Prescription and nonprescription products for a
cough have been provided to children of all ages for
many years. Numerous products are available as
combinations of antihistamines (eg, brompheniramine,
chlorpheniramine, and diphenhydramine), decongestants
(eg, phenylephrine and pseudoephedrine), antitussives (eg,
codeine and dextromethorphan) and/or expectorants
(guaifenesin). These medications have rarely undergone
rigorous clinical trials evaluating their efficacy and safety
and much of the data in children has been extrapolated
from the sparse adult information. However, over the past
few years, the FDA has evaluated the use of hydrocodone-containing cough products and in 2007 began to actively
enforce regulations against unapproved hydrocodone-containing products and ordered them to be removed from
the market. Physicians and pharmacists should be aware of
these changes and understand which therapies are appropriate to prescribe and dispense for a cough in children.
The FDA is responsible for protecting the public health,
and, thus, it regulates foods, drugs, biologics, medical
devices, cosmetics, and products that emit radiation.1 The
FDA approves medications based upon clinical studies for
efficacy and safety that the manufacturer is required to
supply to the agency. The average review time for approval
of a drug by the FDA is six months.2 However, currently
there are prescription and nonprescription drugs on the
market that have evaded the FDA process and, thus, are
It is thought that there are thousands of unapproved
drugs available to the public today.3 This could be due to
the change in laws over the past 100 years. In 1906, the
Federal Food and Drugs Act was the first US act that regulated drugs. Then, in 1938, the Federal Food, Drug, and
Cosmetic Act stated that new drugs must be evaluated and
approved for safety. In 1962, this act was amended to state
that new drugs must be proven safe and effective for
approval. Thus, the FDA contracted with researchers to
evaluate the efficacy of previously approved drugs; however, numerous drugs came to the market prior to 1962
without approval. In June of 2006, the FDA began a new
program, the Drug Safety Initiative, which would remove
unapproved drugs from the market. The program uses a
risk-based approach for drug selection in which drugs with
potential safety risks are the highest priority. Once a risk is
assessed, the FDA can take any of the following actions:
request voluntary compliance; provide notice of action in
a Federal Register notice; issue an untitled letter or a
warning letter; or initiate a seizure, injunction, or other
proceeding of the product. Since the introduction of this
program, the FDA has taken actions against the following
drugs: balanced salt solution (ophthalmic) products,
carbinoxamine, hydrocodone, injectable colchicine, quinine sulfate, trimethobenzamide hydrochloride suppositories, topical drug products containing papain, ergotamine-containing drug products, and timed-release drug products containing guaifenesin.
Hydrocodone-containing products, commonly prescribed as antitussive agents, were specifically targeted by
the FDA in September 2007.4 There were concerns regarding formulation changes in unapproved hydrocodone-containing products and confusion between names of
approved and unapproved products, possibly resulting in
medication errors. Some of these products were FDA
approved for pain, but most of the products claiming to
suppress coughs were unapproved. In addition, by 2005,
the FDA had received more than 400 reports of serious
adverse effects involving antitussive hydrocodone-containing products. The most commonly reported adverse
effects were central nervous system, gastrointestinal, pulmonary, and hypersensitivity effects as well as intentional
and unintentional overdoses. Due to the concerns of medication safety, the FDA mandated that manufacturers of
all unapproved hydrocodone-containing products labeled
for children less than six years of age stop manufacturing
and distribution by October 31, 2007. At that time, no
products were FDA approved for use as a cough suppressant in children less than six years of age; however, some
of these products were promoting doses for children two
years of age. Those manufacturers who were marketing
unapproved hydrocodone-containing products to all others were instructed to stop manufacturing by December
31, 2007, and end shipments by March 31, 2008. There
were approximately 200 unapproved hydrocodone-containing products on the market at the time of the rule to
cease manufacturing. Only seven cough-suppressant products were FDA approved and available at the time of the
ruling (Table 1).
