Methotrexate-resistant rheumatoid arthritis is common

Leflunomide, used to treat rheumatoid arthritis

Dtsch Arztebl 2001; 98 (28-29): A-1881 / B-1588 / C-1484
Leflunomide (LEF, trade name Arava) has been approved in Germany as a new basic therapeutic agent for the treatment of rheumatoid arthritis (RA) since 1999. LEF primarily inhibits the proliferation of activated lymphocytes, which play an essential role in the pathogenesis of RA. Dihydroorotate dehydrogenase, a key enzyme in the new synthesis of pyrimidine, is directly inhibited by LEF. In RA, LEF was superior to placebo in all respects in controlled studies and was clinically as effective as sulfasalazine (SSZ) 2 g / day and methotrexate (MTX) 15 mg / week orally. LEF slows the radiologically measurable progression of joint destruction significantly compared to a placebo and is as effective as SSZ and MTX. Due to its pharmacokinetics, it can also be used with impaired kidney function, and LEF extends the limited range of basic therapeutic agents. If the response to MTX monotherapy is insufficient, the combination with LEF has proven to be effective. Adverse effects are gastrointestinal complaints such as diarrhea, skin allergies, hair loss and elevated transaminases. Like MTX, LEF is teratogenic. The ultimate role of LEF in the treatment of RA will in future become evident in everyday clinical practice.

Key words: leflunomide, dihydroorotate dehydrogenase inhibition, new pyrimidine synthesis, methotrexate, rheumatoid arthritis

Leflunomide in the Treatment of Rheumatoid Arthritis
Leflunomide (LEF) is a new disease modifying antirheumatic drug which inhibits the proliferation of activated lymphocytes by blocking the enzyme dihydroorotate dehydrogenase, the key enzyme in the de novo synthesis of pyrimidines. In controlled clinical trials in the treatment of rheumatoid arthritis, LEF was superior to placebo and comparable with sulfasalazine (SSZ) 2 g / day and oral methotrexate (MTX) 15 mg / week. LEF slows the radiographic visible progression of bone destructions significantly better than placebo, but comparable with SSZ and MTX. In contrast to MTX and due to its pharmacokinetics LEF can be used in patients with decreased renal function. Furthermore, LEF has been proven to be effective in combination with MTX in severely diseased patients who can not
Be sufficiently treated with MTX alone. Side effects of LEF are gastrointestinal complaints, for instance diarrhea, skin allergy, transient alopecia and pathological liver function. LEF as well as MTX is teratogenic. The definitive rank of LEF in the treatment of rheumatoid
arthritis still has to be evaluated in further clinical practice.

Key words: leflunomide, dihydroorotate dehydrogenase blocking, de novo synthesis of pyrimidine, methotrexate, rheumatoid arthritis

