Acta Med Scand 203: 425428, 1978

Adverse Reactions with Methyldopaa Decade's Reports Anna-Karin Furhoff From the Section of Adverse Drug Reactions, Department of Drugs, National Board of Health and Welfare, Uppsala, Sweden

ABSTRACT. During 1966-75 the Swedish Adverse Drug Reaction Committee received some 300 reports of reactions to methyldopa. As the Swedish rules for reporting adverse reactions emphasize the importance of severe and unexpected reactions, the relative incidence of various adverse effects differs greatly from what would be found in an intensive study. The three most commonly reported reactions are fever, hemolysis and hepatic effects. Two-thirds of these patients were women. The median age of the groups differed, from 57 years (hepatic effects) to 69 years (hemolysis). The clinical picture of the different reactions was consistent, in the main, with what has been described previously. Between 70 and 85% of the patients in these groups were admitted to hospital because of the adverse reaction.

Methyldopa has been used in Sweden for treatment of hypertension since the beginning of the 60s. In the period 1971-75 methyldopa sales varied between l l .2 and 16.8 tons a year, corresponding to 3.7-5.7 defined daily doses per lo00 inhabitants (one defined daily dose= 1 g 1-methyldopa)( 5 ) . Adverse reactions of various kinds have been reported over the years. Tiredness, sleepiness, nasal obstruction and dryness of the mouth occur chiefly at the beginning of treatment and are then often transient. Nightmares, depression, paresthesias and Parkinsonism have been reported. Sexual disturbances are probably not uncommon. There have also been reports of altered intestinal function (flatulence, diarrhea, obstipation), edema with weight increase, and galactorrhea. Fever is reported to occur in about 3 % and is considered to have Present address: The Primary Care Centre, St. Erik's Hospital, S-11282 Stockholm, Sweden.

an allergic genesis, as is the hepatic reaction which may likewise occur with methyldopa treatment. Hemolytic anemia is another potentially serious reaction with an immunologic background (8). Although deaths have been reported in connection with hemolysis or liver damage, withdrawal of methyldopa is followed as a rule by a rapid recovery. In the decade 1966-75 the Swedish Adverse Drug Reaction Committee, which started to obtain reports of adverse ractions in Nov. 1965, received more than 300 reports on such reactions with methyldopa. Most of these reactions took the form of fever, hemolysis or hepatic effects. This paper presents some clinical characteristics of these adverse reactions as described in the reports. MATERIAL In the decade 1966-75 a total of 308 reports were received about adverse reactions in connection with methyldopa treatment, where a causal relationship between drug and reaction was considered probable or could not be ruled out. This does not include reports involving a cornbination of drugs. A special study has been performed of the report3 of reaction- '- the form of fever, hernolysis or hepatic effect' reports could not be traced, the present s* v covcrs 249 cases.

RESULTS

The frequency of the different reactions that were reported after treatment with methyldopa is indicated in Table I. Several patients had more than one symptom. Allergic reactions mainly involved the skin (exanthema, urticaria). Diarrhea was the most common Acta Med Scand 203

A . - K . Furhoff

426

Table I. Adverse reactions t o methyldopu reported to the Swedish Adverse Drug Reuction Committee during 1966-75 (308 patients) 40

Fever Hemolysis Hepatic effects Allergic reaction Gastrointestinal symptoms Psychic and neurologic symptoms Other hematologic reactions, incl. pos. Coombs' test Other

I66 67 29 23 17 13

II

I1It hi

4IiMl 20

~

r

lo

16

I

n

I

0

gastrointestinal reaction. Of the 13 reports of adverse reactions from the nervous system, 9 concerned depression. The group "other hematologic effects" includes one case each of thrombocytopenia and leucopenia, in addition to four cases of a positive Coombs' test without demonstrable hemolysis. Fe L

w .

