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Review of Cold and Cough Medications use in Children

2008-03-26

Introduction :

The purpose of this review is to evaluate the effect of over-the-counter (OTC) cough and cold medications in children less than 2 years of age and determine the risks and benefits of using these products. Over-the-counter cough and cold preparations include various combinations of antihistamines, decongestants, antitussives, and expectorants. Within the pediatric community in the United States (US), concern over the effectiveness and safety of such products has been growing for more than two decades. Since 1985, many randomized, placebo-controlled studies of the use of cough and cold preparations in children under 12 years of age have not shown any meaningful differences between the active drugs and placebo. In 1997, the American Academy of Pediatrics noted in a policy statement on cough medications that “indications for their use in children have not been established.” In 2006, the American College of Chest Physicians found that “literature regarding over-the-counter cough medications does not support the efficacy of such products in the pediatric age group.” Meanwhile, poison-control centers in the US have reported more than 750,000 calls of concern related to cough and cold products since January 2000.

A recent report from the Centers for Disease Control and Prevention (CDC) in the US identified more than 1500 emergency room visits in 2004 and 2005 for children under 2 years of age who had been given cough or cold products. Among other concerns are findings in children under six linking decongestants to cardiac arrhythmias and other cardiovascular events, antihistamines to hallucinations, and antitussives to depressed levels of consciousness and encephalopathy. A review by the US Food and Drug Administration (FDA) identified 123 deaths related to the use of such products in children under six during the past several decades. Serious adverse effects have been associated with accidental overdose, inadvertent misuse, and drug–drug or drug–host interactions in children given standard doses.

Side Effects in Pediatric Patients:

A variety of side effects of Over the counter cough and cold products can happen because each one contains various ingredients such as antihistamines, decongestants , antitussives and expectorants. The side effects vary from minor to serious and life-threatening .

A- Decongestants:

Decongestants cause vasoconstriction of blood vessels in the nasal mucosa. These medications target as well as ß receptors, which explain their potential side effects, including tachycardia and hypertension. Pseudoephedrine, phenylephrine and ephedrine are example of drugs used as decongestants.

Below are examples of side effects extracted from the FDA Adverse Event Reporting System (AERS) database for all pediatric serious adverse event cases that were reported to the Agency associated with pseudoephedrine between (1/1/2002 – 5/11/2007) include:

  • Cardiac disorders (17 cases) such as cardiac arrest, myocarditis, cyanosis and tachycardia.
  • Endocrine disorders (1 case) diabetes mellitus.
  • Eye disorders (11 cases) such as blepharospasm , eye pain ,erythema of eyelid ,mydriasis, strabismus and blurred vision.
  • Gastrointestinal disorders (19 cases) such as abdominal pain, diarrhea , constipation , food intolerance , gingival swelling, nausea and vomiting .
  • General disorders and administration site conditions (32 cases) such as cold sweat , death , edema fatigue, listless, pyrexia , sudden infant death syndrome and swelling.
  • Hepatobiliary disorders (3 cases) such as hepatic steatosis, jaundice and liver disorder.

*Note : (a report may contain more than one adverse event term)

B- Antihistamines:

The first-generation antihistamines block H1 receptors on nasal vasculature and compete with histamine for receptor sites. They can also cross the blood-brain barrier and affect the central nervous system (CNS). Diphenhydramine, chlorpheniramine and brompheniramine are H1 antagonists available in numerous over-the-counter preparations. The drying action of the mucous membranes is due to the anticholinergic properties of the first-generation antihistamines. Diphenhydramine often used for its sedative effects in adults, can cause paradoxical central nervous system stimulation in children, with effects ranging from excitation to seizures and death.

Below are examples of side effects extracted from the FDA Adverse Event Reporting System (AERS) database for all Pediatric serious adverse events cases that were reported to the Agency associated with Diphenhydramine between (1/1/2002 – 5/11/2007) include:

  • Nervous system disorders (63 cases) such as convulsion, febrile convulsion and partial seizures. Other was: brain oedema, coma and somnolence.
  • Psychiatric disorders (28 cases)such as hallucination , hallucination-auditory , hallucination-visual, abnormal behavior.
  • Respiratory disorders (31 cases): dyspnea , respiratory arrest , nasal congestion and asphyxia.

C- Antitussives:

Dextromethorphan is an opioid derivative with antitussive activity and little to no analgesic, addictive, or CNS depressive properties.

Most common side effect of antitussives on pediatric is depressed levels of consciousness and encephalopathy. Below are examples of side effects extracted from the FDA Adverse Event Reporting System (AERS) database for all Pediatric serious adverse event cases that were reported to the Agency associated with dextromethorphan between (1/1/2002 – 5/11/2007) include:

  • Nervous system disorders (80 cases): such as convulsion, febrile convulsion, petit mal epilepsy. Other: anoxic encephalopathy, coma, encephalopathy and somnolence.
  • Respiratory, thoracic disorders: (21 cases) such as cough, cyanosis , dyspnoea , hyperventilation , respiratory arrest , respiratory distress, respiratory failure ,throat tightness.