|Hydrocodone bitartrate and homatropine methylbromide
- Homatroprine methylbromide and hydrocodone bitartrate: 5 mg/1.5 mg tablet (Actavis Totowa)
- Hycodan: 5 mg/1.5 mg tablet and 5 mg/1.5 mg/5 mL
syrup (Endo Pharm)*
- Hydrocodone compound: 5 mg/1.5 mg/5 mL syrup
(Actavis Mid Atlantic)
- Mycodone: 5 mg/1.5 mg/5 mL syrup (Morton Grove)
- Tussigon: 5 mg/1.5 mg tablet (King Pharm)
Hydrocodone polistirex and chlorpheniramine polistirex
- Tussionex Pennkinetic: 10 mg/8 mg/5 mL
- Tussicaps: 10 mg/8 mg and 5 mg/4 mg capsule
|*Products discontinued by manufacturer: syrup 5/14/2008, tablets 1/4/2008
CLINICAL SAFETY AND
EFFICACY OF HYDROCODONE
Cough is a common chief complaint in a pediatric practice. It is a response to inflammatory, mechanical, or chemical irritation of the airways. Coughing helps clear the airway of excessive secretions. Thus, it may be dangerous to
suppress cough in many airway and pulmonary diseases.
Acute cough may be infectious or noninfectious. It
can be caused by a wide variety of clinical conditions such
as pneumonia, bronchiolitis, asthma, laryngotracheobronchitis (croup), sinusitis, pertussis, and airway foreign
body. The most common cause of acute cough in children
is the “common cold.” It is viral in etiology and usually
accompanied by rhinorrhea and nasal congestion. Cough
occurs in about one-third of children with the common
cold. It is secondary to increased airway secretions and
irritation of the respiratory tract. Some patients may continue to cough several weeks after the acute illness because
of viral-induced airway hyperreactivity.
Children usually have about three to ten episodes of
the common cold per year. Major concerns of parents are
over their children’s discomfort and their inability to drink,
resulting in dehydration. Parents and children lose sleep
because of the cough. Depending on the severity of symptoms, children can potentially miss school. Management of
the common cold is mainly centered towards relief of
symptoms until the viral infection runs its course, which is
usually 10 to 14 days.5
Symptomatic relief can be accomplished with oral
hydration, frequent nasal suctioning, and relief of discomfort or fever with antipyretics/analgesics. Treatment
is usually directed towards complications such as otitis
media, sinusitis, dehydration, and resulting asthma exacerbation.5 Physicians are usually then faced with the
dilemma of parents demanding medications to relieve
the cough and congestion of their children. Pharmacists
face similar situations when parents seek advice about
the safety of over-the-counter (OTC) or prescription
cough and cold medications.
Cough suppressants are divided into non-narcotic preparations such as dextromethorphan and narcotic
preparations such as codeine and hydrocodone that affect
the medullary cough center in the brainstem. They are
usually marketed in combination with antihistamines,
decongestants, expectorants, or antipyretics.
In recent years, the safety of cough and cold preparations has been questioned. Between 2004 and 2005, the
Centers for Disease Control and Prevention (CDC)
reported a total of 1,519 emergency room visits related
to cough and cold preparations among children less than
two years of age.6 Reported deaths associated with cough
and cold preparations in infants less than 12 months
were investigated by both the CDC and the National
Association of Medical Examiners. A study by Rimsza
and Newberry looked into unexpected infant deaths
related to cough and cold medications. About 10 out of
90 unexpected infant deaths were attributed to the recent
administration of cough and cold preparations. Only
four infants received medical care, and there is no evidence that any of their caregivers received counseling on
Over the past 20 years, randomized placebo-controlled studies of the use of cough and cold preparations
among children have not documented differences between
placebo and the medications. Despite these data, a recent
survey of 400 family physicians and 100 pediatricians
across Ontario showed that 16% of family physicians and
4% of pediatricians recommended cold medications for
infants up to 6 months of age (p=0.01).8 In addition, 38%
of family physicians and 14% of pediatricians recommended cold medications for infants 6 to 12 months of
Facts About Coughs and Colds
It is estimated that over one billion Americans
experience a cold every year.
