FormalPara Key Points

The potential risks associated with the prescription opioid cough and cold medication hydrocodone/chlorpheniramine in patients < 18 years of age outweigh the benefits.

Conclusions from this benefit risk assessment have contributed to a decision by the FDA to limit the use of hydrocodone-containing cough and cold medications to patients aged ≥ 18 years of age.

This review highlights the need to continually re-evaluate the safety and efficacy of older, established drugs using up to date clinical evidence and modern methods.

1 Introduction

The escalation of therapeutic opioid use is a key concern in modern medicine and public health [1, 2]. The supply of opioids in the USA increased from the equivalent of 96 mg of morphine per person in 1997 to 710 mg in 2010 [1, 3]. This has been accompanied by a corresponding increase in fatalities and other adverse events (AEs). In the USA, the death rate from prescription opioids increased from 6.1 per 100,000 population in 2009 to 13.8 per 100,000 population in 2013, and between 2006 and 2012, almost 22,000 pediatric patients were treated for opioid poisoning in US emergency departments [4].

Hydrocodone is one such prescription opioid following this trend, prescriptions of which increased by 280% between 1997 and 2007 [5]. This semisynthetic narcotic analgesic has multiple actions, qualitatively similar to those of codeine [6, 7]. In October 2014, hydrocodone-containing antitussive agents were reclassified from schedule III to schedule II drugs by the US Drug Enforcement Administration in recognition of their high potential for drug abuse [8].

In January 2018, the US Food and Drug Administration (FDA) announced an update to the safety labelling of prescription opioid cough and cold medications. Consequently, manufacturers of cough and cold medications containing codeine or hydrocodone will be required to update the labeling with a “Boxed Warning” explaining the risks of opioid misuse, abuse, addiction, overdose, death, and breathing difficulties. The FDA also made the decision to limit the use of these medications to patients aged ≥ 18 years, stating “these products will no longer be indicated for use to treat cough in any pediatric population” [9, 10]. One medication affected by this safety update is Tussionex® Pennkinetic® (hydrocodone polistirex/chlorpheniramine polistirex). Each 5-ml dose of this extended-release suspension contains hydrocodone polistirex equivalent to 10 mg hydrocodone bitartrate, plus the antihistamine chlorpheniramine polistirex, equivalent to 8 mg chlorpheniramine maleate [11].

Tussionex® Pennkinetic® was first filed as a new drug application in 1983 after the first hydrocodone product, Hycodan®, was found to be effective for the symptomatic relief of cough during the FDA’s Drug Efficacy Study Implementation (DESI) review [12]. The 1962 DESI program required that all drug products approved in the USA between 1938 and 1962 be reviewed for effectiveness, whereas previous approval was based solely on demonstrating safety [13]. During this process the FDA took action on 3443 products, 2225 of which were found to be effective based on existing evidence at the time [14].

Tussionex® Pennkinetic® was licensed for use in adults and children in 1987 for the symptomatic relief of cough and upper respiratory symptoms associated with cold and allergies. In May 2007, due to safety concerns and reports of a number of serious adverse events (SAEs) in children < 6 years of age, including a number of fatalities, the manufacturer submitted a “changes being effected” (CBE) labeling supplement (S-015) to the FDA [15, 16]. This included a contraindication in children < 6 years of age and a recommendation to use a more accurate measuring device to reduce the risk of overdose. The FDA also responded to these safety concerns, releasing a public health alert on the correct use of the drug in 2008 [17]. To address concerns around overdosing, in October 2011 the manufacturer launched a unit of use package (115 ml deliverable volume), which included a dosing device validated to allow for accurate dosing, and at the same time the 473-ml bottle was discontinued.

Traditional pharmacovigilance analysis, based upon regulatory guidance, involves review of the safety database, data from the health authority database and the literature. Here, we present findings from a modern pharmacovigilance analysis that includes thorough and comprehensive review of the available safety and efficacy data for hydrocodone/chlorpheniramine use in pediatric patients between 6 and < 18 years of age, current standards of care in clinical practice, previous FDA advisory board meeting minutes and real-world evidence. The results were used as supporting evidence for the FDA’s decision to update the safety labeling for opioid-containing prescription cough and cold medication [10].

