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Current Medical Research and Opinion
Vol. 3, No. 5 , 1975
Adverse reactions to alclofenac
J. F. Hort, M.B., B.Chir.
C u r . med. Res. Opin., (1975),3, 333.
Medical Department, Berk Pharmaceuticals Ltd., Godalming, England
Paper read: 6th June 1975
Summary By far the largest proportion of adverse reactions reported with the use of alclofenac relate to skin rashes. Estimates of the incidence of rash in approximately 1,500 patients participating in clinical trials suggest that this reaction occurred principally with the tablet (10.3 %) rather than the later capsule formulation (2.1 %) and since the tablet form has been discontinued there have been fewer reports. Detailed investigation of medical records and re-examination of patients developing a rash with alclofenac therapy indicate that there may be a ‘cross-sensitivity’ between alclofenac and other drugs such as penicillin, gold salts and salicylates. Other adverse reactions to alclofenac, such as gastro-intestinal haemorrhage and blood disorders, have been reported only rarely. Key words: Alclofenac - adverse drug reactions
Introduction Since most of the serious adverse reactions to drugs are fortunately rare events, it is unlikely that they will be detected in animal toxicity tests and also they may not show up in early clinical trials because of the relatively small numbers of animals or patients exposed to a new drug before it is released on to the market. Marketing, therefore, may be the first adequate safety trial, and the Medical Department of a pharmaceutical company producing a drug maintains a register of all available reports of adverse reactions associated with the use of the drug. This register is compiled from information received from several sources, (Figure I). The prescribing physician noticing an adverse reaction in a patient will sometimes report this to the Committee on Safety of Medicines. He seldom notifies the company responsible for the drug, however, and companies rely on their representatives collecting information during their visits to doctors. These reports from representatives form the bulk of the company’s information on possible adverse effects of the drug when it is used in a large population under a variety of conditions and, although this information is often scanty and sometimes inaccurate, it is valuable in spite of this because details of the event can usually be obtained and checked by direct contact with the physician concerned. All adverse effects known to the company are reported to the Committee on Safety of Medicines, and liaison with the Medical Officers of the Adverse Reactions Sub-committee provides further information for the company’s register. The Committee’s own register therefore 333
Adverse reactions to alclofenac
Figure 1. Reporting of adverse reactions
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
rzziF-1
contains all reported adverse reactions regardless of who received the report, and the information is stored by computer after evaluation by the medical staff of the section. Table I summarises and compares the number of main adverse reactions to some established and some recently-introduced antirheumatic drugs, as reported to the Committee on Safety of Medicines.3 Although it is probable that all but rare adverse reactions will be known once a drug has been on the market and in wide use for several years, and analysis of the raw computer data will give an indication of its adverse reaction profile, helping draw attention to a particular problem, it is extremely difficult to estimate the incidence of any one adverse reaction from data collected in this way. It is probable that because the reporting of reactions by the practising doctor is voluntary not all reactions are recorded, and many of the milder ones may go unrecognised or be regarded as not important. In addition, the frequency will obviously be determined by the volume of drug usage and the number of patients at risk. For example, comparison of the number of reports of adverse reactions to oxyphenbutazonewith prescribing statistics indicates an incidence of both reports and deaths (80 reports and 18 deaths per million prescriptions) almost exactly double that associated with phenylbutazone (40 reports and 9 deaths per million prescriptions) despite the smaller total number of reports on oxyphenbutazone. As will be seen, a high proportion of the adverse reports on alclofenac relate to skin rashes and as a result the Committee on Safety of Medicines drew doctors’ attention4 to this as a possible hazard in the use of the product. It will also be noted, however, that there have been only 5 reports of associated gastro-intestinal haemorrhage over the same period, and other adverse reactions have been rarely reported. 334
J. F.Hort
Table I. Comparison of main adverse reactions to some established and some recently-introduced non-steroidalantirheumatic drugs: reports to the Committee on Safety of Medicines (data after Cuthbert3) ~.