Children have about three to ten colds a year.
Adults average about two to four colds a year.
Handwashing is the simplest and most effective way
to keep from getting colds.
Heavy smokers get more severe colds with
accompanying severe cough.
Approximately one in ten US children uses one or more
cough and cold medications during a given week.
Approximately 95 million cough and cold products
are purchased each year for use in children.
The outflow of a cough can reach air speeds greater
than 100 mph.
|Source: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
The American Academy of Pediatrics issued a policy
statement in 1997 that indications for use, safety, and efficacy of cough suppressants have not been established in
children.9 In 2006, the American College of Chest
Physicians issued a statement that cough suppressants
should not be used in children since they may experience
significant morbidity and mortality.10 A Cochrane review
found insufficient evidence for the use of antitussives as
an adjunct treatment for acute pneumonia in both adults
and children.11 Another review showed that OTC cough
and cold preparations are no more effective than placebo
in the relief of acute cough in both adults and children
with acute respiratory infection.12
Many of the recent discussions regarding cough suppressants, particularly narcotic preparations containing
codeine and hydrocodone, have centered on their potential adverse effects. These adverse effects include respiratory depression, obtundation, dizziness, nausea and vomiting, rash, and pruritus. Dosages of codeine and
hydrocodone have not been established in children.
Established dosage recommendations in children were
extrapolated from adult studies. Toxicity from codeine
occurred at dosages of 3 to 5 mg/kg/day. Deaths have
been reported at dosages greater than 5 mg/kg/day.
Toxicity can potentially occur at lower doses with repetitive administration.
Several factors contribute to the predisposition of
children to codeine toxicity. Hepatic glucuronidation,
which inactivates codeine, is incompletely developed in
children. Other factors include drug-drug interactions
(especially in multi-ingredient preparations), the pharmacodynamics of the drug, and the underlying illnesses,
most commonly respiratory illnesses that can lead to mild
hypoxemia or airway obstruction. Morbidity and mortality have been reported from accidental overdose, intentional overdose, and misuse of the medications.7,9
Because of the availability and use of cough suppressants in adults, physicians and pharmacists should take
time to educate parents about the adverse effects of these medications in children. They should be advised that
cough in children should be treated according to etiology.
Parents should also be educated on the self-limiting course
of an acute upper respiratory infection or common cold
and the expected time of its resolution to alleviate their
anxiety and demand for the use of medications to relieve
DRUG INFORMATION RESOURCES
Physicians and pharmacists need to know where to locate
information regarding which hydrocodone-containing
products are FDA approved. As previously noted, the
seven current FDA-approved hydrocodone-containing
antitussives are listed in Table 1. There are several
resources that can be utilized to find approved medications; however, the FDA website is the optimal place to
search for approved products. Currently, no OTC
hydrocodone-containing product is available or FDA
CHPA Member Companies
To Restrict Use of OTC Cough and
Cold Meds in Children Under Age Four
The Consumer Healthcare Products Association (CHPA), an association that represents most of the manufacturers of over-the-counter (OTC) cough and cold medicines for children, recently announced that its members are voluntarily modifying the product labels for consumers of OTC cough and cold medicines to state “do not use” in children under four years of age. Additionally, the manufacturers are introducing new child-resistant packaging and new measuring devices for use with the products.
The steps that are being taken by the CHPA will not affect the availability of the medicines, but this voluntary action will result in a transition period where the instructions for use of some OTC cough and cold medicines in children will be different from others. The FDA does not typically request removal of OTC products with previous labeling from the shelves during a voluntary label change such as this one. Therefore, some medicines will have the new recommendation “do not use” for children under four years of age, whereas others will instruct that they not be used for children under two years of age. If parents or caregivers have or purchase a product that does not have the voluntarily modified labeling, the FDA recommends that they should adhere to the dosage instructions and warnings on the label that accompany the medication. They should not, under any circumstances, give adult medications to children. If parents or caregivers are just not sure about how to use a product, they should consult with their doctor or pharmacist.
