Letter to the Editor

Drug safety guidelines: Are they effective? Access this article online Website: www.ijp-online.com

Quick Response Code:

DOI: 10.4103/0253-7613.121392

Sir, Paracetamol (acetaminophen) is the most extensively used over-the-counter analgesic and antipyretic agent. Over dosing of paracetamol can lead to hospital admissions.[1,2] In the United Kingdom, nearly 50% of drug poisoning occurs due to paracetamol over dosing and nearly 100-200 people die every year from it. The Toxic Exposure Surveillance System of the American Association of Poison Control Centers estimated that in 2004, 19,590 children aged less than 6 years experienced paracetamol poisoning.[3] Similar incidences are also reported in other countries like Denmark and Australia.[4] There are multiple reasons for accidental occurrences of pediatric paracetamol poisoning such as public perception about its safe nature, easy availability in the market, lack of child proof packing at homes and dosing errors caused by pharmacists, parents and physicians.[5] In India, the data on paracetamol poisoning is not captured completely due to poor documentation. Based on the findings of a 10 year retrospective hospital-based study, about 0.32% cases of poisoning are due to acute paracetamol overdosing.[4] The Drugs Controller General (DCGI), the apex drug regulatory authority in India, besides banning drugs,

periodically issues drug safety guidelines and box warnings. In 2012, the DCGI issued safety guidelines and box warnings for paracetamol, nimesulide and statins.[6] On 4th April 2012, the DCGI sent letters to all the state drug controllers (SDCs) limiting the paracetamol content in prescription combination products and issuing box warning due to paracetamol’s liver toxicity. The letter was issued based on the recommendation of the Drug Technical Advisory Board, the highest statutory authority on technical matters. In combination products, the paracetamol content is restricted to just 325 mg.[6] In an attempt to find out the compliance to safety guidelines by the pharmaceutical companies, we did a survey at Sahaswan (Uttar Pradesh) in August 2013. The paracetamol combination products were examined for their paracetamol content and box warnings. Our findings showed that the paracetamol content was still in the range of 500 mg to 650 mg and was not restricted to 325 mg in spite of DCGI’s notification and circular. Table 1 lists some of the findings. It is unfortunate that the safety guidelines are ignored by the manufacturers and that the SDC fail to enforce the guidelines. The manufacturing falls under the jurisdiction of state Drugs Controller. In India, several paracetamol combination products are available for a number of indications such as cough and cold, pain, sprains etc. without a prescription. Like other developing countries, in India, self-medication is rampant. There is every possibility that the patient may consume paracetamol from medications for different conditions such as fever, cough and cold, which may lead to overdosing. The excess dosing may also come from prescriptions and self-medication. The violation of the safety guidelines for paracetamol by the pharmaceutical companies puts the common people at high-risk

Table 1: Paracetamol combination products in the market and manufactured after April 2012 Brand name


Manufacture date/batch no.


T. Voran

Paracetamol 500 mg+diclofenac potasium 50 mg


New Tennis Pharma

Arflur 3D

Paracetamol 500 mg+aceclofenac 100 mg+serratiopeptidase 15 mg




Paracetamol 500 mg+aceclofenac 100 mg


Pharma Corp. Inc. (P) Limited

Oxalgin DP

Paracetamol 500 mg+diclofenac Sodium 50 mg


Zydus Cadila


Paracetamol 650 mg+diclofenac potassium 50 mg+caffaeine 25 mg


Medwin Impex (P) Ltd.


Paracetamol 500 mg+serratiopeptidaze 15 mg+diclofenac potassium 50 mg


Torque Pharmaceuticals Pvt. Ltd.


Paracetamol 500 mg+diclofenac sodium 50 mg+chlorpheniramine maleate 4 mg+magnesium trisilicate 100 mg


Laborate Pharmaceuticals India Ltd.


Paracetamol 500 mg+magnesiumtrisilicate 100 mg+chlorpheniramine 4 mg+diclofenac sodium 50 mg

May-13/CFI-M 259

Feezo Chem Formulations Pvt. Ltd.

D. Cold total

Paracetamol 500 mg+phenylephrine 10 mg+caffeine 32 mg


Paras Pharmaceuticals Ltd.


Paracetamol 500 mg+ibuprofen 400 mg


Aristo Pharmaceuticals Pvt. Ltd.

Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 641

Letter to the Editor

for liver toxicity. The regulatory authorities need to be vigilant and ensure industries’ adherence to guidelines to protect the interests of the public. Akram Ahmad, Isha Patel1, Guru Prasad Mohanta Department of Pharmacy Practice, Annamalai University, Annamalai Nagar, Chidambaram, Tamil Nadu, India, 1 Department of Clinical, Social and Administrative Sciences, University of Michigan, Ann Arbor, MI-48104, USA Correspondence to: Dr. Akram Ahmad, E-mail: [email protected]

References 1. Buckley N, Eddleston M. Paracetamol (acetaminophen) poisoning. Clin Evid. 2005;14:1738-44. 2. Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka PA, et al. Acetaminophen poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2006;44:1-18. 3. Sia JY, Chan YC. Case report: Paracetamol poisoning in a 2-year-old child-From international overview to the role of the Hong Kong poison information Centre. Hong Kong J Emerg Med 2006;13:225-31. 4. Nambiar NJ. Management of paracetamol poisoning: The old and the new. J Clin Diagn Res 2012;6:1101-4.

5. Losek JD. Acetaminophen dose accuracy and pediatric emergency care. Pediatr Emerg Care 2004;20:285-8. 6. Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. Available from: http://www.cdsco.nic.in/circulars_rev.htm. [Last accessed on 2013 Mar 30].

Fatal anaphylactic reaction to iron sucrose in pregnancy: Iron-induced Kounis syndrome? Access this article online Website: www.ijp-online.com

Quick Response Code:

DOI: 10.4103/0253-7613.121393

Sir, Parenteral iron preparations are administered to patients who are unable to tolerate or absorb oral iron preparations, or are unwilling to cooperate. Studies[1] have shown that iron absorption from food increases when the serum ferritin is below 30 ng/ml, and decreases when it is more than 300 ng/ml. In hemodialysis patients, in particular, oral absorption of iron does not occur when serum ferritin is approximately 50 ng/ml. Parenteral iron administration is occasionally associated with severe side effects. Intravenous iron preparations such as high and low molecular weight iron dextran, ferrous gluconate, and iron sucrose are associated with adverse effects at a rate of 38 per million.[2] Rapid iron infusion can cause adverse effects because it induces oversaturation of transferrin and releases free iron. Free iron is responsible for toxicity, hypersensitivity, and vasomotor reactions. The first adverse symptoms might be pruritus or burning sensation of the tongue, so an initial test dose of small amount of preparation followed by the whole dose is recommended. Intravenous iron generates oxidative stress, inflammation, endothelial dysfunction, as well as cardiovascular and renal injury. The propensity for these events is increased with non dextran iron. However, iron dextran, especially the large molecular form, is complicated by anaphylactic reactions and death. Iron sucrose is typically administered as a slow push injection or a 15-30 min infusion in doses of 100-200 mg. This requires multiple outpatient visits and repeated intravenous 642 Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6

doses in order to achieve the standard therapeutic course of 1000 mg elemental iron. Iron dextran is given as a single dose, but this requires administration over a period of 4 to 6 h. In addition, iron dextran complexes can cause fatal dextraninduced anaphylactic reactions. Anaphylactic reactions to iron sucrose are rare and include generalized pruritus, burning sensation of the tongue, and peribuccal hyperaesthesia. In the very interesting report published recently in this journal[3] a 20-year-old primigravida without any previous allergic history, suffering from severe iron deficiency anemia developed anaphylactic shock following an infusion of iron sucrose. Despite treatment with intravenous adrenaline, hydrocortisone, antihistamines, H2 blockers, ventilatory and inotropic support, she succumbed from cardiac arrest within 24 h. Postmortem examination and pre and postmortem tryptase levels were not obtained. This report raises some important clinical, therapeutic pathophysiological issues. The patient died from cardiac arrest within 24 h after she had taken the iron sucrose infusion and despite vigorous antianaphylactic therapy. Was the cause of death a fatal Kounis syndrome?[4] She received, wisely, adrenaline, hydrocortisone, antihistamines, H2 blockers, ventilatory and inotropic support. Had this combined treatment served as an adjunct to iron sensitivity? Is the coronary artery injury a primary effect of anaphylaxis leading to cardiac arrest and Kounis syndrome? Today, Kounis syndrome is defined as the concurrence of acute coronary syndromes such as coronary spasm and coronary thrombosis with conditions associated with mast cell and platelet activation. It is caused by inflammatory mediators released during the mast cell degranulation process and/or platelet activation via FcγRI, FcγRII, FcεRII, and FcεRII receptors situated on the platelet surface.[4] Assumed that the patient’s symptoms such as giddiness and difficulty in breathing that appeared soon after on sucrose infusion were due to an allergic reaction to iron, a Kounis syndrome type I leading to cardiac arrest could not be excluded. Ideally pre and postmortem

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