~~
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
Drug
Period (dates)
~
~
~
Total no. reports
~~
~-
~
~~~~
~~~
Main type of adverse reaction Blood disorders
Gastro-intestinal haemorrhage No. %
No.
Yo
Phenylbutazone
6/64-1/73
1276 (294)
398 (204)
31.2
8.2
Oxyphenbutazone
6/64-1173
421 (96)
157 (74)
17.6
3.8
Indomethacin
6/64-1173
9.6
6164-1/73
157 (25) 95 (17) 34 (5)
12.5
Aspirin
1261 (114) 787 (148) 480 (19) 179 (6) 102 (32) 50 (3) 413 I.I ,)
12.1
16.3
7.1
7.7
lbuprofen
691-1174
Naproxen
9/73-9174
Gold
6/64-9174
D-peniciI lamine
6/6&9/74
Alclofenac
6/71-1/74
Other
No.
%
397*
30.7
53** (26) 89***
6.7 18.5
294f
71.2
29.1 41
(21) 22 (2) 3
40.2
10.8
44.0
8.0
0.72
1.2 .
I
Note: Figures in parentheses are the number of fatal reactions. *reactions involving the central nervous system, mainly headache, giddiness, vertigo, confusion, and abnormalities of vision. **analgesic nephropathy. Reporting very incomplete because of vast over-the-counter sales. ***reactions involving central nervous system, including 18 reports of visual disturbances. tskin reactions.
Skin rushes Alclofenac was first made generally available in the U.K. in July 1971, and over the months a higher incidence of skin rash was reported than had been predicted from the results of most of the clinical trials by then completed. The rashes reported were mainly allergic in type and a proportion of them, probably about 10 %, were severe and accompanied by systemic upset. All resolved completely once the drug was withdrawn. Alclofenac was initially marketed as a tablet formulation and only later in capsule form. Detailed examination of the reports gave grounds for the suspicion that the tablet formulation was producing more rashes than was the capsule, but it was not possible at this stage to obtain any accurate information on incidence. As already commented, although it is possible to judge from sales figures the approximate number of patients exposed to a drug, under-reporting or nonrecognition of adverse reactions by the practising physician makes it difficult to assess the true incidence of any one reaction. A more reliable guide to the incidence of the common reactions may be obtained from the reports of clinical trials because the number of patients at risk and the number of reports recorded are known exactly. Once sufficient patients had completed trials with both tablet and capsule formulations, it was possible to make a reasonably reliable assessment of the incidence of skin rash and to see if there was any correlation with one or other formulation of the drug. Table I1 gives an analysis of approximately 1,500 patients 335
Adverse reactions to alclofenac
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
completing trials with alclofenac in the U.K., and it is apparent that, as suspected, the incidence of skin rashes is much less in patients taking the capsules. As a result, the tablet presentation of alclofenac was no longer supplied after May 1974 and since then there have been fewer reports. It must be stressed, however, that rashes still occur with alclofenac and when they do arise the drug should be discontinued promptly in that patient. Table ZI.