hemoly.tis and hepatic q f f c t s

Two-thirds of the patients with fever, hemolysis o r hepatic effects in connection with methyldopa treatment were women (Table 11). The predominance of women is most marked among the cases of hemolysis and hepatic effects (76 and 74 %, respectively). The groups of reactions also differ in terms of median age, this being lowest (57 years) for patients with hepatic effects and highest (69 years) for those who developed hemolysis. There are also large differences in the length of the interval from the start of treatment to the onset of symptoms. Fever developed as a rule (in 82%) within three weeks (in 117 of 142 cases with a record of treatment dates). There are 13 cases (9%), however, where more than four weeks appear to Table 11. Sex und age distribution ofputients Mith adverse reactions with methyldopu ffever, hemo-

lysis or heparic effects)

Women Men Total

Fever

Hemolysis

Hepatic effects

98 61 I59

48 15 63

20 7 27

69 52-86

57 22-80

Age (v.)

Median Range Acta

65 34-86

M c d Siwnd 203

Total 166

83 249

2

4

6

8

& x) 12 U 16

I

7

weeks

Fig. 1 . Duration of treatment before onset of symptoms among patients with fever in connection with methyldopa

treatment. have elapsed before the onset of fever (Fig. I ) . The hemolysis group has the longest period of treatment before symptoms were detected (median 12 months, range two months to several years). The patients with hepatic effects had been treated with methyldopa for periods between one month up to several years (median 6 months) (Fig. 2). The dose at the onset of adverse reactions ranged from 0.125 to 1.5 g/d. The median value for the group with fever is 0.5 g/d. and for each of the other groups 0.75 g/d. The patients with fever are reported as a rule t o have presented a typical clinical picture with a high temperature. which fell back in a couple of days once methyldopa had been withdrawn (8). Several patients underwent provocation tests and developed fever again within 12 hours. In addition t o fever, 13 of the reports note pathologic liver tests, in all cases referring to moderately increased transaminase levels-the maximum values for S G O T and SGPT were 204 and 316 IU, respectively (SASAT and S-ALAT 3.5 and 5.4 pkat). Eight of the patients had skin manifestations (exanthema, urticaria, erythema nodosum and petechiae), and gastrointestinal complaints accompanied the fever in four. Two patients are reported to have had eosinophilia. All the patients with hemolysis had a positive Coombs' test. The H b level rose in all cases once methyldopa had been withdrawn. There are no records of whether and, if so, when the Coombs' test became negative again. The cases of hemolysis after methyldopa that were reported in the period 1965-70 have been analyzed in a previous paper (3).

427

Adverse reactions with methyldopa =hepatic effects W hemolysis

n l

0

4

8

l2 16 20 24m

?

months

to the attention of the doctor in charge, quite apart from leading to a report. Many patients are disinclined to discuss sexual problems, for instance, with their doctor. In other cases the patient may attribute the symptoms, particularly those of a psychic nature, to other causes than medication. Active questioning in this respect yields quite different results from a spontaneous account by the patient (1).

Fig. 2. Duration of treatment before onset of symptoms among patients with hemolysis or hepatic effects in connection with methyldopa treatment.

The patients with hepatic effects appear to have presented a clinical picture with many similarities to infectious hepatitis, in good agreement with the hepatitic reaction that is considered to be typical with methyldopa (4). Icterus was the symptom in a majority of cases which prompted an examination that led to a diagnosis. Altogether 180 of these patients (72 %) were hospitalized for the symptoms that arose in connection with methyldopa treatment. The proportion is highest among those with hepatic effects (85%) and lowest for those with hemolysis (70%). The patients reported in the period 1-72 have the same proportion (98 of 136, 72 %) as those reported in 1973-75 (82 of 1 13,73 %) . Methyldopa appears to have been used fairly frequently as the drug of first choice in the treatment of hypertension. Almost half of the patients with fever, hemolysis or hepatic effects were taking methyldopa as the only medicine for hypertension; the proportion was higher in the period 1966-72 (54%) than in the later years (39%) (Table 111). A comparison between the periods 1%6-72 and 1973-75 reveals only moderate differences in the choice of other antihypertensive drugs. Beta-blockers are introduced, furosemide is used to an increasing extent and the number of patients treated with chlorthalidone decreases.