Methotrexate (MTX) in a dosage of 7.5 to 25 mg per week is considered the most established standard therapy worldwide in the treatment of severe rheumatoid arthritis (RA), either as monotherapy or in combination with other basic therapeutic agents. This is supported by the favorable relationship between effect and undesirable effects and the proven ability to slow down the progression of the disease. A recently published Australian long-term study over twelve years on the use of MTX in 460 patients with RA showed that after this period, 53 percent of those treated were still using MTX (35). However, in the majority of patients, at least one further basic therapeutic agent had to be given as an additive due to an insufficient effect. In only 17 percent of all patients, MTX was still sufficient as monotherapy (35). In addition to its often inadequate effectiveness, the use of MTX is limited by undesirable effects (such as cytopenia) and increasing complications in the case of impaired kidney function (22). As a new basic therapeutic agent for the treatment of RA, LEF could close the therapeutic gap in these patients, both as monotherapy and in combination with MTX.
Mechanism of action
Within many models of the pathogenesis of RA, it has been established that activated lymphocytes play an important role in the development and progression of this disease (6). Depending on the dose, LEF or its main metabolite A771726 inhibits the new synthesis of pyrimidine, which is essential for the proliferation of activated T lymphocytes, by reversibly inhibiting its key enzyme dihydroorotate dehydrogenase (21) (Figure). Cells can meet their nucleotide needs in a number of ways. Recycling via a "salvage pathway" saves energy than new synthesis and is mainly used as a supply path by less active cells. In contrast to this, activated lymphocytes are essentially dependent on the new synthesis of pyrimidines, since their need for nucleotides increases up to eight times. Under LEF, there is a pyrimidine deficiency in the activated lymphocytes and thus a persistence in the S phase of the cell division cycle. The effect of A771726 can be canceled by the exogenous administration of pyrimidines - but not purines. Since the recycling route of pyrimidine synthesis is not affected, resting lymphocytes and other less active cells remain unaffected (2, 21). Furthermore, an anti-inflammatory effect of LEF via various other mechanisms is assumed. Some findings suggest that LEF suppresses the transcription factor NFkB, a potent inflammatory mediator, reduces the production of interleukin-1 and tumor necrosis factor-a, and leads to a decrease in the glycosylation of adhesion molecules (1). LEF or A771726 is teratogenic. In women who wish to have children, it must be ensured that the plasma concentration of the active metabolite is below 0.02 mg / l. This can be achieved by waiting two years after discontinuing LEF or by washing out with colestyramine 8 g three times a day for eleven days. Regardless of the method chosen, the manufacturer recommends a plasma level below 0.02 mg / l in two tests every 14 days. In addition, a waiting period of three months should be observed between the measurement of this plasma level and the conception.
LEF is converted into its main active metabolite A771726 during absorption through the intestinal wall and during passage through the liver; the starting substance itself is hardly detectable in the plasma. The half-life of A771726 is approximately two weeks. Its volume of distribution largely corresponds to that of plasma, with a binding to albumin of over 99 percent. Food intake does not affect pharmacokinetics. A771726 is excreted in equal proportions in the urine and faeces (32). In order to quickly achieve therapeutic levels in metabolic equilibrium, a dose of 100 mg per day is usually given for the first three days of treatment, followed by a maintenance dose of 20 mg daily. This recommended dose is the consequence of an early study on dose finding (16), which showed a clear dose-response relationship between 5 mg and 25 mg LEF per day. Higher doses were associated with more adverse effects, particularly gastrointestinal ones, but also such as weight loss and hair loss.
Clinical studies
The results of three multicenter controlled studies with LEF as monotherapy for up to two years are currently available (10) (table).
Study design
In all three studies, patients with LEF received an initial starting dose of 100 mg for the first three days, followed by 20 mg per day as a maintenance dose. Sulfasalazine (SSZ) was gradually increased to the final dose of 2 g per day. MTX was initially given orally at 7.5 mg per week and increased to 15 mg per week in 60 percent of patients within the first twelve months due to insufficient effect. After the first year, the MTX dose could be increased up to 20 mg per week. While all patients with MTX in the placebo-controlled study in the USA received an additive 2 mg folic acid daily, MTX was not regularly combined with folic acid in the European comparative study. In all studies, glucocorticoids with a maximum of 10 mg prednisolone equivalent daily and non-steroidal anti-inflammatory drugs were allowed. All the groups examined were comparable in terms of their demographic data, severity and duration of RA, as well as the number of previous treatments with basic therapeutic agents and concomitant therapies with glucocorticoids.
In all studies, the effectiveness was rated according to the criteria of the American College of Rheumatology (ACR) as response rates of 20 and 50 percent (20), that is, a decrease in the number of swollen and painful joints of at least 20 and 50 percent respectively. In addition, there had to be such a decrease in three of the five following parameters:
- Assessment of disease activity by the doctor
- Assessment of the disease activity by the patient
- Pain intensity on an analog scale
- sedimentation rate or C-reactive protein
- Measurement of the joint function according to the "Health Assessment Questionnaire" (HAQ) or its modified version (MHAQ) and the health-related quality of life according to the "Short Form 36" (SF-36).
