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Pamidronate Disodium and Possible Ocular Adverse Drug Reactions
Pamidronate Disodium and Possible Ocular Adverse Drug Reactions Veronika Macarol, M.D., and F. T. Fraunfelder, M.D.
Ciba-Geigy Central Epidemiology and Drug Safety Center has received 23 reports of sus pected ocular adverse drug reactions associat ed with the use of intravenous pamidronate disodium, an inhibitor of bone résorption that is used primarily in the management of tu mor-induced hypercalcemia and Paget's dis ease of the bone. Anterior uveitis, bilateral in six of seven patients, occurred within 24 to 48 hours after the drug was administered. The anterior uveitis recurred in four of the five patients who were rechallenged. Three re ports involved unilateral episcleritis or scleritis occurring within one to six days after the administration of the drug. Only the episcle ritis patient was rechallenged five months later, when the patient again had the episcle ritis occur in the same eye. Thirteen patients reported nonspecific transitory conjunctivitis within six to 48 hours after pamidronate diso dium was given intravenously. This was posi tive on rechallenge in six of eight patients. These data indicate that, on rare occasions, pamidronate disodium is a probable cause of anterior uveitis or nonspecific transitory con junctivitis and is a possible cause of episcleri tis or scleritis. 1 AMiDRONATE DISODIUM (3-amino-l-hydroxypropylidene-l,l-bisphosphonatepentahydrate) is an inhibitor of bone résorption that is used worldwide in the management of hypercalce mia of malignancy, painful bone métastases, and Paget's disease of the bone. Pamidronate, etidronate, and clodronate are commercially available bisphosphonates. Pamidronate has been reported to cause bilateral uveitis in one Accepted for publication March 7, 1994. From Ciba-Geigy Limited, Basel, Switzerland (Dr. Macarol); and the Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon (Dr. Fraunfelder). This study was supported, in part, by a grant from Research to Prevent Blindness, New York, New York. Reprint requests to Veronika Macarol, M.D., CibaGeigy, Limited, Central Epidemiology and Drug Safety, CH-4002 Basel, Switzerland.
220
patient. 1 We reviewed possible and probable ocular adverse drug reactions with use of pami dronate disodium (Aredia, Ciba-Geigy Limited, Basel, Switzerland).
Subjects and Methods Worldwide case reports on ocular adverse drug reactions with pamidronate treatment are recorded at the Central Drug Safety Center, Ciba-Geigy Limited, in Basel, Switzerland. The database comprises cases reported within the framework of the spontaneous reporting sys tem, that is, individual patients treated with the commercially available drug, cases for which the drug was obtained on a named patient basis, and cases from clinical trials. The adverse drug reactions are recorded as reported by the attending physician. This report comprises data on ocular adverse drug reactions collected until August 31, 1993. One case of bilateral uveitis was published elsewhere 1 (Case 1 of Table 1). Twenty-three patients, 14 men and nine women, ranging in age from 26 to 79 years received daily between 30 and 120 mg of intra venous pamidronate disodium on various time schedules. The indication for treatment was Paget's disease of the bone in 20 patients, familial osteolysis in two patients, and algoneurodystrophy in one patient. The onset of the adverse drug reactions varied, since not all onsets occurred with the first dosage. Possible adverse drug reactions occurred in the follow ing three categories: Group 1, anterior uveitis—After receiving in travenous pamidronate, bilateral anterior uvei tis occurred in six patients, and unilateral uvei tis occurred in one patient (Case 2 of Table 1). In one patient, this occurred or went unrecog nized until 17 days after treatment, while in the remaining patients uveitis occurred within 24 to 48 hours after receiving the drug. The uveitis was minimal, not requiring treatment, in two patients and cleared within 24 hours. Two pa-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 118:220-224, AUGUST, 1994
Adverse Reactions to Pamidronate Disodium
Vol. 118, No. 2
221
TABLE 1 NONSPECIFIC ANTERIOR UVEITIS ASSOCIATED WITH PAMIDRONATE DISODIUM USE IN GROUP 1 ADVERSE
TIME UNTIL ADVERSE
CASE NO.,
DAILY
DRUG REACTION
AGE (YHS), GENDER
DOSE
AFTER
DRUG REACTION
(MG)
DOSE NO.