Incidence of skin rash in trial patients taking different formulations of alclofenac ~
Formulation Tablets Capsules
No. trial patients
~~~~
~
~~~~~~~
~
~
~
No. reports of rash
Incidence
387
40
10.3
1,129
24
2.1
(%I
It was decided to carry out a detailed investigation of those patients who developed a rash out of a group of 110 patients participating in controlled trials with alclofenac.’ Most of them were taking the tablet formulation. Fourteen of the 110 patients developed a rash. Of these, however, 2 were morbilliform in patients who had been in contact with cases of rubella, and clinical examination revealed enlarged posterior cervical and suboccipital lymph nodes : haematological and immunologicaI investigations confirmed that they were suffering from rubella and they continued to take aIclofenac. The incidence of rash in the group studied, therefore, was 10.9%, and was in line with that reported in the larger trial population. It is customary in such trials to enquire at initial assessment about a patient’s past drug history, particularly any drug sensitivities. Analysis of the data revealed that out of the 100 patients all 12 of those who exhibited rashes with alclofenac also reported past intolerance to at least one of the following drugs: penicillin, gold salts, or salicylates. To investigate the significance of such past histories, medical record cards were consulted and the patients re-interviewed. As a comparison, a random sample of 50 patients who had taken alclofenac but who had not exhibited rashes were also re-interviewed and had their past medical records examined. The findings indicated an unexpectedly high incidence of penicillin sensitivity in the group exhibiting rashes with alclofenac. In fact, 9 of the 12 patients had welldocumented accounts of past sensitivity to the penicillins. In one of these 9 patients, sensitivity was recorded following benzylpenicillin and streptomycin, so one cannot rule out the latter drugs’ contribution to the skin reaction. The next most frequent past drug sensitivity was that recorded with a sulphonamide and this occurred in 4 patients’ histories. A past history of sensitivity to indomethacin was recorded in 3 patients, to salicylates in 3, to phenylbutazone in 2, to gold salts in 2, and 1 case of sensitivity was recorded to each of the following agents: codeine compound tablets, mefenamic acid, and hydroxychloroquine. It should be noted that only adverse reactions recorded as cutaneous manifestations are included in this section. The past records of 50 randomly selected ‘control’ patients were reviewed. These patients had received alclofenac at 3.0 g. daily for periods greater than 21 days and had exhibited no adverse reactions. Whereas the percentage of sensitivity to 336
J . F. Hort
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
penicillin was 75 % in those exhibiting rashes with alclofenac, the percentage in this control group was only 4%. The total number of patients with known sensitivities in the control group was 7 cases (14%), whereas in the alclofenac rash group only 1 patient did not have a recorded sensitivity in their past medical history. It seems likely from the limited evidence available that this ‘cross-sensitivity’ is a feature of alclofenac itself rather than of the tablet formulation.
Other adverse reactions Of the 5 reported instances of gastro-intestinal haemorrhage associated with the use of alclofenac, it has been possible to investigate the circumstances in 3 of the patients. In 1, haematemesis occurred 4 days after the patient stopped taking alclofenac: the barium meal was normal except for some delay at the lower end of the oesophagus. In the second case, the gastro-intestinal bleeding was of fresh blood per rectum in an elderly woman; and in the third, also elderly, the origin of the melaena had not been found but she had had two previous episodes unconnected with alclofenac. This illustrates the need to get as much information as possible because in all 3 of these cases the original reports only stated that a doctor had told a representative that a patient had bled while taking alclofenac. Similarly, investigation of reports of anaphylactoid reactions has given valuable information. While it seems unlikely that all 3 of the cases of gastro-intestinal haemorrhage described were caused by the drug, 5 of the 6 anaphylactoid reactions probably were, since in all of these 5, the patients had taken a short course of alclofenac previously and developed the reaction immediately after they started taking it again some months later. The 6th case was probably not anaphylactoid but a faint due to conditions unconnected with any therapy. Two cases of leucopenia associated with alclofenac have been registered, but 1 of these patients has since been diagnosed as a case of Felty’s syndrome. The 3 recorded cases of vasculitis with alclofenac have been reported elsewhere.2 Very nearly all reported reactions to alclofenac have occurred within the first 3 weeks of starting the drug and most of them have occurred within 10 days of this. In a group of 80 patients monitored monthly over 3-years’ continuous use of alclofenac at full dosage, no reactions have occurred after the first 2 weeks, and none of the laboratory tests have shown any adverse effects. References 1. Aylward, M., (1974). Personal communication. 2. Billings, R. A,, Bury, H. C., Ernslie, F. S., and Kerr, G . D., (1974). Vasculitis with alclofenac therapy. Brit. med. J., 4,263. 3. Cuthbert, M. F., (1974). Adverse reactions to non-steroidal antirheumaticdrugs. Curr. med. Res. Opin., 2,600. 4. Mansell-Jones,D., (1974). Adverse reactions to alclofenac. Brit. med. J., 1,60.
