludan)(1998 )Withdrawn because of risk of cardiac arrhythmias; superseded by fexofenadine Tolcapone (Tasmar)(1998 )Hepatotoxicity Temazepam (Restoril, Euhypnos, Normison, Remestan, Tenox, Norkotral)(1999) Withdrawn in Sweden and Norway because of diversion, abuse, and a relatively high rate of overdose deaths in comparison to other drugs of its group. This drug continues to be available in most of the world including the U.S., but under strict controls. Astemizole (Hismanal)(1999) Arrhythmias because of interactions with other drugs Troglitazone (Rezulin)(2000) Withdrawn because of risk of hepatotoxicity; superseded by pioglitazone and rosiglitazone Cisapride (Propulsid)(2000) Withdrawn in many countries because of risk of cardiac arrhythmias Phenylpropanolamine (Propagest, Dexatrim)2000 Withdrawn because of risk of stroke in women under 50 years of age when taken at high doses (75mg twice daily) for weight loss. Cerivastatin (Baycol, Lipobay)(2001) Withdrawn because of risk of rhabdomyolysis Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University)

7 Food Drug Interaction CONTD.
Rofecoxib (Vioxx)(2004) :Withdrawn because of risk of myocardial infarction Thioridazine (Melleril)(2005): Withdrawn from U.K. market because of cardiotoxicity Natalizumab (Tysabri)( ):Voluntarily withdrawn from U.S. market because of risk of Progressive multifocal leukoencephalopathy (PML): Returned to market July, 2006. Pergolide (Permax)(2007):Voluntarily withdrawn in the U.S. because of the risk of heart valve damage. Still available elsewhere. Inhaled insulin (Exubera)(2007):Withdrawn in the UK due to poor sales caused by national restrictions on prescribing, doubts over long term safety and too high a cost Rimonabant (Accomplia)(2008):Withdrawn around the world because of risk of severe depression and suicide Efalizumab (Raptiva)(2009):Withdrawn because of increased risk of progressive multifocal leukoencephalopathy; to be completely withdrawn from market by June 2009 Sibutramine (Reductil)(2010):Withdrawn in Europe and Australasia because of increased cardiovascular risk. This drug continues to be available in the U.S. Gemtuzumab ozogamicin (Mylotarg)(2010)Withdrawn in the U.S. due to increased risks of veno-occlusive disease and based on results of a clinical trial in which it showed no benefit in acute myeloid leukemia (AML) Rosiglitazone (Avandia)(2010)Withdrawn in Europe because of increased risk of heart attacks and death. This drug continues to be available in the U.S. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

8 B- Methodologies involved
Spontaneous Reporting Systems Case Reports Case Control Studies Cohort studies Randomized Clinical Trials Database research and Monitoring Meta Analysis Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

9 Spontaneous Reporting System
Food Drug Interaction CONTD. Spontaneous Reporting System By Healthcare Professional or Consumer To Company , Regulatory Authority or Other organisation (WHO, Regional centre , Poison control Centres) Through WHO international System US FDA MedWatch UK ‘Yellow Card “ system National Pharmacovigilance System : India Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

10 Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU )

11 Case Reports Reported by Practioners to share their indiviual experiences Eg: Phentermine and Fenfluramine. When given in combination for weight loss produced valvular defects in women : therefore withdrawn from the market. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

12 Case Control Studies Analytical , Retrospective study comparing People with a particular Disease with Controls. Essential for Reno- compromised and Hepato-compromised patients. Cross sectional Studies: To study prevalence : Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University -DPSARU)

13 Cohort Studies A group of Individuals are identified, charecterised and followed over time to determined the incidence of some predetermined outcome. Control Cohort Studies Uncontrolled Cohort Studies Types: Prospective : Reason may be convenience. Retrospective Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

14 Other Methodologies Randomised Clinical Trials
Two or more treatment groups and controls are given treatment with active drug and , placebo or both. Database research and monitoring Computerised Databases are used to analyse drug histories with medical records – This allows to design cost effective studies. Meta Analysis When two or more individual studies are combined into one large study. This is done to bring an outcome of the study which was not possible with the single study. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

