Regulatory Toxicology and Pharmacology xxx (2014) xxx–xxx
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An analysis of legal warnings after drug approval in Thailand Pakawadee Sriphiromya a,b,⇑, Anuchai Theeraroungchaisri b a b
Health Product Vigilance Center, Food and Drug Administration, Ministry of Public Health, Thailand Chulalongkorn University, Phayathai Road, Bangkok, Thailand
a r t i c l e
i n f o
Article history: Received 31 August 2014 Available online xxxx Keywords: Drug risk management Drug safety Legal warnings Pharmacovigilance Adverse drug reactions
a b s t r a c t Drug risk management has many tools for minimizing risk and black-boxed warnings (BBWs) are one of those tools. Some serious adverse drug reactions (ADRs) emerge only after a drug is marketed and used in a larger population. In Thailand, additional legal warnings after drug approval, in the form of black-boxed warnings, may be applied. Review of their characteristics can assist in the development of effective risk mitigation. This study was a cross sectional review of all legal warnings imposed in Thailand after drug approval (2003–2012). Any boxed warnings for biological products and revised warnings which were not related to safety were excluded. Nine legal warnings were evaluated. Seven related to drugs classes and two to individual drugs. The warnings involved four main types of predictable ADRs: drug–disease interactions, side effects, overdose and drug–drug interactions. The average time from first ADRs reported to legal warnings implementation was 12 years. The triggers were from both safety signals in Thailand and regulatory measures in other countries outside Thailand. Ó 2014 Elsevier Inc. All rights reserved.
1. Introduction Drug risk management (DRM) is the overall and continuing process of minimizing risk throughout the life cycle of a product to optimize its benefit and risk balance (McEwen, 2004). According to the United States’ Code of Federal Regulation (CFR), the serious risks which led to death or serious injury are to be displayed in new warnings or added in black box warnings (BBWs) (Willy and Li, 2004). The 21CFR 201.57 in part states: ‘‘Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box. The boxed warning ordinarily shall be based on clinical data, but serious animal data toxicity may also be the basis of a boxed warning in the absence of clinical data’’ (Willy and Li, 2004). Adverse drug reactions (ADRs) surveillance is essential for DRM after approval as it enables the detection of significant ADRs in the post marketing surveillance phase. In the first study to describe additional or non-routine risk minimization measures (ARMMs) in 225 risk management plans submitted to the United Kingdom regulatory authority, the most common types of risk requiring an ARMM were ADRs (39%) (Keddie, 2013). In order to ensure drug safety, various methods such as change of drug labeling, black box warnings, written communication ⇑ Corresponding author at: Health Product Vigilance Center, Food and Drug Administration, Ministry of Public Health, Thailand. E-mail address:
[email protected] (P. Sriphiromya).
to healthcare professionals, restriction of supply and withdrawal from the market have been used to manage a drug’s risk (Ehrenpreis et al., 2012). BBWs describe serious ADRs and potential safety hazards (Wang et al., 2010). After an adverse reaction has led to death or serious injury, it is added to the prescribing information (Murphy and Roberts, 2006). Most often, they were added in the post marketing phase, in response to spontaneous events in the population. In the USA, 8.2% of drugs had acquired one or more box warnings for safety reasons after drug marketing (Lasser et al., 2002). Another study analyzing drug labeling changes and the prevalence of BBWs found that around 11% of all safety related labeling actions of the US Food and Drug Administration (US FDA) were BBWs. A total of 174 black-box changes were made in the 3 year period 2004–2006, of which 97 (55.7%) were revisions in BBWs (Cook et al., 2009). Mostly serious ADRs were reported after drug approval. BBWs can be the effective tools to manage drugs risk and make awareness to prescribers and patients. There was not enough space for details or guidelines in BBWs but serious risks were primarily displayed for approval (Wagner et al., 2006). Zarowitz found that ADRs, monitoring requirements, drug–drug interactions, drug–disease interactions, drug–laboratory test interactions are the criteria focused on in BBWs. Zarowitz also emphasizes the need for special training of health care professionals about BBWs, especially in nursing and aged care facilities (Zarowitz, 2008). In an paper analyzing all drugs prescribed from ten US Health Maintenance Organizations during a 30 month period of study,
http://dx.doi.org/10.1016/j.yrtph.2014.10.013 0273-2300/Ó 2014 Elsevier Inc. All rights reserved.