337
Current Medical Research and Opinion
Vol. 3, No. 5 , 1975
Adverse reactions to alclofenac
J. F. Hort, M.B., B.Chir.
C u r . med. Res. Opin., (1975),3, 333.
Medical Department, Berk Pharmaceuticals Ltd., Godalming, England
Paper read: 6th June 1975
Summary By far the largest proportion of adverse reactions reported with the use of alclofenac relate to skin rashes. Estimates of the incidence of rash in approximately 1,500 patients participating in clinical trials suggest that this reaction occurred principally with the tablet (10.3 %) rather than the later capsule formulation (2.1 %) and since the tablet form has been discontinued there have been fewer reports. Detailed investigation of medical records and re-examination of patients developing a rash with alclofenac therapy indicate that there may be a ‘cross-sensitivity’ between alclofenac and other drugs such as penicillin, gold salts and salicylates. Other adverse reactions to alclofenac, such as gastro-intestinal haemorrhage and blood disorders, have been reported only rarely. Key words: Alclofenac - adverse drug reactions
Introduction Since most of the serious adverse reactions to drugs are fortunately rare events, it is unlikely that they will be detected in animal toxicity tests and also they may not show up in early clinical trials because of the relatively small numbers of animals or patients exposed to a new drug before it is released on to the market. Marketing, therefore, may be the first adequate safety trial, and the Medical Department of a pharmaceutical company producing a drug maintains a register of all available reports of adverse reactions associated with the use of the drug. This register is compiled from information received from several sources, (Figure I). The prescribing physician noticing an adverse reaction in a patient will sometimes report this to the Committee on Safety of Medicines. He seldom notifies the company responsible for the drug, however, and companies rely on their representatives collecting information during their visits to doctors. These reports from representatives form the bulk of the company’s information on possible adverse effects of the drug when it is used in a large population under a variety of conditions and, although this information is often scanty and sometimes inaccurate, it is valuable in spite of this because details of the event can usually be obtained and checked by direct contact with the physician concerned. All adverse effects known to the company are reported to the Committee on Safety of Medicines, and liaison with the Medical Officers of the Adverse Reactions Sub-committee provides further information for the company’s register. The Committee’s own register therefore 333
Adverse reactions to alclofenac
Figure 1. Reporting of adverse reactions
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
rzziF-1
contains all reported adverse reactions regardless of who received the report, and the information is stored by computer after evaluation by the medical staff of the section. Table I summarises and compares the number of main adverse reactions to some established and some recently-introduced antirheumatic drugs, as reported to the Committee on Safety of Medicines.3 Although it is probable that all but rare adverse reactions will be known once a drug has been on the market and in wide use for several years, and analysis of the raw computer data will give an indication of its adverse reaction profile, helping draw attention to a particular problem, it is extremely difficult to estimate the incidence of any one adverse reaction from data collected in this way. It is probable that because the reporting of reactions by the practising doctor is voluntary not all reactions are recorded, and many of the milder ones may go unrecognised or be regarded as not important. In addition, the frequency will obviously be determined by the volume of drug usage and the number of patients at risk. For example, comparison of the number of reports of adverse reactions to oxyphenbutazonewith prescribing statistics indicates an incidence of both reports and deaths (80 reports and 18 deaths per million prescriptions) almost exactly double that associated with phenylbutazone (40 reports and 9 deaths per million prescriptions) despite the smaller total number of reports on oxyphenbutazone. As will be seen, a high proportion of the adverse reports on alclofenac relate to skin rashes and as a result the Committee on Safety of Medicines drew doctors’ attention4 to this as a possible hazard in the use of the product. It will also be noted, however, that there have been only 5 reports of associated gastro-intestinal haemorrhage over the same period, and other adverse reactions have been rarely reported. 334
J. F.Hort
Table I. Comparison of main adverse reactions to some established and some recently-introduced non-steroidalantirheumatic drugs: reports to the Committee on Safety of Medicines (data after Cuthbert3) ~.