15 C- Other Avenues Which cannot be Ignored
Herbal Drug Interactions. Food Drug Interactions. Drug Drug Interaction. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

16 Herbal drugs interactions
S.No Herbal Product Uses: Interactions 1. Hawthorn Anti-Cholestrol (Angina) Should be avoided with Digoxin, reduces Heart rate to dangerous levels. 2. Ginseng It increase Blood Pressure. Produces Insomnia Should be avoided with Blood thinning drugs/agents such as garlic , ginger . It should also be avoided with caffeine. 3. Garlic Carminative . Blood Thinner. Anti Diabetic Decrease the blood glucose levels to extremely low levels. Should be avoided with Anticoagulants. 4. Goldenseal Cough ,Stomach upset,menstrual problems and arthirits It should be avoided with Beta Blockers. 5. Feverfew Migraine Should be avoided with Imitrex (Anti-Migraine) as this combination increases Heart Rate and B.P. 6. Gaurana CNS stimulant Causes insomnia, anxiety,palpitation, hyperactivity when taken in combination with cafeine. 7. Kava Antianxiet, Pain Relieving , Muscle relaxant,Anticonvulsant Should be avoided with CNS drugs such as alcohol,barbiturates , antidepressant, Antipsychotic. 8. St.John’s Wart Mild Depression Contains Hpericin(Structrually similar to MAO inhibitors) causes excessive stimulation and Dizziness. 9. White Willow Headache, Pain May lead to G.I irritation, Stomach ulcers 10 IsabGul Anti-Diarrheal Entraps Antibiotics and decreases their activity. 11 Grape Juice Enzyme inducer Degrades many common drugs and decrease their action. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU )

17 Food Drug interactions
S.No Drugs Interactions Anti biotics 1 Cephalosporins, penicillin Take on an empty stomach to speed absorption of the drugs. 2 Erythromycin Don't take with fruit juice or wine, which decrease the drug's effectiveness. 3 Sulfa drugs Increase the risk of Vitamin B-12 deficiency 4 Tetracycline Dairy products reduce the drug's effectiveness. Lowers Vitamin C absorption AntiDepressant 5 Fluoxetine Reduce appetite and can lead to excessive weight loss 6 Lithium A low-salt diet increases the risk of lithium toxicity; excessive salt reduces the drug's efficacy 7 MAO Inhibitors Foods high in tyramine (aged cheeses, processed meats, legumes, wine, beer, among others) can bring on a hypertensive crisis. 8 Tricyclics Many foods, especially legumes, meat, fish, and foods high in Vitamin C, reduce absorption of the drugs. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU )

18 Food Drug Interaction CONTD.
S.No Drugs Interactions Anticonvulsants 9. Dilantin, phenobarbital Increase the risk of anemia and nerve problems due to deficiency of folalte and other B vitamins. Antihypertensives, Heart Medications 10. ACE inhibitors Take on an empty stomach to improve the absorption of the drugs. 11. Alpha blockers Take with liquid or food to avoid excessive drop in blood pressure. 12. Antiarrhythmic drugs Avoid caffeine, which increases the risk of irregular heartbeat. 13. Beta blockers Take on an empty stomach; food, especially meat, increases the drug's effects and can cause dizziness and low blood pressure. 14. Digitalis Avoid taking with milk and high fiber foods, which reduce absorption, increases potassium loss. 15. Diuretics Increase the risk of potassium deficiency. 16. Potassium sparing diuretics Unless a doctor advises otherwise, don't take diuretics with potassium supplements or salt substitutes, which can cause potassium overload. 17. Thiazide diuretics Increase the reaction to MSG. Asthma Drugs 18. Pseudoephedrine Avoid caffeine, which increase feelings of anxiety and nervousness. 19. Theophylline Charbroiled foods and high protein diet reduce absorption. Caffeine increases the risk of drug toxicity.