2 Methods

2.1 Estimated Patient Exposure to Hydrocodone/Chlorpheniramine

The total exposure to hydrocodone/chlorpheniramine during the period of 1 January 2007 to 31 July 2017 was estimated based on the manufacturer’s sales data; 1 January 2007 was the earliest time point at which sales data could be extracted.

In line with the Summary of Product Characteristics, the standard daily dose (SDD) for hydrocodone was assumed to be 20 mg [11]. Patient years (PY) of exposure were calculated using the following formula:

$$ {\text{PY}}\;{ = }\;\frac{{ ( {\text{Total mg of product distributed/SSD)}}}}{ 3 6 5. 2 5} $$

2.2 Review of the Sponsor Safety Database

The manufacturer’s global safety database provides spontaneous and solicited AE reports from worldwide sources (including healthcare professionals [HCPs], consumers, non-interventional studies and the literature) for all manufacturer marketed products, as well as SAE reports from clinical trials of any compounds in development. A cumulative search of the database covering the period from 1 January 1900 (in line with the manufacturer’s patient safety search conventions) to 7 August 2017 was conducted for all individual case safety reports (ICSRs). The search was performed by product family name “hydrocodone/chlorpheniramine” and was inclusive of all MedDRA system organ classes, then further stratified by age (< 18 years).

2.3 Literature Review to Examine Safety and Effectiveness of Opioid Antitussive Treatments

A comprehensive literature review assessed the evidence relating to the safety and effectiveness of opioid use for cough and cold in pediatrics, covering the period of 19 March 2015–8 June 2016. Literature sources included, but were not limited to: the manufacturer’s review of safety data, medical literature such as a 2012 review of studies of cough medications in children [18], the 2015 joint meeting of the Pediatric and Drug Safety Advisory Committees [19], the 2015 European Medicines Agency (EMA) review [20], the American Academy of Pediatrics Clinical Report [21], and epidemiological (prescription) data (see Table 1 for a complete list of sources used).

Table 1 Sources for the literature review on the safety and efficacy of opioid antitussive treatment
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3 Results

3.1 Patient Exposure to Hydrocodone/Chlorpheniramine

Between 1 January 2007 and 31 July 2017, total exposure to hydrocodone/chlorpheniramine for patients < 18 years was estimated to be 673,487 PY; exposure was highest in 2008, followed by an overall decline through to 2017 (Fig. 1).

Fig. 1
figure 1

Patient years of exposure to hydrocodone/chlorpheniramine per fiscal year from 1 January 2007–31 July 2017. The manufacturer’s sales data were used to estimate annual exposure to hydrocodone/chlorpheniramine. aData available from 1 January 2017–31 July 2017. PY patient years. Exposure is based on a standard daily dose of 20 mg used in adults; the actual daily dose in pediatric patients is likely to have been lower, resulting in higher annual exposure rates than presented

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3.2 Cumulative Review of Pediatric Safety Data from the Sponsor Safety Database

A cumulative review of the manufacturer’s global safety database identified 391 ICSRs associated with the hydrocodone/chlorpheniramine combination product since 1 January 1990. Of these, 35 ICSRs (9%) were in pediatric patients < 18 years of age. Most cases, 24/35 ICSRs (66.7%), described use in pediatric patients < 6 years of age. Trend analysis of annual ICSR reporting rates between 1 January 2007 and 31 July 2017 showed 2009 had the highest reporting rate at 5.67 cases/100,000 PY (Fig. 2). No pediatric cases were identified in the global safety database after 1 January 2011.