In all three studies, after LEF, there was a significant improvement in the primary outcome measures, usually already during the first four weeks. The effect was comparable to that of SSZ and significantly stronger than that in the respective placebo group (11, 26, 27). The two comparison groups with MTX differed significantly from each other. Only 46 percent of patients who received MTX plus folic acid achieved a response rate of 20 percent according to ACR after one year. In the European study with MTX, but without folic acid, this proportion was significantly higher after one year, namely 65 percent (table) (5, 28). After two years, this difference was largely balanced at 67 percent versus 72 percent, and the response showed no significant deviation from LEF. The 20 percent response rates for LEF in the three studies after twelve and 24 months were 52 and 79 percent (US301), 67 and 82 percent (MN301), and 51 and 64 percent (MN302) (Table) (3). The initially differently strong effect of MTX in the two comparative studies mentioned could be due to the differing supplementation with folic acid. Until now, it was assumed that the addition of folic acid greatly reduced the undesirable effects caused by MTX - in particular gastrointestinal and mucosal ones - without, however, significantly influencing the effectiveness of MTX itself (8, 18). Ede et al. (4) found in a randomized double-blind study that 38 percent of the patients with MTX without folic acid dropped out of the study prematurely compared to only 17 percent of the patients who received MTX plus folic acid. Patients on folic acid concomitant medication required a higher dose of MTX (18 mg per week) in order to achieve the same effect as in patients without folic acid administration (14.5 mg per week). If
The weakened effect of MTX also applies to the usual administration of folic acid once a week in Germany on the day after MTX administration or only to the daily administration of folic acid, must remain open at the moment. In a comment on the different response rates to MTX compared to LEF, Strand et al.
(29) found that a comparison of the MTX groups in studies US301 and MN302 does not make sense because only one of the two was placebo-controlled and the study conditions therefore differed. With unchanged folic acid concomitant medication, the (apparent?) Differences in efficacy were largely evened out after two years (3, 29).
With regard to the effectiveness of MTX, it should also be noted that in all LEF comparative studies, MTX was dosed orally and relatively low, namely in 60 percent of the correspondingly treated patients with a maximum of 15 mg per week in the first twelve months. Earlier studies have shown that there is a clear dose-response relationship for MTX in the dose range between 15 and 25 mg per week, without a relevant increase in adverse effects in the higher dose range (23). It has also been observed that the bioavailability of MTX after oral administration can be very different intra- and interindividually and is significantly lower than after parenteral administration (9).
In a comparison of MTX and LEF, it remains to be finally checked whether LEF in the approved dose and applied parenterally is equal to the higher dose of MTX often used in Germany, and whether - conversely - LEF in a higher dose, which has already been used in pilot studies can lead to a significant increase in effectiveness.
Inhibition of the radiologically visible progression
In all studies, the course was documented by radiological images of the hands and forefeet, certainly one of the most informative criteria for the effectiveness of a basic therapy (table). For comparison with MTX, the results of the US301 study after twelve months and the European study MN302 after 24 months are available; for comparison with SSZ results of study MN301 after six months (25). Here, like the active substances of the other treatment groups, LEF was significantly superior to placebo in all studies, but there was no difference compared to SSZ and MTX.
The effectiveness on the radiologically visible progression correlated only weakly with the clinical findings corresponding to the 20 percent response rate according to the ACR. This underlines the need for regular x-ray controls regardless of the clinical course. For the European comparative study MTX versus LEF, data are also available after 24 months. No differences were found between the two substances after twelve months. In the second year of treatment, there was no further progression with LEF. In patients treated with MTX, there was even a slight regression of the radiologically proven destruction.
Influence on joint function and quality of life
HAQ, MHAQ and health-related quality of life were examined using SF-36. The treatment groups performed significantly better than the placebo group in all categories.
After twelve months, leflunomide was significantly more effective in improving function and physical categories in the SF-36 compared to methotrexate - regardless of the use of folic acid. In contrast to the radiologically visible course, the improvements in these parameters correlated closely with the response rate after ACR. Compared to sulfasalazine, leflunomide also showed a more effective improvement in functional parameters (24, 30, 31).
Combination of leflunomide with methotrexate
Due to the different mechanisms of action of LEF and MTX, a combination of both drugs is recommended. Low-dose MTX inhibits purine synthesis and increases the production of adenosine, whereas LEF inhibits the new synthesis of pyrimidines (13).
The combination was initially investigated in a small, uncontrolled study for safety and tolerability, pharmacokinetic interactions and clinical efficacy. 30 patients in whom the disease was still active for at least six months despite long-term therapy with MTX were treated additively with 10 to 20 mg LEF per day over 52 weeks in an open study. During the additive treatment with LEF, the plasma levels for MTX did not differ at any point in time from the values ​​measured with MTX as monotherapy. The plasma levels of the LEF metabolite A771726 in combination with MTX were also unchanged compared to LEF monotherapy. In three patients the study was terminated because of a persistent increase in transaminases over three times the norm, in two patients because of a lack of efficacy. Overall, 53 percent of the patients showed a 20 percent response rate according to the ACR (34).
The first results of a controlled, placebo-controlled double-blind study on the combination of MTX and LEF are now available. 266 patients were included whose RA was still active despite a sufficiently long treatment with MTX in medium doses - between 16 and 17 mg per week orally (12). They received either 10 to 20 mg of LEF additive after a starting dose of 100 mg over two days or a placebo for ongoing treatment with MTX. The ACR 20 percent response rate after 24 weeks was 46.2 percent for the combination versus 19.5 percent for the placebo group (p < 0,0001).="" in="" den="" kategorien="" gelenkfunktion="" (im="" mhaq)="" und="" lebensqualität="" (im="" sf-36)="" kam="" es="" in="" 24="" wochen="" ebenfalls="">
significant improvements in the combination of MTX and LEF (7, 12).
LEF is therefore recommended as a further combination partner for MTX. It remains to be seen whether this combination will compete with the so-called O’Dell scheme with MTX, SSZ and hydroxychloroquine (17) in terms of effectiveness and tolerability.