19 Cholesterol Lowering Drugs Heartburn and Ulcer Medications
Food Drug Interaction –CONTD. S.No Drugs Interactions Cholesterol Lowering Drugs 20. Cholestyramine Increases the excretion of folate and vitamins A, D, E, &K. 21. Gemfibrozil Avoid fatty foods, which decrease the drug's efficacy in lowering cholesterol. Heartburn and Ulcer Medications 22. Antacids Interfere with the absorption of many minerals; for maximum benefit, take medication 1 hour after eating. 23. Cimetidine, Fanotidine, Sucralfate Avoid high protein foods, caffeine, and other items that increase stomach acidity. Hormone Preparations 24. Oral contraceptives Salty foods increase fluid retention. Drugs reduce the absorption of folate, vitamin B-6, and other nutrients; increase intake of foods high in these nutrients to avoid deficiencies. 25. Steroids Salty foods increase fluid retention. Increase intake of foods high in calcium, vitamin K, potassium, and protein to avoid deficiencies. 26 Thyroid drugs Iodine-rich foods lower the drug's efficacy. Pain Killers 27 Aspirin and stronger non-steroidal anti-inflammatory drugs Always take with food to lower the risk of gastrointestinal irritation; avoid taking with alcohol, which increases the risk of bleeding. Frequent use of these drugs lowers the absorption of folate and vitamin C. 28. Codeine Increase fiber and water intake to avoid constipation. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University- DPSARU)

20 Drug + Drug Interactions
Mechanism of Drug Drug Interactions Pharmacokinetic interactions Absorption Distribution Biotransformation*** Excretion Pharmacodynamic interactions Receptor interaction Receptor sensitivity Neurotransmitter release/Drug transportation Electrolyte balance Physiological interactions Pharmaceutical interactions Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

21 Drug + Drug Interactions CONTD.
List of drug the most common interacting drug Ketoconazole Antacids Cimetidine Digoxin Warfarin Theophylline Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU )

22 D- Work Done at DIPSAR Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University)

23 I- Presence of Heavy Metals in Cosmetics
Food Drug Interaction CONTD. I- Presence of Heavy Metals in Cosmetics Results Lipstick : out of Sixteen brands 12 were found to contain Heavy metals . Eg: REVLON and ELLE-18. Talcum Powder: Out of 10 brands 5 were found to contain heavy metals Eg: Nycil, Dermicool , Spinz , Spice. Godrej cinthol. Shampoos : Out of 7 , four brands contained heavy metals. Eg: Heads and Shoulder , Clinic All Clear and Pantene. KAJAL: Out of 15 brands , 14 were found to contain Heavy metals: Eg: Revlon , Sheetal , Lakme . Hair Colors : Out of 11 brands 7 were found to contain heavy metals: Eg: Super Vasmol , Black Rose , Godrej and Streax. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

24 Presence of Heavy Metals in Cosmetics
Violation of Laws Violation of Drugs and Magic Remedies Act Standards of BIS (Bureau of Indian Standards) not Followed. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

25 28 Days Sub Acute Toxicity Study In Rats
Studies was performed as per OECD guidelines 407 for chemicals study approved by the IAEC of DIPSAR vide approval no- IAEC/2010/018 Dose selected As per the research paper (loretz et al ,2005)dose selected for study are 1.4 and 2.8 mg/kg body weight. Administration Lipstick suspension were administered by oral gavage once daily for 28 days.

26 Toxic effect of lipstick seen in our studies on rat’s liver.
B Control Lipstick sheel group A slide section liver showing a normal portal triad in the liver parenchyma. PV = Portal Vein, BD = Bile Duct (HE x 400). B section of liver showing another portal triad with pronounced periportal inflammatory cell infiltration. (HE x 400)

27 Presence of Heavy Metals in Cosmetics
Consequences: Heavy metals like ARSENIC and LEAD have cumulative toxicities on various organs leading to : Asthma , Dermatitis Skin Cancer Neck Pain Hepatic Cancer Breast Cancer Seizures , Neurological Deaths . Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University DPSARU)

28 II- Presence of PDE-5 Inhibitors in Herbal Aphrodisiacs
Results: 15 Marketed Herbal Drugs were evaluated for the presence of PDE-5 inhibitors viz: sildenafil and Tadalafil 5 of them were found to contain therapeutic levels of Sildenafil and Tadalafil : Sildenafil : Titanic K2( 71 mg /Capsule) , Supersonic ( 119mg /Capsule) , Sikander-E Azam( 76 mg /Cap), 2Much Gold( 2 mg/Capsule Tadalafil : Musli Power Xtra (32 mg/Capsule). Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University -DPSARU)