Please cite this article in press as: Sriphiromya, P., Theeraroungchaisri, A. An analysis of legal warnings after drug approval in Thailand. Regul. Toxicol. Pharmacol. (2014), http://dx.doi.org/10.1016/j.yrtph.2014.10.013
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P. Sriphiromya, A. Theeraroungchaisri / Regulatory Toxicology and Pharmacology xxx (2014) xxx–xxx
around 40% of patients received at least one medicine with a BBWs that could potentially apply to them (Wagner et al., 2006). In a study which aimed to find whether current US FDA boxed-warning drugs were included in eight on line standard reference resources (e.g. DRUGDEX, Facts and Comparisons and PDR), only 32% were covered in all eight (Cheng et al., 2010). The sensitivity of these on line information sites (= number of true BBW on a site total number of BBW 100) was as low as 42% (this was with on line PDR) (Cheng et al., 2010). Yong et al. identified new BBWs for which the US FDA issued a press release, talk paper or Public Health Advisory (n = 52) and examined subsequent mentions (n = 551) in top ten US newspapers, 5 most viewed television networks and a news wire service (Associated Press) (Yong et al., 2009). They defined six core messages (which were brand name, generic name, treatment indication, reason for BBW, clinical recommendations for patients and recommendation for patients to discuss with their healthcare practitioners). US FDA documents included a median of 5 of the 6; the media studied included a median of 3 of 6 (Yong et al., 2009). Knowledge about the mechanisms of ADRs and their risk factors is essential for the preparation of new BBWs. The basic classification for ADRs comprises type A (augmented) reactions and type B (bizarre or idiosyncratic) reactions. Type A reactions or predictable adverse reactions are those in which the adverse reaction occurs with a dose relationship to the administered drug and usually reflects the known pharmacologic actions and pharmacokinetics of the drug. Predictable ADRs are observed in patients without known predisposing factors and include toxicity, side effects, secondary drug effects, and drug interactions. Type B reactions are unpredictable and unrelated to the known pharmacology of the drug. The reactions are frequently more severe and potentially fatal. The mechanisms of action are influenced by immunological and genetic factors (Khan and Solensky, 2010). Unpredictable serious ADRs have been one of the most important types added in new BBWs. The current drug surveillance system in Thailand has been established for more than 20 years. A legal warning (black-boxed warning) may sometimes be mandatorily applied at approval in Thailand. In addition, the Drug Safety Advisory Subcommittee of the Thai Food and Drug Administration (Thai FDA) is assigned to decide the significance of various safety signals and give recommendations to add or revise the legal warnings after a drug’s authorization. The Drug Safety Advisory Subcommittee reports to the Drug Committee which makes the final recommendations to the Thai FDA. This study aimed to identify the criteria or category of risks in legal warnings in Thailand in the post marketing phase. The specific characteristics of warnings after drugs approval were evaluated. Additionally, the triggers of legal warnings were also assessed.
2. Methods The study was a cross sectional review of legal warnings which were recommended by the Drug Safety Advisory Subcommittee of the Thai FDA and implemented in Thailand after drug authorization. The study period was from January 2003 to June 2012. The study setting was at the Thai FDA, Ministry of Public Health, Thailand. The sources of information were the minutes of the Drug Safety Advisory Subcommittee and the Drug Committee. The review was designed to trace and document the characteristics of all the legal warnings. The analysis was done from the stage when the subcommittee was alerted by any type of safety signals until the legal warning was required. A classification of ADRs in two main classifications of ADRs (predictable and unpredictable ADRs) was the initial framework for the review.