Fig. 2
figure 2

Trend analysis of annual reporting rates for pediatric cases from 1 January 2007–31 July 2017. ICSRs were analyzed by trend analysis to calculate reporting rate for pediatric cases/100,000 PY. aData available from 1 January 2017–31 July 2017. ICSR individual case safety report, PY patient years. Exposure is based on a standard daily dose of 20 mg used in adults; the actual daily dose in pediatric patients is likely to have been lower, resulting in higher annual exposure rates than presented

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Overall, 18/35 of the pediatric ICSRs were considered serious. Of these, ten were fatal (Fig. 3), with nine fatalities attributed to overdose or error in drug prescribing by a HCP and/or administration by a family member (Table 2). One fatality, involving a 4-year-old patient, occurred after the < 6 years contraindication was implemented, and two fatalities involved co-suspect medication azithromycin (Table 2), a known CYP450 substrate able to disrupt hydrocodone metabolism, potentially resulting in the accumulation of hydrocodone to toxic levels [22].

Fig. 3
figure 3

Number of individual case safety reports associated with hydrocodone/chlorpheniramine treatment by seriousness in pediatric patients < 18 years from 1 January 1900–7 August 2017. Number of ICSRs per age group are reported according to whether the AE was considered serious and fatal, serious but not fatal, or non-serious. AE adverse event, ICSR individual case safety report

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Table 2 Summary of fatalities reported from 1 January 1900 to 7 August 2017 in pediatric patients receiving hydrocodone/chlorpheniramine
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The remaining eight serious ICSRs were non-fatal (Fig. 3), with hydrocodone/chlorpheniramine medication prescribed by a HCP. Of these, five cases involved patients < 6 years of age, all of which occurred prior to the contraindication in this age group and described respiratory depression and/or breathing difficulties. The other three serious cases were reported in patients aged 6 to 17 years, of which two were classified as hydrocodone/chlorpheniramine overdose. There were no reported events of respiratory depression/breathing problems in these three cases, which were either poorly documented or implied other risk factors in the patients’ medical history for the reported events.

Of the 35 ICSRs reported for pediatric patients, 17 were non-serious (Fig. 3). Twelve of these cases involved patients < 6 years of age, nine of which described prescribing or medication error without any associated clinical AEs reported. Three of the 12 cases described events which were listed AEs (such as sedation and somnolence) as per the United States Prescribing Information (USPI) or involved use of other concomitant medication such that causality due to hydrocodone/chlorpheniramine could not be confirmed. The three non-serious ICSRs described in pediatric patients ≥ 6 years were all in patients aged 9 to 16 years and were poorly documented. Two cases lacked details such as time to onset or medical history, and one case described drug prescribing error (wrong dose) with no associated clinical events. The two remaining non-serious ICSRs involved pediatric patients of unknown age, where one case was again poorly documented for the reported events and the other described medication error (reported as “giving child an adult dose”) with no associated clinical events.

Further analysis of the 24 ICSRs reported in patients < 6 years revealed a total of 56 AEs, with some patients experiencing more than one AE. For patients aged 6 to 17 years, a total of 47 AEs were reported in the ICSRs (Table 3). Two AEs, one case each of medication error and movement disorder, were reported in pediatric patients of unknown age.

Table 3 Summary of all adverse events associated with hydrocodone/chlorpheniramine use in pediatric patients < 18 years, from 1 January 1900 through to 7 August 2017
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3.3 Efficacy and Safety of Opioid Antitussive Treatment in Pediatric Populations in the Literature

A targeted review of the literature identified no reports of efficacy data for hydrocodone for the relief of cough and upper respiratory symptoms associated with allergy or a cold within the 6 to < 18 years subpopulation; the literature indicates that cough and cold in pediatric patients should ideally be managed by treatment of the underlying disorder rather than the symptoms [23]. Furthermore, the evidence identified regarding the safety of hydrocodone in the 6 to < 18 years patient population was inconclusive. For example, post-operative use of codeine and hydrocodone in 6- to 17-year-old patients with obstructive sleep apnea syndrome has been found to increase oxygen desaturation, compromising respiratory drive [24], whilst a study investigating post-operative use of a hydrocodone/acetaminophen combination product in the same age group reported no deaths or significant AEs associated with the study drug [25].