The FDA has a website, Drugs@FDA
which provides only FDA-approved drug listings to a
query of drug names (Figure 1). Once the drug name is
searched, the site provides a table of products listed by
drug name and components. After a specific product is
chosen, it is detailed further. A table provides drug name,
strength, and dosage form and indicates whether the drug
is prescription, OTC, or discontinued. This is helpful,
since the inquirer can see which drugs are currently available. Note that the table does not offer information on
drug shortages or manufacturing issues. Therapeutic
equivalency codes (codes stating whether the FDA has
approved the drug product to be therapeutically equivalent to another) are also listed, with only those starting
with ‘A’ granted equivalency by the FDA. The manufacturer and date of approval are also listed, as well as subsequent web pages that state therapeutic equivalents,
approval letters/history, and labels. The website is updated
daily, which ensures current approval information and
provides data back to 1939. This website is also available
to the public to search as well.
Additionally, the FDA provides a public searchable
website that lists drug recalls, market withdrawals, and
safety information for the past 60 days
webpage, the FDA Enforcement Report, provides weekly
agency actions dating back to 1995.14
The “Orange Book” (Approved Drug Products with
Therapeutic Equivalence Evaluations) lists all drug products approved for safety and efficacy by the FDA under
the Federal Food, Drug, and Cosmetic Act
(http://www.fda.gov/cder/ob/). Older drugs only approved
for safety or those prior to the 1938 drug laws are not in
this reference. Any person can search this website by
active ingredient, brand name, application holder or number, or patent. The electronic data are updated monthly,
but generic drug data are updated daily.
If a product has a National Drug Code (NDC) number on the prescription label, it can be searched in the NDC directory. Just because a product has an NDC does not mean it is FDA approved; however, the NDC directory will distinguish FDA-approved and FDA-unapproved products. It is easiest to search the NDC directory by drug brand name or generic name. If only the NDC number is known, it can be searched by entering the first 5 digits (the labeler code). The next webpage provides drug product information. Next to the “FDA application No.,” if a number is provided, then the drug is FDA approved. If “other” is listed, then the product has not been approved for safety and efficacy by the FDA.
|CASE STUDY 1: PHARMACIST PERSPECTIVE
A parent calls into the automatic refill telephone line and requests a refill of her three-year-old child’s hydrocodone-containing cough syrup. No refills are left on the prescription, and the pharmacist notices that the product prescribed is no longer available, since it is not FDA approved. What should the pharmacist do?
There are two issues that need to be addressed at this time. First, the pharmacist should call the parent and explain why she can no longer obtain this medication for her child. Appropriate education to the parent regarding why this product is not on the market is essential. Additionally, the pharmacist should inquire why the patient is asking for refills. Is her child sick or coughing from allergies or asthma? It is important to assess the indication and make an appropriate physician referral if warranted. The pharmacist can also call and educate the physician on why this medication is no longer on the market and to provide other product options for future prescriptions.
Many physicians and pharmacists may utilize the Physician’s Desk Reference (commonly referred to as the PDR), which consists primarily of FDA-approved medication package inserts. There is a selection process of manufacturers that ultimately determines which products are included in the publication; not all manufacturers participate. Thus, this reference does not include all FDA-approved medications, and the content of the hard cover version is subject to publication of new editions. General medication references such as Micromedex, Drug Information Handbook, and Drug Facts and Comparisons may provide misleading information since listed drug monographs may not state FDA approval classification. Many monographs state clinical indications and off-label uses but may not indicate whether a drug product is an FDA-approved medication. Most drug references not provided by the FDA do not specify whether a drug product is FDA approved or unapproved and should be used cautiously for this type of information.