ONSET (HRS)
CO-MEDICATION
1,63, F
None
60
1
24
2, 26, F
None
30
2
24
3, 51, F
None
30
2
24
4, 72, F
None
120
2
17 days
83 45
3 1
24 48
30
1
48
5, 56, M None 6, 79, M Nitrazepam, Co-codamol, and cholecalciferol 7, 65, M Metformin, aspirin, isosorbide mononitrate, and bendroflumethiazide
RECHALLENGE
TREATMENT
Positive
Topical corticosteroids Positive after dose None 3; negative after doses 4-6 Positive after None doses 3-6 Negative Corticosteroids and cycloplegics Cycloplegics Not done Positive three Hospitalized months later Not done
Hospitalized
recurrent anterior uveitis; it is possible that uveitis occurred by chance after exposure to the drug. Group 2, episcleritis and scleritis—Three pa tients developed either unilateral episcleritis or scleritis between one and six days after receiv ing intravenous pamidronate disodium treat ment (Table 2). None had a prior history of these diseases. Two patients were treated with this agent for Paget's disease, whereas the third had algoneurodystrophy. The patient with epi scleritis (Case 8 of Table 2) was rechallenged with pamidronate five months later, and the
tients required topical corticosteroids with or without cycloplegics and resolved within sever al days to one month. In three patients, the ophthalmologists considered the uveitis to be severe; two of them were hospitalized. In two patients (Cases 5 and 7 of Table 1) the drug was not reinstituted. However, the remaining five patients were rechallenged, and the uveitis re curred in four patients. Patient 1 (Table 1) previously had bilateral anterior uveitis after receiving oral risedronate, also a bisphosphonate. The patient who had a negative rechal lenge (Case 4 of Table 1) had a long history of
TABLE 2 POSSIBLE EPISCLERITIS OR SCLERITIS ASSOCIATED WITH PAMIDRONATE DISODIUM USE IN GROUP 2
CASE NO., AGE (YRS), GENDER
DAILY DOSE DIAGNOSIS
8, 63, M Episcleritis (LE.) 9, 58, F Anterior scleritis (RE.) 10, 78, M Posterior scleritis (L.E.)
ADVERSE
TIME UNTIL
DRUG REACTION
ADVERSE
(MG)
AFTER DOSE NO.
None
30
None Aspirin
COMEDICATION
DRUG REACTION ONSET
RECHALLENGE
1
6 days
75
2
6 days
Positive five months later Not done
Oral indomethacin Hospitalized
30
3
24hrs
Not done
Oral corticosteroids
TREATMENT
222
August, 1994
AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE 3 NONSPECIFIC CONJUNCTIVITIS ASSOCIATED WITH PAMIDRONATE DISODIUM USE IN GROUP 3 ADVERSE
TIME UNTIL
DRUG
ADVERSE REACTION
CASE NO-
DAILY
AGE (YRS),
DOSE
REACTION AFTER
GENDER
(MG)
DOSE NO.