Legal warnings for biological products and revisions of warnings which were not related to safety were not included in this study. The time between the first ADRs of any sort reported in Thailand for that drug or a member of the drug class and legal warning implementation was analyzed. 3. Results During January 2003 to June 2012, nine legal warnings were revised or added for safety reasons. Most triggers of actions came from safety signals arising in Thailand or actions by other regulatory authorities outside Thailand. One legal warning followed a Market Authorization Holder’s request (Table 1). Seven drug classes and two individual drugs (sulfasalazine and nimesulide) were the subjects of warnings. The warnings for some individual members of some of the drug classes had additional warnings added to the class specific warning. For four of the seven warnings about classes of drugs, the warning mentioned only predictable (type A) ADRs. Concerning predictable ADRs, four main subtypes were found to be the basis for legal warnings in this study; (1) drug–disease interactions, (2) side effects, (3) overdose or toxicity and (4) drug–drug interactions. Potential for liver toxicity in patients with liver disease was the most common drug–disease interactions and adverse effects when taken in pregnancy and lactation were the most common side effects included in the warnings. All the legal warnings included mention of unpredictable (type B) ADRs in addition to predictable effects. A warning that a drug was unsafe in patients with asthma, atrophic rhinitis conditions or a history of allergy to aspirin or other non-steroidal antiinflammatory drugs (NSAIDs) was added to all conventional NSAIDs. Warnings about allergic reactions were required for all in the oral and topical fluoroquinolone classes, sulfonamides and all selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) drugs (Table 2). The average time between the first report in Thailand of any ADRs of any sort to a drug or a member of the drug class and implementation of a legal warning was 12 years. The longest time was found with phenylbutazone (27 years) and the shortest with pioglitazone (2 years). Legal warnings for conventional NSAIDs and selective COX-2 inhibitors were revised twice during the study period. 4. Discussion Our findings showed that the change of safety information by other regulatory authorities outside Thailand had triggered most of the considerations of legal warnings. The primary criterion for warnings about predictable ADRs was drug–disease interactions, such as in hepatic or renal failure patients or other high-risk patients. Murphy and Roberts reported that high-risk patients were the most frequent subjects of additional box warnings in the US (46.11%) (Murphy and Roberts, 2006). The results revealed that potential liver toxicity was the most often specified criterion in the legal warnings, being included in more than half of all warnings in Thailand. This is consistent with a previous study reporting that hepatic failure was the most common topic of additional warnings after drugs were marketed (19%) and that, hepatic reactions were amongst the top five safety reasons for withdrawals from the market (26.2%) (Fung et al., 2001). Stevens–Johnson syndrome caused by ciprofloxacin triggered a box warning for the fluoroquinolone drug class in Thailand. Such an uncommon reaction was not established at the time of the drug’s registration. Other factors may be related to such a serious
Please cite this article in press as: Sriphiromya, P., Theeraroungchaisri, A. An analysis of legal warnings after drug approval in Thailand. Regul. Toxicol. Pharmacol. (2014), http://dx.doi.org/10.1016/j.yrtph.2014.10.013
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P. Sriphiromya, A. Theeraroungchaisri / Regulatory Toxicology and Pharmacology xxx (2014) xxx–xxx Table 1 Drug/drug class with safety signal trigger for legal warnings. No.