It must be mentioned that in Germany in the product information and the leaflet from LEF there is a combination with other
other basic therapeutics, including MTX, are currently not recommended. Individual observations of serious adverse effects when combining LEF with other basic therapeutic agents include cytopenia and severe hepatic side effects (33). They require strict indications for combination therapy.This can be given in the case of therapy resistance to monotherapy with MTX or the triple combination according to the O’Dell scheme (17). It requires particularly tight controls.
unwanted effects
The most common undesirable effects with leflunomide in the controlled studies are diarrhea (18 to 27 percent), nausea (by ten percent), skin allergies (seven to eleven percent) and an increased, after
However, discontinuation of reversible hair loss (five to 17 percent), (text boxes 1 and 2).
Respiratory infections occurred in 14 percent, total infections in up to 48 percent, which was not significantly different from the placebo, SSZ or MTX. Opportunistic infections were not observed in any study. Elevations in liver values ​​in the first twelve months to more than three times the normal occurred in LEF in 2.6 to 4.4 percent of the patients, with a similar frequency as in the patients who received methotrexate plus folic acid (2.7 percent), but less often than with MTX without folic acid (16.7 percent).
The latter underlines the protective effect of adding folic acid to MTX with regard to elevations in liver values. For all other adverse effects, the two groups with MTX showed no differences in the indirect comparison. With leflunomide an increase in blood pressure occurred two to three times more often (six to eleven percent) than in the placebo group or in the comparison groups with the active therapeutic agents; however, there were also more patients with pre-existing hypertension in the group with LEF. The number of newly developed hypertension was the same in the treatment groups.
In the combination of MTX and LEF, diarrhea was the most common side effect with 33 percent, followed by nausea, stomatitis and respiratory symptoms (cough, dyspnoea, infections) with ten percent each. Increased hair loss was observed in 23 percent of the patients. The transaminases were more than twice the norm in 20 percent of the patients and more than three times the norm in 17 percent.
Leaflets for patients and doctors on the use of LEF, including the recommended controls, were drawn up by the "Diagnostic and Therapy Guidelines" project group of cooperative regional rheumatism centers of the German Society for Rheumatology. They are available at the Internet address
First experiences in everyday clinical practice
Outside of the controlled studies described, initial results are available on the use of LEF in everyday clinical practice (15). According to a preliminary report on 119 patients with RA who were treated with LEF for twelve months in rheumatological practices, 48 ​​percent were still taking LEF after one year (57 of 119). In 35 percent of all patients, the therapy was stopped because of ineffectiveness and in 17 percent because of undesirable effects (diarrhea in twelve, cytopenia in three patients). However, since more than half of the patients in this study were taking other basic therapeutic agents at the same time, the relatively high drop-out rate can hardly be compared with that in other studies where only MTX was given (around 25 percent after twelve months) (23).
Leflunomide, used to treat other conditions
So far, the results of open pilot studies on the use of LEF in Wegener's granulomatosis (WG) and systemic lupus erythematosus (SLE) are available. Eleven patients with SLE and a mean score according to ECLAM (European Community
nity Lupus Activity Measure) were treated with LEF for 24 weeks in doses between 20 mg and optionally up to 40 mg per day (19). Thereafter, the ECLAM score improved slightly, and the accompanying steroid therapy was also reduced in four patients. The study was terminated prematurely in seven of the eleven patients, six of them because of adverse effects or ineffectiveness. Values ​​for double-stranded DNA antibodies, C3, C4 and the protein excretion in the urine did not change significantly.
In a further pilot study, 20 patients suffering from a shared flat were treated with LEF to maintain remission following induction therapy consisting of cyclophosphamide and glucocorticoids (14). So far, low-dose MTX, azathioprine, mycophenolate mofetil or cotrimoxazole have been used for this indication.
LEF was tested because, according to the experience given above, it causes cytopenia less frequently, can also be used in the case of residual impaired kidney function, and its effect is significantly faster than that of azathioprine. After a starting dose of 100 mg for the first three days, all patients received 20 mg of LEF. After three months, the daily dose was increased to 30 mg after another “loading dose” of three times 100 mg, optionally a further increase to 40 mg per day was possible. For twelve months, 19 of the 20 patients remained free of recurrences.
There were no discontinuations due to adverse effects during the treatment period. However, it is worth mentioning the emergence or worsening of pre-existing arterial hypertension in four patients. Due to these generally encouraging results, a controlled randomized comparative study between MTX and LEF on remission maintenance in a total of 120 patients with Wegener's granulomatosis is planned within the framework of the Rheumatism Competence Network.
Pharmaceutical economic aspects
The monthly costs for 20 mg leflunomide per day are currently 246.60 DM (status: autumn 2000) plus the one-off starting dose of 100 mg LEF on the first three days of treatment (158.10 DM). In comparison, the monthly costs for methotrexate are DM 310.22 (with four injections per week of Lantarel at 22.5 mg). The monthly costs of Etanercept (Enbrel) are DM 3,968.68 twice a week with 25 mg subcutaneously. Due to the different application intervals and doses related to body weight, the monthly costs of infliximab (Remicade) can only be estimated. They are around 3,000 DM.
Outlook for practice
LEF represents a valuable addition to the limited range of basic therapeutic agents in rheumatoid arthritis. LEF has proven its effectiveness in four controlled studies as monotherapy and in combination with MTX. With comparable efficacy and tolerability to SSZ and MTX, the definitive status of this new substance - primary use as monotherapy or only in the event of failure or intolerance of the classic basic therapeutic agents alone or in combination - will certainly only be achieved when it is widely used in everyday clinical practice and the associated
Experience with regard to effects and undesirable effects must be recognizable.