ONSET (HRS)
RECHALLENGE
Not done Not done Negative after six doses four months later Not done Positive after dose 2; later negative for two doses Not done Positive after doses 2-6 Positive after dose 2 Negative Positive after dose 6 Positive after dose 2 Positive after dose 3 Not done
DRUG
11,64, F 12, 80, M 13,71, M
43 53 52
2 2 4
24 24 24
14,61, F 15, 76, M
60 47
2 1
6 24
F M M M M M M F
47 30 30 60 120 60 60 60
3 1 1 3 5 1 2 6
24 24 24 24 24 24 48 Unknown
16,71, 17, 70, 18,59, 19,68, 20, 64, 21,54, 22, 63, 23, 56,
episcleritis recurred in the same eye. This pa tient was taking no other medication. Both scleritis patients had no apparent cause for their disease. Full recovery occurred in all pa tients. Group 3, nonspecific conjunctivitis—There were 13 patients who had a nonspecific con junctivitis consisting of any or all of the follow ing: conjunctival hyperemia, irritation, epipho ra, with or without discharge, and with or without blurred vision, occurred bilaterally in ten patients and unilaterally in three patients (Table 3). This usually started within the first six to 48 hours after the administration of the drug. Ocular symptoms resolved within a few days, but in one patient resolution required one week. This adverse drug reaction occurred after the first or second dosage in most patients, and after the third, fourth, fifth, or sixth dose in one patient each. Rechallenge was positive in six patients, but in one (Case 15 of Table 3), rechal lenge became negative later. However, the time of rechallenge in this group varied between two and 14 days after the appearance of the first reaction, so symptoms may have overlapped. Five patients were not rechallenged, and for two patients the outcome of rechallenge was negative. Two patients had been previously exposed to pamidronate, of whom one (Case 20 of Table 3) also had a nonspecific conjunctivitis and the other (Case 14 of Table 3) had no
drug-related ocular side effects.
Discussion As a group of drugs, the bisphosphonates have only had two previously published reports in which patients had possible ocular adverse drug reactions associated with their use, name ly, xanthopsia, which lasted for two hours after the first injection of pamidronate and did not occur on re-exposure, 2 and anterior uveitis 1 af ter exposure to pamidronate. This series of 23 patients, including one of the patients previ ously described, 1 is a compilation of all ocular adverse drug reactions reported with the use of pamidronate disodium and recorded at the Central Epidemiology and Drug Safety Center of Ciba-Geigy Limited, in Basel, Switzerland. We reviewed three categories of possible ad verse drug reactions involving the eye coinci dent with pamidronate use. These data are somewhat unique, because, in clinical ocular toxicology, rechallenge associated with a possi ble ocular adverse drug reaction is not com mon. Rechallenge was possible because the indications for the use of this agent are serious, the drug is given in serial intravenous infu sions, and the majority of these adverse drug reactions are rare and of little consequence.
Vol. 118, No. 2
Adverse Reactions to Pamidronate Disodium
We believe that in rare instances pamidronate is probably associated with a low-grade to se vere anterior uveitis (Group 1, Table 1). This association is based on the uveitis recurring in four of five cases that were rechallenged. Six of the seven cases were bilateral, whereas two thirds of the cases of non-drug-related anterior uveitis are unilateral. 3 The severity of the uvei tis varied from minimal to severe, with recovery ranging from one day to one month. The onset of anterior uveitis after drug exposure varied from one day to 17 days. In Case 4 (Table 1) the patient had a 20-year history of recurrent ante rior uveitis, so that the relationship of the adverse drug reaction with treatment could not be established, especially since subsequent re peat rechallenges have been negative. An association between this drug and episcleritis and scleritis (Group 2, Table 2) is not clear. The single case of episcleritis with a positive rechallenge five months later in the same eye is suggestive of a causal relationship; however, this awaits confirmation by similar cases. A single case each of anterior and poster ior scleritis occurring six days after the second drug infusion and 24 hours after the third infusion, respectively, without rechallenge data, is suspect, in part because we and others 4 are not aware of any previous reports of a drug-induced scleritis. Therefore, we classify this adverse drug reaction as possibly related to treatment. One can only speculate as to the possible cause of anterior uveitis, episcleritis, or scleri tis. Thus, we suggest