Dose information and efficacy :

Reviewing the scientific literature revealed no reference data for dosing OTC cough and cold medications for children under 2 years of age.

The following table summarizes FDA approved pediatric dosing:


Category

Ingredient

Pediatric Dosing

12 years of age and above

6 to under 12 years of age

2 to under 6 years of age

Decong-estants

Pseudoe-phedrine

60mg Q 4-6 hrs, not to exceed 240mg/day

30mg Q 4-6 hrs, not to exceed 120mg/day

15mg Q 4-6 hrs, not to exceed 60mg/day


Phenylephrine

10mg Q 4hrs, not to exceed 60mg/day

5mg Q 4hrs, not to exceed 30mg/day

2.5mg Q 4hrs, not to exceed 15mg/day


Diphenhydr-amine

25mg Q 4-6 hrs, not to exceed 300mg/day

12.5 to 25mg Q 4-6 hrs, not to exceed 150mg/day

6.25mg Q 4-6 hrs, not to exceed 37.5mg/day

Antitussives

Dextrometh-orphan

10 to 20mg Q 4hrs or 30mg Q 6-8 hrs, not to exceed 120mg/day

5 to 10mg Q 4hrs or 15mg Q 6-8 hrs, not to exceed 60mg/day

2.5 to 5mg Q 4hrs or 7.5mg Q 6-8 hrs, not to exceed 30mg/day






































Actions Taken
by different regulatory agencies:

Canada – Health Canada:

Life threatening adverse events, including unintentional overdose, have been reported to Health Canada in association with the use of cough and cold products in children under 2 years of age. Health Canada is advising consumers on the appropriate use of "over-the-counter" (non-prescription) cough and cold products in children, including drugs and natural health products, particularly in children under 2 years of age.

Some Important Recommendations Published by Health Canada regarding the use of over-the-counter cough and cold remedies in children:

Children Under 2 years of age:

  • Parents and caregivers should consult a healthcare practitioner to assure that their use of cough and cold products is safe and appropriate.
  • Do not use cough and cold products, including drugs and natural health products, in children less than 2 years of age unless instructed by your physician.
  • Even if the cough and cold products are labeled for use in children under 2 years of age (for example, they use the word "infant" in their name or having dosing instructions for infants) it is still preferable to discuss the use of these products with your healthcare practitioner before giving them to any young child.

Children of all ages:

  • If it is necessary to give a cough and cold product to a child, make sure that you read all labels and instructions before doing so. If the product does not contain dose information for children, then it should not be used in children.
  • Do not give a child a larger dose than is recommended or use the product more frequently than is recommended in the labeling and instructions.
  • Take note of the medicinal ingredients in the product, particularly if you may be giving more than one product to a child. Be aware that many products contain the same medicinal ingredient(s) and combined use could lead to overdose. Some herbs used in cough and cold medications and some over-the-counter medications used to control fever may also have medicinal ingredients similar to those in other cough and cold products.
  • Because cough and cold medications often contain multiple ingredients, it is advised not to give more than one cough and cold product to a child.
  • Talk to your healthcare practitioner if you have questions about the proper use of these products, dosing and administration information, or the medicinal ingredients in the products you are using.
  • There is no cure for the common cold. Children will usually recover from coughs and colds in time on their own. The common cold is a mild, viral infection that can be managed by rest, sufficient fluid intake and comfort measures.
  • In young children and babies, it is sometimes important to rule out serious illnesses (for example, pneumonia or other infections) which may present with cold-like signs and symptoms; this is especially important if symptoms persist or if the child's condition deteriorates.
  • If you are concerned about the child's health, the child should be brought to a healthcare practitioner for medical evaluation.

United States - Food and Drug Administration (FDA):

The FDA informed consumers and healthcare professionals that the agency has completed its review of the safety of using (OTC) cough and cold medicines in children under 2 years of age and recommends that these drugs not be used to treat children in this age group because serious and potentially life-threatening side effects can occur.

The response was based on a joint meeting of the Pediatric Committee and the Nonprescription Drugs Advisory Committee that was convened on October 18 and 19 of 2007.

There are a wide variety of rare, serious adverse events reported with cough and cold products. They include death, convulsions, rapid heart rates, and decreased levels of consciousness. OTC cough and cold products include decongestants, expectorants, antihistamines, and antitussives (cough suppressants) .

FDA has not completed its review of information about the safety of OTC cough and cold medicines in children 2 through 11 years of age. The agency plans to issue its recommendations to the public as soon as the review is complete.

Pending completion of the FDA's ongoing review, parents and healthcare professionals that choose to use OTC cough and cold medicines to children ages 2 to 11 years should:

  • Follow the dosing directions on the label of any OTC medication.
  • Understand that these drugs will NOT cure or shorten the duration of the common cold.
  • Check the "Drug Facts label to learn what active ingredients are in the products because many OTC cough and cold products contain multiple active ingredients.
  • Only use measuring spoons or cups that come with the medicine or those made especially for measuring drugs.