How this article is cited:
Dt Ärztebl 2001; 98: A 1881-1887 [issue 28-29]

The numbers in brackets refer to the bibliography, which is available from the author in an offprint and on the Internet (

Address for the authors:
Prof. Dr. med. Wolfgang L. Gross
Rheumatism Clinic Bad Bramstedt GmbH
Oskar-Alexander-Strasse 26
24576 Bad Bramstedt, Germany
Email: [email protected]

Polyclinic for Rheumatology, University Hospital Lübeck (Director: Prof. Dr. med. Wolfgang L. Gross) and Medical Hospital Department of the Rheumatology Clinic Bad Bramstedt GmbH (Head Physician: Prof. Dr. med. Wolfgang L. Gross)

Scheme of the pyrimidine synthesis and point of attack of leflunomide. DHODH, dihydroorotate dehydrogenase; UMP, uridine monophosphate.

Clinical studies with leflunomide as monotherapy in rheumatoid arthritis
LEF vs. SSZ vs. PL LEF vs. MTX vs. PL LEF vs. MTX
MN301 US301 * 1 MN302 * 2
(11, 24, 26, 27) (3, 25, 28, 30, 31) (3, 5, 25)
Initial patient numbers 133 vs. 133 vs. 92 182 vs. 180 vs. 118 501 vs. 498
Duration of study (in months) 24 24 24
20 percent responders * 3 55% vs. 56% vs. 52% vs. 46% vs. 51% vs. 65%
29%*4 26%
50 percent responders * 3 33% vs. 30% vs. 34% vs. 23% vs. 22% vs. 34%
14%*4 8%
70 percent responders * 3 0% vs. 2% vs. 0% * 4 20% vs. 9% vs. 4% 15% vs. 20%
Slowing down the LEF = SSZ LEF = MTX LEF <>
radiologically visible LEF> PL LEF> PL
Progression * 5 SSZ> PL MTX> PL
Improvement according to MHAQ * 6 LEF> PL LEF> PL
Treatment discontinuation * 4 total 28% vs. 38% vs. 47% vs. 42% vs. 30% vs. 22%
45% 70%