Obtaining a package insert may assist with identifying whether a product is FDA approved. Package inserts are provided with medications and may be passed along to patients. Pharmaceutical companies will often have package inserts available in PDF format on their websites, usually listed with information about their products. It should be noted that although package inserts are available, their presence does not mean a medication is FDA approved. Obtaining the drug name, ingredients, and NDC number from the package insert and double-checking the information on the FDA websites are recommended.
Staying informed about changes in drug regulations is important. The Center for Drug Evaluation and Research (CDER) of the FDA has electronic mailing lists to which anyone can subscribe (http://www.fda.gov/cder/cdernew/listserv.html).15 The Drug Safety Newsletter focuses on postmarketing information to health care providers, MedWatch focuses on medical product safety alerts, and FDA Consumer Education About Medicine provides information to consumers. These lists offer safety information that can enhance the knowledge of health care professionals and patients.
|CASE STUDY 2: PHYSICIAN PERSPECTIVE
The mother of a five-month-old child is concerned that her child had been coughing for more than two weeks. The cough has been more intense with associated posttussive emesis over the past few days. She asks the child's physician about narcotic cough suppressants. She has also been sick with the same symptoms and was prescribed a hydrocodone-containing cough suppressant by her doctor. What should the physician do?
It is important to communicate with the mother about the lack of efficacy of cough suppressants in both children and adults. She should be informed of potential adverse effects associated with these medications and that young children are more susceptible to these adverse effects. Cough in children should be treated based on the etiology. In this particular case, the child was eventually diagnosed with pertussis by the physician. Antimicrobial therapy is indicated for the child to limit the spread of pertussis.
Although the FDA provides several resources to identify FDA-approved products, searching the websites can be very time consuming and confusing to health care professionals as well as the general public, especially the first time searching the databases. In addition, because the market of hydrocodone-containing products has drastically decreased, supplies of approved products may diminish and shortages could occur in the future. However, manufacturers of new hydrocodone-containing products for cough may seek FDA approval and, thus, become available.
Physicians should be aware of the types of prescriptions they are writing, and pharmacists should be aware of the medications on the pharmacy shelves to be dispensed to patients. Physicians should know the FDA status of the hydrocodone-containing products they are prescribing, and pharmacists should educate physicians on approved products if an unapproved product is prescribed. In addition, pharmacists should evaluate the OTC products sold to patients to ensure no product is circumventing the FDA approval process. Both physicians and pharmacists should educate patients and parents on the difference
between unapproved and approved FDA products.
Physicians and pharmacists should also educate patients
and parents about the appropriate use of cough preparations
in children and adults. Teaching about the lack of efficacy
and safety concerns is imperative. Nonpharmacological
therapy should be utilized when a child has a respiratory
infection thought to be a cold due to a virus. Many patients
may hoard unused medication from past prescriptions. It is
important to educate patients that they may have an unapproved medication and that they should check with a physician or pharmacist prior to use. In addition, it may not be
warranted clinically to use the medication.
Finally, pharmacists must educate patients and parents
about the appropriate use of medication dosing devices.
They should provide oral syringes and dosing spoons or
cups while showing the patient or parent how much to fill
the device to ensure the correct dose of medication is
administered. Household tablespoons and teaspoons are
not appropriate devices to use since they do not provide
an accurate dose; potential harm via overdosing can arise
from this administration technique.
Manufacturers of unapproved hydrocodone-containing
products have been mandated to stop the manufacture and
distribution of these products. Only FDA-approved
hydrocodone-containing products should be prescribed and
dispensed to a patient, if there is a clinical indication. It is
incumbent on the pharmacist to stock only FDA-approved
products and to educate physicians when unapproved
products are prescribed. These products should be avoided
in children less than six years of age for cough, since
unwanted adverse effects may occur. Caution should also
be advised in other populations as well, since adverse reactions are not limited to children. Educating patients, as
well as other health care professionals, on approved products and their proper use is warranted for the safety of
FDA Caregiver and Patient Guidelines
on the Use of Cough and Cold Products
Do not give children medications labeled only for adults.