Drug class
Drug name
First safety trigger
Year
1
Fluoroquinolone
Serious skin reactions reported in Thailand and other countries (Lemery, 2012)
2003
2
Conventional NSAIDsa
Revision of all NSAIDs due to referral of some COX2b inhibitors drug class (Heim and Broich, 2006)
2006
3
Selective COX-2 inhibitors
Removal of some COX-2 inhibitors drug class in the EU (Heim and Broich, 2006)
2006
4
Hormone replacement therapy Preferential COX-2 inhibitors
6
Thiazolidinediones
Rosiglitazone
7
Thiazolidinediones
Pioglitazone
8
Sulfonamides
Sulfasalazine
9
Sulfonamides
Sulfadiazine Sulfadoxine Sulfafurazole Sulfamethoxazole Simvastatin Fluvastatin Cerevastatin Atorvastatin Pravastatin
Report of serious thromboembolism in Canada, Australia and the US (Harman, 2006) Suspension in Ireland from liver toxicity and review of benefit and risk in the EU (Khan, 2008) Report of serious cardiovascular events in Canada and the US (Neumann et al., 2012) Report of bladder cancer in France (Neumann et al., 2012) Market authorization holders asked for change of teratogenic class effect in Thailand due to the adjustment of safety profile (Nørgård et al., 2001) Review of teratogenic class effect in Thailand due to the adjustment of safety profile (Nørgård et al., 2001)
2006
5
Ciprofloxacin Ofloxacin Norfloxacin Ibuprofen Ketoprofen Piroxicam Diclofenac Tenoxicam Meloxicam Celecoxib Parecoxib Etoricoxib Estrogen or estradiol and progesterone or progestin Nimesulide
10
a b
Statin
Change of safety information about cardiovascular events in the EU (Magee et al., 2010)
2007 2007 2011 2011
2011
2011
NSAIDs: Non-steroidal anti-inflammatory drugs. COX-2: Cyclo-oxygenase-2.
drug allergy. Patients with multiple drug allergies, familial drug allergy or Human Leukocyte Antigen phenotype (HLA phenotype) are prone to allergic adverse drug reactions (Khan and Solensky, 2010). Sulfonamide antibiotics and derivatives were widely used and known for serious reactions such as skin reactions, liver injury or hematologic reactions from a variety of mechanisms (Vial, 2002). The teratogenic potential of sulfonamides was reported in the large Hungarian case–control surveillance study, especially in the second and third months of pregnancy (Czeizel et al., 2001). These serious occurrences were the basis for the updates to the safety information in Thailand. Based on our results, the average time between the first ADRs reported to new legal warning implementation was 12 years. In our study, the least time between a first ADR report and a legal warning was with topical fluoroquinolones (1 year) and was a consequence of local Thai reporting. A previous study determined the timing of new ADRs described in BBWs to be around 7 years (Lasser et al., 2002). The early dates of first ADR reports show the coverage of the spontaneous drug surveillance system in Thailand. However, under reporting was found even in the active pharmacovigilance countries because the spontaneous reporting had major limitations and this was an important factor of concern for the triggering of signals (Giofrè et al., 2013). The legal warnings were simultaneously added or revised for all drugs in five drug classes (COX-2 inhibitors, fluoroquinolone, hormone replacement therapy, sulfonamides and statins drug class) in Thailand. Two years after initial legal warnings were imposed for the COX-2 inhibitors and the conventional NSAIDs drug class, new safety signals resulted in additional warnings for both drug classes. Our observation is different to a previous study which aimed to evaluate systematically the concordance in the
BBWs labeling between same-class drugs. It found that the median interval time of BBW appearance in another drug of the same class was 5 years (Panagiotou et al., 2011). A 25 years retrospective study of new BBWs (Lasser et al., 2002) found that around 11% of drugs to which new warnings were added were subsequently withdrawn from the market within 2 years. In Thailand, one drug (rosiglitazone) was withdrawn 1 year after a new warning was implemented. Boxed warnings have been a long-standing feature of safety regulation of medicines in the United States of America, but there has been no information about the frequency or nature of the use of boxed warnings in South East Asian countries. Boxed warnings are imposed in Thailand by the Thai FDA with the force of law. Hence, there are termed ‘‘legal warnings’’. The study shows that in Thailand to date the imposition of legal warnings has been largely limited to serious safety concerns identified internationally and about which other major regulatory agencies have also taken action. An advantage of limiting legal warnings to major safety concerns is that the hoped for impact of the information on prescribers will be realized.
5. Conclusions Legal warnings about newly identified ADRs were implemented after drug approval in Thailand with an average of 12 years from the first ADRs report in the pharmacovigilance system. Liver toxicity was the major concern. Compared with previous literatures, these results are consistent. Although the timings of implementation of new box warnings in other studies were nalyzed by different methods, the emergence of safety signals in surveillance systems were similar important triggers for action.