an allergic or immunolog ie phenomenon, possibly because of immunecomplex formation induced by the drug. In the two patients with scleritis (Cases 9 and 10 of Table 2), the onset of ocular adverse drug reac tions was accompanied or preceded by tran sient fever. It is tempting, therefore, to assume that the ocular reactions may be a form of acute-phase response (such as fever or lymphopenia), as seen with aminobisphosphonates. These bisphosphonates stimulate cytokine re lease (interleukin-1 and interleukin-6) and the synthesis of acute-phase proteins. This acutephase response is reported as being unrelated to dose, route of administration, or type or activity of the underlying disease, such as Paget's disease of the bone, malignancy, or osteoporosis. 58 It has been postulated, howev er, that patients with a malignancy are less prone to suffer from these side effects, possibly because of an immunologie defect that sup presses cytokine production. 9 This might ex
223
plain why none of the patients in this series suffered from a malignancy. In all except three patients, the indication for treatment with pa midronate was Paget's disease of the bone. Uveitis, episcleritis, and scleritis have not been associated with Paget's disease of the bone, familial osteolysis, or algoneurodystrophy. It has been suggested 1 that these ocular adverse drug reactions are related to the nitrogen-con taining bisphosphonates, because uveitis, scle ritis, or episcleritis has not been reported with non-nitrogen-containing bisphosphonates. The nonspecific conjunctivitis group, (Group 3, Table 3), in which symptoms occur usually 24 to 48 hours after exposure to pamidronate, was usually bilateral and seldom required treat ment, with symptoms resolving in hours to days. In our opinion, this is a probable adverse drug reaction, on the basis of uniform time until onset after drug exposure, similar ocular patterns among patients, and positive rechal lenges in six of eight patients. The pattern of this nonspecific conjunctivitis indicates that the drug may be secreted by the lacrimal gland in some patients and that the conjunctivitis is due to the presence of the drug in the tears, causing transitory irritation. Thus far, no assay for pa midronate in the tears has been performed. It is estimated that more than 50,000 patients have been exposed to intravenous pamidronate disodium. To date, the total number of cases with ocular adverse drug reactions of which we are aware is 23, which indicates that ocular adverse drug reactions to pamidronate disodi um appear to be quite rare. Regardless, this drug may need to be discontinued in patients who develop significant anterior uveitis, epi scleritis, or scleritis after the administration of the drug, although for episcleritis and scleritis a firm relationship to treatment has not been established.
References 1. Siris, E. S.: Bisphosphonates and iritis. Lancet 341:436, 1993. 2. Morton, A. R., Dodwell, D. J., and Howell, A.: Disodium pamidronate (APD) for the management of hypercalcaemia of malignancy. Comparative studies of single-dose versus daily infusions and of infusion duration. In Burckhardt, P. (ed.): Disodium Pamidro nate (APD) in the Treatment of Malignancy-related Disorders. Toronto, Hans Huber Publishers, 1989, pp. 85-100.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
3. Tilden, M. E., Rosenbaum, J. T., and Fraunfelder, F. T.: Systemic sulfonamides as a cause of bilater al, anterior uveitis. Arch. Ophthalmol. 109:67, 1991. 4. Watson, P. G., and Hazleman, B. L.: The sciera and systemic disorders. In Trevor-Roper, P. D. (ed.): Major Problems in Ophthalmology, vol. 2. Philadel phia, W. B. Saunders, 1976, pp. 197-201. 5. Adami, S., Bhalla, A. K., Dorizzi, R., Montesanti, F., Rosini, S., Salvagno, G., and Lo-Cascio, V.: The acute-phase response after bisphosphonate adminis tration. Calcif. Tissue Int. 41:326, 1987. 6. Bijvoet, O. L., Frijlink, W. B., Jie, K., van der Linden, H., Meijer, C. J., Mulder, H., van Paassen, H. C , Reitsma, P. H., te Velde, ]., de Vries, E., and van der Wey, J. P.: APD in Paget's disease of bone.
August, 1994
Role of the mononuclear phagocyte system? Arthritis Rheum. 23:1193, 1980. 7. Gallacher, S. J., Fraser, W. D., Cruickshank, A. M., Shenkin, A., and Boyle, I. T.: The response of plasma interleukin-6 (IL-6) to pamidronate. Bone (U.S.A.) 11:384, 1990. 8. Harinck, H. I., Papapoulos, S. E., Blanksma, H. J., Moolenaar, A. J., Vermeij, P., and Bijvoet, O. L.: Paget's disease of bone. Early and late respons es to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). Br. Med. J. Clin. Res. Ed. 295:1301, 1987. 9. Gallacher, S. J., Ralston, S. H., Patel, U., and Boyle, I. T.: Side-effects of pamidronate. Lancet 2:42, 1989.