~~
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
Drug
Period (dates)
~
~
~
Total no. reports
~~
~-
~
~~~~
~~~
Main type of adverse reaction Blood disorders
Gastro-intestinal haemorrhage No. %
No.
Yo
Phenylbutazone
6/64-1/73
1276 (294)
398 (204)
31.2
8.2
Oxyphenbutazone
6/64-1173
421 (96)
157 (74)
17.6
3.8
Indomethacin
6/64-1173
9.6
6164-1/73
157 (25) 95 (17) 34 (5)
12.5
Aspirin
1261 (114) 787 (148) 480 (19) 179 (6) 102 (32) 50 (3) 413 I.I ,)
12.1
16.3
7.1
7.7
lbuprofen
691-1174
Naproxen
9/73-9174
Gold
6/64-9174
D-peniciI lamine
6/6&9/74
Alclofenac
6/71-1/74
Other
No.
%
397*
30.7
53** (26) 89***
6.7 18.5
294f
71.2
29.1 41
(21) 22 (2) 3
40.2
10.8
44.0
8.0
0.72
1.2 .
I
Note: Figures in parentheses are the number of fatal reactions. *reactions involving the central nervous system, mainly headache, giddiness, vertigo, confusion, and abnormalities of vision. **analgesic nephropathy. Reporting very incomplete because of vast over-the-counter sales. ***reactions involving central nervous system, including 18 reports of visual disturbances. tskin reactions.
Skin rushes Alclofenac was first made generally available in the U.K. in July 1971, and over the months a higher incidence of skin rash was reported than had been predicted from the results of most of the clinical trials by then completed. The rashes reported were mainly allergic in type and a proportion of them, probably about 10 %, were severe and accompanied by systemic upset. All resolved completely once the drug was withdrawn. Alclofenac was initially marketed as a tablet formulation and only later in capsule form. Detailed examination of the reports gave grounds for the suspicion that the tablet formulation was producing more rashes than was the capsule, but it was not possible at this stage to obtain any accurate information on incidence. As already commented, although it is possible to judge from sales figures the approximate number of patients exposed to a drug, under-reporting or nonrecognition of adverse reactions by the practising physician makes it difficult to assess the true incidence of any one reaction. A more reliable guide to the incidence of the common reactions may be obtained from the reports of clinical trials because the number of patients at risk and the number of reports recorded are known exactly. Once sufficient patients had completed trials with both tablet and capsule formulations, it was possible to make a reasonably reliable assessment of the incidence of skin rash and to see if there was any correlation with one or other formulation of the drug. Table I1 gives an analysis of approximately 1,500 patients 335
Adverse reactions to alclofenac
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
completing trials with alclofenac in the U.K., and it is apparent that, as suspected, the incidence of skin rashes is much less in patients taking the capsules. As a result, the tablet presentation of alclofenac was no longer supplied after May 1974 and since then there have been fewer reports. It must be stressed, however, that rashes still occur with alclofenac and when they do arise the drug should be discontinued promptly in that patient. Table ZI.