Please cite this article in press as: Sriphiromya, P., Theeraroungchaisri, A. An analysis of legal warnings after drug approval in Thailand. Regul. Toxicol. Pharmacol. (2014), http://dx.doi.org/10.1016/j.yrtph.2014.10.013
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Drug class
Drug name
First drug approvala
First ADR reportedb
Classification of adverse reactions (ADRs)c
Warnings
Time to new legal warning after first ADR reported (in years)
Time to new legal warning after first drug approval (in years)
Statin
Simvastatin Pravastatin Fluvastatin Cerevastatin Atorvastatin
1990 1993 1998 1998 1997
1993 (Simvastatin)
Predictable
12 (Simvastatin)
15 (Simvastatin)
Fluoroquinolone (oral form)
Ciprofloxacin Ofloxacin Norfloxacin
1988 2001 2001
1993 (Ciprofloxacin)
Predictable
10 (Ciprofloxacin)
15 (Ciprofloxacin)
Fluoroquinolone (topical form)
Ofloxacin Levofloxacin
2001 2001
2008 (Ofloxacin)
Predictable
1 (Ofloxacin)
8 (Ofloxacin)
Conventional NSAIDs
Ibuprofen Ketoprofen Piroxicam Diclofenac Tenoxicam Meloxicam
1983 1984 1984 1984 1994 2000
1998 (Ibuprofen)
Unpredictable Predictable
Side effect: unsafe during lactation and pregnancy Drug–disease interaction: unsafe for hepatic patients Toxicity: if myalgia occurred, stop medicine and consult physicians Side effect: Unsafe to pregnancy and lactation Toxicity: if rash, myalgia occurred, stop medicine and consult physicians Drug–disease interaction: Unsafe to hepatic and renal function Toxicity: if red eyes, eye edema, rash, myalgia occurred, stop medicine and consult physicians Drug–disease interaction: unsafe to hepatic and renal function Allergic Side effect: unsafe to pregnancy last trimester Drug–disease interaction: harmful to bleeding gastritis Drug–disease interaction: unsafe to hepatic and renal patients Drug–disease interaction: unsafe to dengue fever patients Allergic, asthma, atrophic rhinitis from allergy to aspirin or NSAIDS Side effect: unsafe to pregnancy last trimester Drug–disease interaction: harmful to bleeding gastritis Drug–disease interaction: unsafe to hepatic and renal patients Drug–disease interaction: unsafe to dengue fever patients Drug–disease interaction: unsafe to aplastic anemia patients Allergic, asthma, atrophic rhinitis from allergy of aspirin or NSAIDs Toxicity: always monitor therapy with physicians Drug–disease interaction: unsafe to cardiovascular, cerebrovascular disease or history of thromboembolism Toxicity: long term use is increasing risk or severity of breast cancer Drug–disease interaction: unsafe to congestive heart failure (NYHAd level 3 and 4) Drug–drug interactions: drug interaction with insulin causing edema and congestive heart failure
12 (Ibuprofen)
27 (Ibuprofen)
27
27
10
10
Unpredictable Conventional NSAIDs
Phenylbutazone
1983
1983
Predictable
Unpredictable Hormone replacement therapy
Estrogen or estradiol and Progesterone or Progestin
Thiazolidinediones
All
1999
1999
Predictable
Predictable
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Please cite this article in press as: Sriphiromya, P., Theeraroungchaisri, A. An analysis of legal warnings after drug approval in Thailand. Regul. Toxicol. Pharmacol. (2014), http://dx.doi.org/10.1016/j.yrtph.2014.10.013
Table 2 Drug name/drug class with legal warnings (January 2003–June 2012).