Ciba-Geigy Central Epidemiology and Drug Safety Center has received 23 reports of sus pected ocular adverse drug reactions associat ed with the use of intravenous pamidronate disodium, an inhibitor of bone résorption that is used primarily in the management of tu mor-induced hypercalcemia and Paget's dis ease of the bone. Anterior uveitis, bilateral in six of seven patients, occurred within 24 to 48 hours after the drug was administered. The anterior uveitis recurred in four of the five patients who were rechallenged. Three re ports involved unilateral episcleritis or scleritis occurring within one to six days after the administration of the drug. Only the episcle ritis patient was rechallenged five months later, when the patient again had the episcle ritis occur in the same eye. Thirteen patients reported nonspecific transitory conjunctivitis within six to 48 hours after pamidronate diso dium was given intravenously. This was posi tive on rechallenge in six of eight patients. These data indicate that, on rare occasions, pamidronate disodium is a probable cause of anterior uveitis or nonspecific transitory con junctivitis and is a possible cause of episcleri tis or scleritis. 1 AMiDRONATE DISODIUM (3-amino-l-hydroxypropylidene-l,l-bisphosphonatepentahydrate) is an inhibitor of bone résorption that is used worldwide in the management of hypercalce mia of malignancy, painful bone métastases, and Paget's disease of the bone. Pamidronate, etidronate, and clodronate are commercially available bisphosphonates. Pamidronate has been reported to cause bilateral uveitis in one Accepted for publication March 7, 1994. From Ciba-Geigy Limited, Basel, Switzerland (Dr. Macarol); and the Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon (Dr. Fraunfelder). This study was supported, in part, by a grant from Research to Prevent Blindness, New York, New York. Reprint requests to Veronika Macarol, M.D., CibaGeigy, Limited, Central Epidemiology and Drug Safety, CH-4002 Basel, Switzerland.
220
patient. 1 We reviewed possible and probable ocular adverse drug reactions with use of pami dronate disodium (Aredia, Ciba-Geigy Limited, Basel, Switzerland).
Subjects and Methods Worldwide case reports on ocular adverse drug reactions with pamidronate treatment are recorded at the Central Drug Safety Center, Ciba-Geigy Limited, in Basel, Switzerland. The database comprises cases reported within the framework of the spontaneous reporting sys tem, that is, individual patients treated with the commercially available drug, cases for which the drug was obtained on a named patient basis, and cases from clinical trials. The adverse drug reactions are recorded as reported by the attending physician. This report comprises data on ocular adverse drug reactions collected until August 31, 1993. One case of bilateral uveitis was published elsewhere 1 (Case 1 of Table 1). Twenty-three patients, 14 men and nine women, ranging in age from 26 to 79 years received daily between 30 and 120 mg of intra venous pamidronate disodium on various time schedules. The indication for treatment was Paget's disease of the bone in 20 patients, familial osteolysis in two patients, and algoneurodystrophy in one patient. The onset of the adverse drug reactions varied, since not all onsets occurred with the first dosage. Possible adverse drug reactions occurred in the follow ing three categories: Group 1, anterior uveitis—After receiving in travenous pamidronate, bilateral anterior uvei tis occurred in six patients, and unilateral uvei tis occurred in one patient (Case 2 of Table 1). In one patient, this occurred or went unrecog nized until 17 days after treatment, while in the remaining patients uveitis occurred within 24 to 48 hours after receiving the drug. The uveitis was minimal, not requiring treatment, in two patients and cleared within 24 hours. Two pa-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 118:220-224, AUGUST, 1994
Adverse Reactions to Pamidronate Disodium
Vol. 118, No. 2
221
TABLE 1 NONSPECIFIC ANTERIOR UVEITIS ASSOCIATED WITH PAMIDRONATE DISODIUM USE IN GROUP 1 ADVERSE
TIME UNTIL ADVERSE
CASE NO.,
DAILY
DRUG REACTION
AGE (YHS), GENDER
DOSE
AFTER
DRUG REACTION
(MG)
DOSE NO.