Talk to your health care professional if you have any questions about using cough or cold medicines in children.
Choose OTC cough and cold medicines with child-resistant safety caps, when available. After each use, make sure to close the cap tightly and store the medicines out of the sight and reach of children.
Check the “active ingredients” section of the DRUG FACTS label of the medicines that you choose. This will help you understand what symptoms the “active ingredients” in the medicine are intended to treat. Cough and cold medicines often have more than one active ingredient (such as an antihistamine, a decongestant, a cough suppressant, an expectorant, or a pain reliever/fever reducer).
Be very careful if you are giving more than one medicine to a child, and make sure the medicines do not have the same type of “active ingredients.” If you use two medicines that have the same or similar active ingredients, a child could get too much of an ingredient and that may hurt the child. For example, do not give a child more than one medicine that has a decongestant.
Carefully follow the directions for how to use the medicine in the DRUG FACTS part of the label. These directions tell you how much medicine to give and how often you can give it. If you have a question about how to use the medicine, ask your pharmacist or your doctor. Overuse or misuse of these products can lead to serious and potentially life-threatening side effects such as rapid heartbeat, drowsiness, suppression of the respiratory system, seizures, and other adverse events.
Only use measuring devices that come with the medicine or those specially made for measuring drugs. Do not use common household spoons to measure medicines for children because household spoons come in different sizes and are not meant for measuring medicines.
Understand that using OTC cough and cold medicines does not cure the cold or cough. These medicines only treat your child’s symptom(s) such as runny nose, congestion, fever, and aches and do not shorten the length of time your child is sick.
- Is It Really FDA Approved? US Food and Drug
Administration, September 30, 2008. Available from:
Accessed October 6, 2008.
- Approvals of FDA-Regulated Products. US Food and Drug
Administration. Available from:
www.fda.gov/opacom/7approvl.html. Accessed October 6,
- Marketed Unapproved Drugs: Compliance Policy Guide Center
for Drug Evaluation and Research. US Food and Drug
Administration, June 2006. Available from:
www.fda.gov/cder/guidance/6911fnl.pdf. Accessed October 6,
- Food and Drug Administration. Department of Health and
Human Services. Drug products containing hydrocodone:
enforcement action dates. Fed Register. 2007;72(189):55780-55784.
- Kelly LF. Pediatric cough and cold preparations. Pediatr Rev.
- Infant deaths associated with cough and cold medications: two
states, 2005. MMWR. 2007;56:1-4.
- Rimsza ME, Newberry S. Unexpected infant deaths associated
with use of cough and cold medications. Pediatrics. 2008;122(2):e318-e322.
- Cohen-Kerem R, Ratnapalan S, Djulus J, et al. The attitude of
physicians toward cold remedies for upper respiratory infection
in infants and children: a questionnaire survey. Clin Pediatr.
- American Academy of Pediatrics Committee on Drugs. Use of
codeine- and dextromethorphan-containing cough remedies in
children. Pediatrics. 1997;99:918-920.
- Chang AB, Glomb WB. Guidelines for evaluating chronic
cough in pediatrics: ACCP evidence-based clinical practice
guidelines. Chest. 2006;129(suppl 1):260S-283S.
- Chang CC, Cheng AC, Chang AB. Over-the-counter (OTC)
medications to reduce cough as an adjunct to antibiotics for
acute pneumonia in children and adults. Cochrane Sys Rev.
- Smith SM, Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Sys Rev. 2008;1:CD001831.
- Recalls, Market Withdrawals and Safety Alerts. US Food and
Drug Administration. Available from:
www.fda.gov/opacom/7alerts.html. Accessed October 6, 2008.
- FDA Enforcement Report Index. US Food and Drug
Administration. Available from: www.fda.gov/opacom/Enforce.html. Accessed October 6, 2008.
- CDER Mailing Lists. US Food and Drug Administration.
Available from: www.fda.gov/cder/cdernew/listserv.html.
Accessed October 8, 2008.