DISCUSSION The nature of several adverse reactions to methyldopa is such that they are often not even brought

The regulations for reporting adverse reactions in Sweden emphasize the importance of drawing attention to severe and unexpected reactions (9). Such a system leads to a very low frequency of reports on reactions that are common and familiar (e.g. gastrointestinal complaints after methyldopa). It is thus understandable that the relative incidence of the various adverse reactions which are reported differs greatly from the findings in an intensive study that involves active questioning of the patients. On the other hand, the reports usually contain information that may yield valuable clinical knowledge about the reactions. The spectra of symptoms of the three adverse reactions to methyldopa that were reported most frequently-fever, hemolysis and hepatic effects-are as a rule in good agreement with descriptions in the literature. The moderate rise of transaminase that has been reported in some of the fever cases may have to do with the slight direct hepatotoxic effect which methyldopa is assumed to have (6). It is more difficult to explain the differences betwen the diagnostic groups in terms of age and sex. One would admittedly expect women to predominate, as they appear to be involved more frequently than men in adverse drug reactions in general (2, 7). Their particularly marked dominance in the group with hemolysis, which is considered to be of an autoimmune nature, is likewise Table 111. Other antihypertensive treatment of patients with adverse reactions to methyldopa ffever, hemolysis or hepatic effects) No. of other antihypertensive drugs 0 1 22 ?

1973-75

I S 7 2

%

n

%

n

75 56 4 1

54 41

44

39

54 8 7 I13

48

136

Acla Med Scand 203

428

A . - K . Furhoff

in line with previous experience. But the very large female majority in the group with hepatic effects, as well as the low median age in this group, differ from the usual pattern. There are, however, too few patients with hepatic effects to warrant any definite conclusions. An onset of fever not more than three weeks after the start of treatment, as reported in most cases, also agrees with earlier descriptions. But as many as 9 % of the present patients first presented this symptom after having been on methyldopa for more than one month, which in many cases caused diagnostic difficulties. It is reported in the literature that the onset of hemolysis hardly occurs before methyldopa has been given for at least 6 months (8). In almost onethird of the present cases (16 of the 54 with recorded dates of treatment) methyldopa had been given for not more than six months. It is reasonable, however, that data on the duration of treatment should differ between series. It is seldom possible to establish the actual onset of hemolysis-the record refers to its discovery. Large differences can be explained by, for instance, routines for the frequency with which certain laboratory tests are checked. In several of the present cases the hemolysis was diagnosed before the patient had developed symptoms of anemia. The doses of methyldopa that were used in the treatment of the patients who developed fever, hemolysis or hepatic effects do not appear to differ from the probable average for this drug. The median doses for the various groups are, in fact, smaller than the “defined daily dose”, which is l g I -methyldopa (5). The burden which adverse reactions to methyldopa imposes on the health service is illustrated by the circumstance that almost 3/4 of the patients had to be hospitalized for these reactions. The reasons for admission to hospital are not always given in the reports biut ‘.hey piesvmably incl~dedii neml For niirsing (high f e v e r ) a i w211 as a need h r c‘xaminiitions (indefinite icier-us, hemolysis). kicthyldopa has been used !o a large r‘xieiit as a drug of first choice i n !he iwitrnrn: J[ high BP. The tinding that I%,. prrp;rrion of pl-tlienis with methyldopa as [he only antihypertensive drug fell

from just over half in 1976-72 to about one-third in the last three years of the decade seems to be well in line with development in this area. But even towards the end of the period it was still common to administer methyldopa as the sole drug against hypertension. Of the 13 patients who were reported to have developed fever after methyldopa in 1975 (duration of treatment

Adverse reactions with methyldopa--a decade's reports.

Acta Med Scand 203: 425428, 1978 Adverse Reactions with Methyldopaa Decade's Reports Anna-Karin Furhoff From the Section of Adverse Drug Reactions, D...
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