ONSET (HRS)
CO-MEDICATION
1,63, F
None
60
1
24
2, 26, F
None
30
2
24
3, 51, F
None
30
2
24
4, 72, F
None
120
2
17 days
83 45
3 1
24 48
30
1
48
5, 56, M None 6, 79, M Nitrazepam, Co-codamol, and cholecalciferol 7, 65, M Metformin, aspirin, isosorbide mononitrate, and bendroflumethiazide
RECHALLENGE
TREATMENT
Positive
Topical corticosteroids Positive after dose None 3; negative after doses 4-6 Positive after None doses 3-6 Negative Corticosteroids and cycloplegics Cycloplegics Not done Positive three Hospitalized months later Not done
Hospitalized
recurrent anterior uveitis; it is possible that uveitis occurred by chance after exposure to the drug. Group 2, episcleritis and scleritis—Three pa tients developed either unilateral episcleritis or scleritis between one and six days after receiv ing intravenous pamidronate disodium treat ment (Table 2). None had a prior history of these diseases. Two patients were treated with this agent for Paget's disease, whereas the third had algoneurodystrophy. The patient with epi scleritis (Case 8 of Table 2) was rechallenged with pamidronate five months later, and the
tients required topical corticosteroids with or without cycloplegics and resolved within sever al days to one month. In three patients, the ophthalmologists considered the uveitis to be severe; two of them were hospitalized. In two patients (Cases 5 and 7 of Table 1) the drug was not reinstituted. However, the remaining five patients were rechallenged, and the uveitis re curred in four patients. Patient 1 (Table 1) previously had bilateral anterior uveitis after receiving oral risedronate, also a bisphosphonate. The patient who had a negative rechal lenge (Case 4 of Table 1) had a long history of
TABLE 2 POSSIBLE EPISCLERITIS OR SCLERITIS ASSOCIATED WITH PAMIDRONATE DISODIUM USE IN GROUP 2
CASE NO., AGE (YRS), GENDER
DAILY DOSE DIAGNOSIS
8, 63, M Episcleritis (LE.) 9, 58, F Anterior scleritis (RE.) 10, 78, M Posterior scleritis (L.E.)
ADVERSE
TIME UNTIL
DRUG REACTION
ADVERSE
(MG)
AFTER DOSE NO.
None
30
None Aspirin
COMEDICATION
DRUG REACTION ONSET
RECHALLENGE
1
6 days
75
2
6 days
Positive five months later Not done
Oral indomethacin Hospitalized
30
3
24hrs
Not done
Oral corticosteroids
TREATMENT
222
August, 1994
AMERICAN JOURNAL OF OPHTHALMOLOGY
TABLE 3 NONSPECIFIC CONJUNCTIVITIS ASSOCIATED WITH PAMIDRONATE DISODIUM USE IN GROUP 3 ADVERSE
TIME UNTIL
DRUG
ADVERSE REACTION
CASE NO-
DAILY
AGE (YRS),
DOSE
REACTION AFTER
GENDER
(MG)
DOSE NO.
ONSET (HRS)
RECHALLENGE
Not done Not done Negative after six doses four months later Not done Positive after dose 2; later negative for two doses Not done Positive after doses 2-6 Positive after dose 2 Negative Positive after dose 6 Positive after dose 2 Positive after dose 3 Not done
DRUG
11,64, F 12, 80, M 13,71, M
43 53 52
2 2 4
24 24 24
14,61, F 15, 76, M
60 47
2 1
6 24
F M M M M M M F
47 30 30 60 120 60 60 60
3 1 1 3 5 1 2 6
24 24 24 24 24 24 48 Unknown
16,71, 17, 70, 18,59, 19,68, 20, 64, 21,54, 22, 63, 23, 56,
episcleritis recurred in the same eye. This pa tient was taking no other medication. Both scleritis patients had no apparent cause for their disease. Full recovery occurred in all pa tients. Group 3, nonspecific conjunctivitis—There were 13 patients who had a nonspecific con junctivitis consisting of any or all of the follow ing: conjunctival hyperemia, irritation, epipho ra, with or without discharge, and with or without blurred vision, occurred bilaterally in ten patients and unilaterally in three patients (Table 3). This usually started within the first six to 48 hours after the administration of the drug. Ocular symptoms resolved within a few days, but in one patient resolution required one week. This adverse drug reaction occurred after the first or second dosage in most patients, and after the third, fourth, fifth, or sixth dose in one patient each. Rechallenge was positive in six patients, but in one (Case 15 of Table 3), rechal lenge became negative later. However, the time of rechallenge in this group varied between two and 14 days after the appearance of the first reaction, so symptoms may have overlapped. Five patients were not rechallenged, and for two patients the outcome of rechallenge was negative. Two patients had been previously exposed to pamidronate, of whom one (Case 20 of Table 3) also had a nonspecific conjunctivitis and the other (Case 14 of Table 3) had no
drug-related ocular side effects.