29 SUMMARIZATION OF RESULTS

30 Current Findings after Reporting the matter to DCGI
S.No. Product Name Earlier Studies Situation after reporting the matter to DCGI 1. Musli Power Xtra Tadalafi 32 mg per capsule No Traces found 2. 2 Much Gold Sildenafil 2 mg /capsule Sildenafil found 3. SuperSonic Sildenafil 119 mg/capsule Sildenafil 4. Titanic K2 Sildenafil 71 mg/capsule Tadalafil found 5. Sikander E AzAM Sildenfil 76 mg/capsule Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University)

31 PRODUCTS FOUND TO CONTAIN SILDENAFIL

32 Presence of PDE-5 Inhibitors in Herbal Aphrodisiacs
Violation of Laws Drugs and Cosmetics Law 1940 Drugs and Magic Remedies act for Objectionable Advertisement -1954 Unless prescribed by registered medical practitioners or after consultation with the Drugs and Cosmetics Act 1940, no person or company, shall take any part in the publication of any advertisement referring to any drug that is used for:      a) the miscarriage in woman,   b) maintenance or improvement of the capacity of human beings for sexual pleasures,   c) correction of menstrual disorder in women, and    d) the diagnosis, cure, mitigation, treatment or prevention of any disease. •  No person or company will take part in advertisement which give false impression or makes a false claim for the drug or mislead the people. Whosoever contravenes any of the provision of this Act shall be punishable with imprisonment extended to six months or with fine, or with both for first time conviction. It may extend to one year imprisonment or with fine or with both on subsequent convictions. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

33 Presence of PDE-5 Inhibitors in Herbal Aphrodisiacs
Consequences Geriatric Population – Stable of Nitrates due to Angina , if consumes such products may suffer serious cardiovascular Complication. ( Severe Hypotension) Cases remain Unreported due to Taboo over sexual issues in indian context. Advertisements increases allurement of these products. Authorities are unable to check the menace . Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

34 III-Presence of Nicotine in Dentrifices
Results ToothPowders: 8 Brands were Tested 2 Brands were found to Contain Nicotine : Eg: Vicco And Musa Ka Gul Two brands Stopped after our Earlier reports Eg: Dabur and Baidyanath. Tooth Pastes : 8 Brands were Tested. 4 Were found to be positive for Nicotine Eg. Dabur Red , Arodent , IPCO and Dentobac. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University)

35 Presence of Nicotine in Dentrifices
Violation of Laws Violation of Drugs and Magic Remedies Act-1954 No Mandatory Disclosure of Scorpion on these Products. Some of the Products Like Dabur Red & Vicco are not even mentioning that they are Tobacco Products. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU )

36 Presence of Nicotine in Dentrifices
Consequences Sixty milligrams of nicotine (about the amount in three or four cigarettes if all of the nicotine were absorbed) will kill an adult” Nicotine binds to cholinergic receptors, The more nicotine binding to the nicotinic cholinergic receptors, the more acetylcholine is subsequently released and free to activate other subsets of cholinergic receptors. Nicotine poisoning causes vomiting and nausea, headaches, difficulty breathing, stomach pains and seizures Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

37 Conclusions No Single method is suitable to cover all type of studies to report Adverse events in PMS. Awareness among the healthcare professional regarding the importance need to be spread. Need to carry out safety assessment of Cosmetics/herbal products and Dentifrices. There is a need to carry out safety assessment of Marketed medicines in context with the food interactions. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

38 Conclusion Contd.. Need to Broaden the Spectrum of Pharmacovigilance.
It includes detection of ADR’S. should it not include the detection of chemical ( Heavy metals ) , which are causing ADRs? It should contain HERBOVIGILANCE and COSMETOVIGILANCE. Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)

39 Thank You Professor S.S.Agrawal (Delhi Pharmaceutical Science & Research University-DPSARU)


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