Rosiglitazonee
1999
2001
Predictable
Thiazolidinediones
Pioglitazone
2008
2010
Predictable
Sulfonamides
All
Sulfonamides
Sulfasalazine
Predictable
1984
1998
Unpredictable Predictable
Unpredictable
Selective COX – 2 inhibitors
All
Selective COX – 2 inhibitors
Celecoxib Parecoxib
Drug–disease
1999
2000 (Celecoxib)
Unpredictable Predictable
Unpredictable
Selective COX – 2 inhibitors
Etoricoxib
2003
2004
Predictable
Unpredictable
As for all thiazolidinediones plus: Drug–disease interaction: unsafe to ischaemic heart disease Drug–drug interactions: drug interaction with nitrate causing ischemic heart disease As for all thiazolidinediones plus: Toxicity: increased risk of bladder cancer Drug–disease interaction: harmful to bladder cancer patients Overdose: long term use more than 1 year can increase risk of bladder cancer Drug–disease interaction: consider benefit and risk of use in patients with history of bladder cancer or having previous risks of bladder cancer Drug–disease interaction: harmful to hepatic and renal functions Side effect: unsafe in infant less than 2 months Side effect: unsafe in lactation and pregnancy Allergic Drug–disease interaction: harmful to hepatic and renal functions Side effect: unsafe in infant less than 2 months Side effect: unsafe in lactation and pregnancy Allergic Side effect: severe rash Side effect: Stevens–Johnson syndrome Side effect: unsafe during lactation and pregnancy Drug–disease interaction: unsafe for immediate postoperative period Drug–disease interaction: increased mortality with cardiovascular disease and cerebrovascular disease Allergic Side effect: unsafe during lactation and pregnancy Drug–disease interaction: unsafe for immediate postoperative period Drug–disease interaction: increased mortality with cardiovascular disease and cerebrovascular disease Allergic Side effect: severe rash Side effect: Stevens–Johnson syndrome As for all selective COX-2 inhibitors plus: Drug–disease interaction: unsafe in uncontrolled hypertension Allergic
11
13
2
4
14
28
10 (Celecoxib)
11 (Celecoxib)
6
7
P. Sriphiromya, A. Theeraroungchaisri / Regulatory Toxicology and Pharmacology xxx (2014) xxx–xxx
(continued on next page)
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Please cite this article in press as: Sriphiromya, P., Theeraroungchaisri, A. An analysis of legal warnings after drug approval in Thailand. Regul. Toxicol. Pharmacol. (2014), http://dx.doi.org/10.1016/j.yrtph.2014.10.013
Thiazolidinediones
P. Sriphiromya, A. Theeraroungchaisri / Regulatory Toxicology and Pharmacology xxx (2014) xxx–xxx
Conflict of interest None. Ethical considerations 14
Time to new legal warning after first drug approval (in years)
6
Time to new legal warning after first ADR reported (in years)
4 Side effects: unsafe to pregnancy in last trimester Side effects: harmful to bleeding gastritis Drug–disease interaction: unsafe to hepatic and renal patients Drug-disease interaction: unsafe to dengue fever patients Overdose:limit treatment to not more than 15 days Allergic, asthma, atrophic rhinitis from allergy to aspirin or NSAIDs
e
c
d
The drug approval year in Thailand (the year sale may be varied from the approval year). The first ADRs reported in the pharmacovigilance system in Thailand. Khan and Solensky (2010). New York Heart Association functional classification. Withdrawal from Thailand in year 2002.
Unpredictable
References
a
Nimesulide Preferential COX-2 inhibitors
The author thanks the Thai Food and Drug Administration for permission to conduct this study. This study would not have been possible without the help and support of Dr. John McEwen from the Therapeutic Goods Administration (TGA), Australia for which I am deeply grateful. This work was partially supported by Chulalongkorn University graduate school thesis grant, Thailand. This study is a part of the research of the author to fulfill the requirement for Doctoral Degree in Social and Administrative Pharmacy, Faculty of Pharmaceutical Science, Chulalongkorn University.
b
Drug name
1997
2007
Predictable
Acknowledgments
Drug class
Table 2 (continued)
First drug approvala
First ADR reportedb
Classification of adverse reactions (ADRs)c
Warnings
The study did not directly deal with humans.
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Please cite this article in press as: Sriphiromya, P., Theeraroungchaisri, A. An analysis of legal warnings after drug approval in Thailand. Regul. Toxicol. Pharmacol. (2014), http://dx.doi.org/10.1016/j.yrtph.2014.10.013