Discussion As a group of drugs, the bisphosphonates have only had two previously published reports in which patients had possible ocular adverse drug reactions associated with their use, name ly, xanthopsia, which lasted for two hours after the first injection of pamidronate and did not occur on re-exposure, 2 and anterior uveitis 1 af ter exposure to pamidronate. This series of 23 patients, including one of the patients previ ously described, 1 is a compilation of all ocular adverse drug reactions reported with the use of pamidronate disodium and recorded at the Central Epidemiology and Drug Safety Center of Ciba-Geigy Limited, in Basel, Switzerland. We reviewed three categories of possible ad verse drug reactions involving the eye coinci dent with pamidronate use. These data are somewhat unique, because, in clinical ocular toxicology, rechallenge associated with a possi ble ocular adverse drug reaction is not com mon. Rechallenge was possible because the indications for the use of this agent are serious, the drug is given in serial intravenous infu sions, and the majority of these adverse drug reactions are rare and of little consequence.
Vol. 118, No. 2
Adverse Reactions to Pamidronate Disodium
We believe that in rare instances pamidronate is probably associated with a low-grade to se vere anterior uveitis (Group 1, Table 1). This association is based on the uveitis recurring in four of five cases that were rechallenged. Six of the seven cases were bilateral, whereas two thirds of the cases of non-drug-related anterior uveitis are unilateral. 3 The severity of the uvei tis varied from minimal to severe, with recovery ranging from one day to one month. The onset of anterior uveitis after drug exposure varied from one day to 17 days. In Case 4 (Table 1) the patient had a 20-year history of recurrent ante rior uveitis, so that the relationship of the adverse drug reaction with treatment could not be established, especially since subsequent re peat rechallenges have been negative. An association between this drug and episcleritis and scleritis (Group 2, Table 2) is not clear. The single case of episcleritis with a positive rechallenge five months later in the same eye is suggestive of a causal relationship; however, this awaits confirmation by similar cases. A single case each of anterior and poster ior scleritis occurring six days after the second drug infusion and 24 hours after the third infusion, respectively, without rechallenge data, is suspect, in part because we and others 4 are not aware of any previous reports of a drug-induced scleritis. Therefore, we classify this adverse drug reaction as possibly related to treatment. One can only speculate as to the possible cause of anterior uveitis, episcleritis, or scleri tis. Thus, we suggest an allergic or immunolog ie phenomenon, possibly because of immunecomplex formation induced by the drug. In the two patients with scleritis (Cases 9 and 10 of Table 2), the onset of ocular adverse drug reac tions was accompanied or preceded by tran sient fever. It is tempting, therefore, to assume that the ocular reactions may be a form of acute-phase response (such as fever or lymphopenia), as seen with aminobisphosphonates. These bisphosphonates stimulate cytokine re lease (interleukin-1 and interleukin-6) and the synthesis of acute-phase proteins. This acutephase response is reported as being unrelated to dose, route of administration, or type or activity of the underlying disease, such as Paget's disease of the bone, malignancy, or osteoporosis. 58 It has been postulated, howev er, that patients with a malignancy are less prone to suffer from these side effects, possibly because of an immunologie defect that sup presses cytokine production. 9 This might ex
223