Incidence of skin rash in trial patients taking different formulations of alclofenac ~
Formulation Tablets Capsules
No. trial patients
~~~~
~
~~~~~~~
~
~
~
No. reports of rash
Incidence
387
40
10.3
1,129
24
2.1
(%I
It was decided to carry out a detailed investigation of those patients who developed a rash out of a group of 110 patients participating in controlled trials with alclofenac.’ Most of them were taking the tablet formulation. Fourteen of the 110 patients developed a rash. Of these, however, 2 were morbilliform in patients who had been in contact with cases of rubella, and clinical examination revealed enlarged posterior cervical and suboccipital lymph nodes : haematological and immunologicaI investigations confirmed that they were suffering from rubella and they continued to take aIclofenac. The incidence of rash in the group studied, therefore, was 10.9%, and was in line with that reported in the larger trial population. It is customary in such trials to enquire at initial assessment about a patient’s past drug history, particularly any drug sensitivities. Analysis of the data revealed that out of the 100 patients all 12 of those who exhibited rashes with alclofenac also reported past intolerance to at least one of the following drugs: penicillin, gold salts, or salicylates. To investigate the significance of such past histories, medical record cards were consulted and the patients re-interviewed. As a comparison, a random sample of 50 patients who had taken alclofenac but who had not exhibited rashes were also re-interviewed and had their past medical records examined. The findings indicated an unexpectedly high incidence of penicillin sensitivity in the group exhibiting rashes with alclofenac. In fact, 9 of the 12 patients had welldocumented accounts of past sensitivity to the penicillins. In one of these 9 patients, sensitivity was recorded following benzylpenicillin and streptomycin, so one cannot rule out the latter drugs’ contribution to the skin reaction. The next most frequent past drug sensitivity was that recorded with a sulphonamide and this occurred in 4 patients’ histories. A past history of sensitivity to indomethacin was recorded in 3 patients, to salicylates in 3, to phenylbutazone in 2, to gold salts in 2, and 1 case of sensitivity was recorded to each of the following agents: codeine compound tablets, mefenamic acid, and hydroxychloroquine. It should be noted that only adverse reactions recorded as cutaneous manifestations are included in this section. The past records of 50 randomly selected ‘control’ patients were reviewed. These patients had received alclofenac at 3.0 g. daily for periods greater than 21 days and had exhibited no adverse reactions. Whereas the percentage of sensitivity to 336
J . F. Hort
Curr Med Res Opin Downloaded from informahealthcare.com by Mcgill University on 11/02/14 For personal use only.
penicillin was 75 % in those exhibiting rashes with alclofenac, the percentage in this control group was only 4%. The total number of patients with known sensitivities in the control group was 7 cases (14%), whereas in the alclofenac rash group only 1 patient did not have a recorded sensitivity in their past medical history. It seems likely from the limited evidence available that this ‘cross-sensitivity’ is a feature of alclofenac itself rather than of the tablet formulation.
Other adverse reactions Of the 5 reported instances of gastro-intestinal haemorrhage associated with the use of alclofenac, it has been possible to investigate the circumstances in 3 of the patients. In 1, haematemesis occurred 4 days after the patient stopped taking alclofenac: the barium meal was normal except for some delay at the lower end of the oesophagus. In the second case, the gastro-intestinal bleeding was of fresh blood per rectum in an elderly woman; and in the third, also elderly, the origin of the melaena had not been found but she had had two previous episodes unconnected with alclofenac. This illustrates the need to get as much information as possible because in all 3 of these cases the original reports only stated that a doctor had told a representative that a patient had bled while taking alclofenac. Similarly, investigation of reports of anaphylactoid reactions has given valuable information. While it seems unlikely that all 3 of the cases of gastro-intestinal haemorrhage described were caused by the drug, 5 of the 6 anaphylactoid reactions probably were, since in all of these 5, the patients had taken a short course of alclofenac previously and developed the reaction immediately after they started taking it again some months later. The 6th case was probably not anaphylactoid but a faint due to conditions unconnected with any therapy. Two cases of leucopenia associated with alclofenac have been registered, but 1 of these patients has since been diagnosed as a case of Felty’s syndrome. The 3 recorded cases of vasculitis with alclofenac have been reported elsewhere.2 Very nearly all reported reactions to alclofenac have occurred within the first 3 weeks of starting the drug and most of them have occurred within 10 days of this. In a group of 80 patients monitored monthly over 3-years’ continuous use of alclofenac at full dosage, no reactions have occurred after the first 2 weeks, and none of the laboratory tests have shown any adverse effects. References 1. Aylward, M., (1974). Personal communication. 2. Billings, R. A,, Bury, H. C., Ernslie, F. S., and Kerr, G . D., (1974). Vasculitis with alclofenac therapy. Brit. med. J., 4,263. 3. Cuthbert, M. F., (1974). Adverse reactions to non-steroidal antirheumaticdrugs. Curr. med. Res. Opin., 2,600. 4. Mansell-Jones,D., (1974). Adverse reactions to alclofenac. Brit. med. J., 1,60.
337
