Approved and Unapproved
Hydrocodone-Containing Cough Products:
What Do You Need To Know?

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.

FDA REGULATION

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 illegal.

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).

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 these medications.⁷

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 age (p<0.001).

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 symptoms.

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 approved.

The FDA has a website, Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/), 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 (http://www.fda.gov/opacom/7alerts.html).¹³ Another 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.

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.

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.

COMMUNICATION

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.

CONCLUSION

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 patients.

REFERENCES

1. Is It Really FDA Approved? US Food and Drug Administration, September 30, 2008. Available from: www.fda.gov/consumer/updates/approvals093008.html. Accessed October 6, 2008.
2. Approvals of FDA-Regulated Products. US Food and Drug Administration. Available from: www.fda.gov/opacom/7approvl.html. Accessed October 6, 2008.
3. 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, 2008.
4. Food and Drug Administration. Department of Health and Human Services. Drug products containing hydrocodone: enforcement action dates. Fed Register. 2007;72(189):55780-55784.
5. Kelly LF. Pediatric cough and cold preparations. Pediatr Rev. 2004;25:115-123.
6. Infant deaths associated with cough and cold medications: two states, 2005. MMWR. 2007;56:1-4.
7. Rimsza ME, Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics. 2008;122(2):e318-e322.
8. 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. 2006;45:633-640.
9. American Academy of Pediatrics Committee on Drugs. Use of codeine- and dextromethorphan-containing cough remedies in children. Pediatrics. 1997;99:918-920.
10. Chang AB, Glomb WB. Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(suppl 1):260S-283S.
11. 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. 2007;4:CD006088.
12. 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.
13. Recalls, Market Withdrawals and Safety Alerts. US Food and Drug Administration. Available from: www.fda.gov/opacom/7alerts.html. Accessed October 6, 2008.
14. FDA Enforcement Report Index. US Food and Drug Administration. Available from: www.fda.gov/opacom/Enforce.html. Accessed October 6, 2008.
15. CDER Mailing Lists. US Food and Drug Administration. Available from: www.fda.gov/cder/cdernew/listserv.html. Accessed October 8, 2008.

Back to Top