4 Discussion

Prescription opioid use and abuse has led to major concerns among the US medical community, government officials and the general public, and is considered a serious public health issue [1,2,3]. Tussionex® Pennkinetic® is a prescription combination product containing the opioid hydrocodone in addition to chlorpheniramine. Here, we report results from a modern pharmacovigilance review of the benefit risk profile of hydrocodone/chlorpheniramine within patients aged 6 to < 18 years. Findings from this review were used to support a recent update to the labelling of opioid-containing cough and cold medications such that these products will no longer be indicated for use in any patient < 18 years of age [9].

Between 2007 and 2017, the peak reporting rate for pediatric ICSRs relating to hydrocodone/chlorpheniramine was in 2009. From 2011 onwards no ICSRs were reported within the manufacturer’s global safety database. This decline in reporting rates coincides with the 2008 labeling supplement and 2011 introduction of unit of use packaging by the manufacturer, both of which may have contributed to the absence of pediatric ICSRs since 2011.

Our review of all available safety data for hydrocodone/chlorpheniramine use in pediatric patients confirms that the contraindication for children < 6 years remains appropriate due to the susceptibility of this population to life-threatening and fatal respiratory depression. Overall, the data identified in both the literature and the sponsor safety database for the pediatric population aged 6 to < 18 years were less conclusive. This age group accounted for 39% of all pediatric SAEs recorded in the global safety database, and 18% of the non-serious AEs. However, many of the ICSRs identified were poorly documented such that causality with hydrocodone/chlorpheniramine could not be confirmed.

Alongside the safety risks, there is now evidence to suggest a possible association between legitimate opioid prescribing for pediatric patients ≤ 18 years and misuse in later years [26, 27]. In particular, a US study found that individuals prescribed an opioid medication for a legitimate indication by age 17 to 18 years were on average 33% more likely to misuse prescription opioids by age 23 years than those with no history of opioid prescription [28]. This evidence is from observational, population-based studies, and as such no specific causal relationship can be proven or inferred. However, these findings should be considered when prescribing opioid products to pediatric patients.

The efficacy of hydrocodone and chlorpheniramine in the treatment of cough and upper respiratory symptoms is well established in adults through clinical trials [29,30,31]. However, our review identified no published randomized controlled trials investigating efficacy of the product in pediatric patients (< 18 years), from which we conclude that efficacy has not been demonstrated in this patient population. A 2016 review of the Cochrane Library also found no evidence either in support of, or opposition to, the use of codeine and its derivatives for the treatment of chronic cough in children [32]. The discrepancy between this up-to-date review and the 1962 DESI process, which found hydrocodone/chlorpheniramine to be effective for pediatric cough relief, highlights the importance of continually re-assessing older, established drugs using modern methods; over 2000 drugs were assessed as having sufficient efficacy for approval within their indicated populations by the DESI review [14].

Current opinion in clinical practice considers that the risks associated with opioid use in pediatric patients for self-limiting conditions such as cough and cold far outweigh any potential benefit of medication [18, 19, 32]. Alternative remedies such as honey [33,34,35,36], vapor rubs [37], and roots of the plant Pelargonium sidoides [38] have been shown to be effective in symptomatic cough relief without the risks that accompany over-the-counter and prescription medications. Furthermore, there is little evidence supporting the use of over-the-counter and prescription cough suppressants in general in children [18, 39,40,41,42]; coughing itself can assist recovery from respiratory infections through clearing the airways [43], so suppression of cough could in fact delay recovery.

5 Conclusion

Given the lack of evidence supporting the efficacy of hydrocodone/chlorpheniramine as an antitussive agent in patients < 18 years of age, together with evidence from review of the manufacturer’s safety database and existing safety concerns within the medical community, this review concludes that the benefit risk profile is not favorable. As communicated by the FDA, hydrocodone/chlorpheniramine should not be indicated for use in the 6 to 18 years patient population, aligning with the restriction already implemented for patients < 6 years old. This case study highlights the importance of regular re-evaluation of the benefit risk profile for existing drugs as new safety and efficacy evidence becomes available in the literature and clinical practice evolves.