United Kingdom (UK) - Medicines and Healthcare products Regulatory Agency (MHRA):

Drugs containing pseudoephedrine and ephedrine could soon be reclassified as prescription-only in the UK, in proposals drawn by the Medicines and Healthcare Products Regulatory Agency (MHRA).

The MHRA's favored course of action, based on recommendations from the Commission on Human Medicines (CHM), is to change the legal status of pseudoephedrine-/ephedrine-containing products to prescription-only by the end of the year

 

Saudi Arabia – Ministry of Health (MOH):

A memorandum from Drug Registration Committee at MOH was released on 9/11/1428H. The memorandum was issued based on the US FDA alert with regards to OTC cough and cold medications. The memorandum advised manufacturers to update the monograph warnings section of the OTC cough and cold medications label " not to be used for children under 2 years of age" in addition to deletion of dosing information section for such age group from the label.

Medication registered in MOH List (syrup dosage forms):

Active ingredient

Content

Medication

Dextromethorphan

Antitussive

Kafosed

Dextrokuf

Contrasal

Sedofan-p

Kafosed

Dexofan

Riaphan

Romin

Romilar

Chlorpheneramine

Antihistamine

Allerfin

Gripine

Histop

Chlorpheniramine

Pheniram

Histant

Chlorohistol

Pirafene

Polaramin

Diphenhydramine

Antihistamine

Benylin

Ezipect

Amydramine ii

Benadryl

Amydramine expectorant

Viscodril expectorant

Exylin pediatric syrup

Dramylin

Diphelin paediatric

Phenylepherine

Decongestant

Rhinofrin

Carbenoxamine pseudoephedrine

Rhinostop oral drops

Chlorpheniramine phenylepherine

Antihistamine

decongestant

Sine-up syrup

Chlorpheniramine pseudoephedrine

Flumed

Allergetin

Chlorpheniramine naphazolin

Nazophen

Loratadine pseudoephedrine

Lorinase syrup

Brompheniramine pseudoephedrine

Dimetapp elixir

Dimethindene phenylephrine

Vibrocil nasal drops

Dextromethorphan diphenhydramine

Antitussive antihistamine

Mentex

Benafed

Dextromethorphan guaifenesin

Antitussive expectorant

Guaphan dm syrup

Vicks 44 e pediatric

Guaifenesin pseudoephedrine

Expectorant

decongestant

Robitussin-pe syrup

Guafedrin

Bronex

Triprolidine pseudoephedrine dextromethorphan

Antihistamine

decongestant antitussive

Tripofed

Unifed

Chlorpheniramine

paracetamol pseudoephedrine

Antihistaminic analgesic decongestant

Emidol cold syrup

Fludrex syrup

Codeine chlorpheniramine ephedrine

Antitussive antihistamine decongestant

Codaphed syrup

Tussivan

Codeine pseudroephedrine

triprolidine

Antitussive decongestant antihistamine

Actifed compound

Guaifenesin dextromethorphan

pseudoephedrine

Expectorant antitussive decongestant

Robitussin cf syrup

Paracetamol pseudoephedrine dextromethorphan

Analgesic decongestant antitussive

Vicks day quil

Saudi Food and Drug Authority Recommendations:

Evidence from randomized controlled clinical trials have be unable to differentiate cough and cold preparations from placebo in treating children up to 12 years of age. The Saudi Food and Drug Authority recommendations follow those of other drug regulatory authorities around the world. Briefly, these products should not be given to children less than 2 years of age. In the age group ranging from 2 to 11 years of age these products should only be given after consultation with a pharmacist or physician.

Children Under 2 years of age:

  • Over-the-counter (OTC) cough and cold products should not be used for infants and children under 2 years of age because serious and potentially life-threatening side effects could occur.
  • Manufacturers should update the monograph warnings section of labeling information for all cough and cold products to inform patients and health care providers that these products should not be used for children less than 2 years of age.
  • If infants and children under 2 years of age experience cough and cold symptoms, drinking plenty of fluids may help loosen mucus and keep children hydrated and using saline nasal drops, and gently suctioning mucus from the nose with a bulb syringe.
  • In case of fever, fever reducers such as acetaminophen or ibuprofen can be used.
  • If a child’s cold symptoms do not improve or get worse, doctor should be contacted.

Children 2 to 11 years of age:

Pending completion of a comprehensive review of these products by US authorities, the SFDA recommends, parents and caregivers that choose to use OTC cough and cold medicines to children ages 2 to 11 years should:

  • Consult a pharmacist or physician before using one of these products.
  • Follow the dosing directions on the label for any OTC medications.
  • Understand that these drugs will NOT cure or shorten the duration of the common cold.
  • Only use measuring spoons or cups that come with the medicine or those made specially for measuring drugs.

Conclusion :

After reviewing the published scientific literature and actions of foreign regulatory agencies, SFDA strongly recommends that over-the-counter (OTC) cough and cold products should not be used for infants and children under 2 years of age because serious and potentially life-threatening side effects could occur. Warnings sections and dosage information should be updated by the manufacturers of cough and cold preparations. SFDA should inspect public pharmacies to check if the manufacturers have performed these updates on their products.