plain why none of the patients in this series suffered from a malignancy. In all except three patients, the indication for treatment with pa midronate was Paget's disease of the bone. Uveitis, episcleritis, and scleritis have not been associated with Paget's disease of the bone, familial osteolysis, or algoneurodystrophy. It has been suggested 1 that these ocular adverse drug reactions are related to the nitrogen-con taining bisphosphonates, because uveitis, scle ritis, or episcleritis has not been reported with non-nitrogen-containing bisphosphonates. The nonspecific conjunctivitis group, (Group 3, Table 3), in which symptoms occur usually 24 to 48 hours after exposure to pamidronate, was usually bilateral and seldom required treat ment, with symptoms resolving in hours to days. In our opinion, this is a probable adverse drug reaction, on the basis of uniform time until onset after drug exposure, similar ocular patterns among patients, and positive rechal lenges in six of eight patients. The pattern of this nonspecific conjunctivitis indicates that the drug may be secreted by the lacrimal gland in some patients and that the conjunctivitis is due to the presence of the drug in the tears, causing transitory irritation. Thus far, no assay for pa midronate in the tears has been performed. It is estimated that more than 50,000 patients have been exposed to intravenous pamidronate disodium. To date, the total number of cases with ocular adverse drug reactions of which we are aware is 23, which indicates that ocular adverse drug reactions to pamidronate disodi um appear to be quite rare. Regardless, this drug may need to be discontinued in patients who develop significant anterior uveitis, epi scleritis, or scleritis after the administration of the drug, although for episcleritis and scleritis a firm relationship to treatment has not been established.
References 1. Siris, E. S.: Bisphosphonates and iritis. Lancet 341:436, 1993. 2. Morton, A. R., Dodwell, D. J., and Howell, A.: Disodium pamidronate (APD) for the management of hypercalcaemia of malignancy. Comparative studies of single-dose versus daily infusions and of infusion duration. In Burckhardt, P. (ed.): Disodium Pamidro nate (APD) in the Treatment of Malignancy-related Disorders. Toronto, Hans Huber Publishers, 1989, pp. 85-100.
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3. Tilden, M. E., Rosenbaum, J. T., and Fraunfelder, F. T.: Systemic sulfonamides as a cause of bilater al, anterior uveitis. Arch. Ophthalmol. 109:67, 1991. 4. Watson, P. G., and Hazleman, B. L.: The sciera and systemic disorders. In Trevor-Roper, P. D. (ed.): Major Problems in Ophthalmology, vol. 2. Philadel phia, W. B. Saunders, 1976, pp. 197-201. 5. Adami, S., Bhalla, A. K., Dorizzi, R., Montesanti, F., Rosini, S., Salvagno, G., and Lo-Cascio, V.: The acute-phase response after bisphosphonate adminis tration. Calcif. Tissue Int. 41:326, 1987. 6. Bijvoet, O. L., Frijlink, W. B., Jie, K., van der Linden, H., Meijer, C. J., Mulder, H., van Paassen, H. C , Reitsma, P. H., te Velde, ]., de Vries, E., and van der Wey, J. P.: APD in Paget's disease of bone.
August, 1994
Role of the mononuclear phagocyte system? Arthritis Rheum. 23:1193, 1980. 7. Gallacher, S. J., Fraser, W. D., Cruickshank, A. M., Shenkin, A., and Boyle, I. T.: The response of plasma interleukin-6 (IL-6) to pamidronate. Bone (U.S.A.) 11:384, 1990. 8. Harinck, H. I., Papapoulos, S. E., Blanksma, H. J., Moolenaar, A. J., Vermeij, P., and Bijvoet, O. L.: Paget's disease of bone. Early and late respons es to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). Br. Med. J. Clin. Res. Ed. 295:1301, 1987. 9. Gallacher, S. J., Ralston, S. H., Patel, U., and Boyle, I. T.: Side-effects of pamidronate. Lancet 2:42, 1989.