Therapy discontinuation due to 14% vs. 19% vs. 22% vs. 10% vs. 20% vs. 16%
adverse effects 7% 9%
LEF, leflunomide; SSZ, sulfasalazine; MTX, methotrexate; PL, placebo; MHAQ, modified "Health Assessment Questionaire".
* 1 methotrexate plus folic acid
* 2 Methotrexate without folic acid
* 3 after twelve months, according to criteria of the American College of Rheumatology (ACR)
* 4 MN301 after six months, then the placebo arm was transferred to the verum group. MN302 and US301 after twelve months.
* 5 MN301 data after six months; US301 after twelve months, MN302 after 24 months.
* 6 US301 after twelve months, MN301 after 24 months.

Contraindications *
Leflunomide should not be given
- Patients with known hypersensitivity to the active substance leflunomide or other components
- Patients with severe immunodeficiency, for example AIDS
- Patients with markedly impaired bone marrow function or marked anemia, leukopenia (less than 3,000), neutropenia or thrombocytopenia for causes other than rheumatoid arthritis
- patients with severe infections
- Patients with moderate to severe renal impairment, as insufficient clinical experience is available to treat this group of patients
- patients with impaired liver function
- Patients with severe hypoproteinemia such as nephrotic syndrome
- Pregnant women or women of childbearing potential who do not use reliable contraception, both during treatment with leflunomide and after discontinuation of therapy, as long as the plasma level of the active metabolite is above 0.02 mg / l. Pregnancy must be ruled out before starting treatment with leflunomide.
Women should not breast-feed while taking leflunomide. Men should be aware that their treatment with leflunomide may pose a toxic risk to the fetus. Therefore, reliable contraception should be ensured during the treatment with leflunomide.
- Patients under 18 years of age, as there is no experience on the safety and efficacy in this age group

Warnings and Precautions for Use *
The active metabolite of leflunomide has a long half-life, usually one to four weeks. Serious side effects could therefore occur even after stopping treatment with leflunomide. If such toxic reactions occur or if you switch to another basic therapeutic agent after the end of therapy with leflunomide or if pregnancy is desired, a washout procedure should therefore be carried out.
8 g of cholestyramine are administered three times a day or 50 g of activated charcoal powder four times a day. A complete washout phase usually lasts eleven days. However, depending on the clinical or laboratory variables, the duration can be changed accordingly.

* Extract from the "Summary of Product Characteristics" of the European Medicines Evaluation Agency, German version of October 20, 1999.

Unwanted effects*
common: increased blood pressure (generally mild)

Gastrointestinal tract, liver
common: diarrhea, nausea, vomiting, loss of appetite, diseases of the oral mucosa (e.g. aphthous stomatitis, mouth ulcers), abdominal pain, increased liver parameters (transaminases, more rarely g-GT, alkaline phosphatase, bilirubin)
rare: severe liver dysfunction

Metabolism and nutrition disorders
common: weight loss (generally negligible)
uncommon: hypokalaemia

Nervous system
common: headache, dizziness, asthenia, paresthesia
occasionally: changes in taste, feeling of anxiety

Musculoskeletal system
common: tendinitis
occasionally: tendon rupture

Skin and appendages
common: increased hair loss, eczema, dry skin
very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Allergic reaction
common: mild allergic reactions, skin rash (including maculopapular rash), pruritus
occasionally: hives
very rare: severe anaphylactic or anaphylactoid reactions

Blood and lymphatic system
common: leukopenia (leukocytes over 2 G / l)
uncommon: anemia, mild thrombocytopenia (platelets below 100 g / l)
rare: eosinophilia, leukopenia (leukocytes below 2 G / l), pancytopenia (possibly due to antiproliferative mechanisms)
very rare: agranulocytosis

Classification of the expected frequencies:
common = 1 to 10 percent of patients; occasional = 0.1 to 1 percent of patients;
rare = 0.01 to 0.1 percent of patients; very rare = 0.01 percent of patients or less.

Recommended controls
Blood count, including differential blood count, GOT, GPT every two weeks for the first six months and every four weeks thereafter. Regular blood pressure checks, see also on the Internet at

* Extract from the "Summary of Product Characteristics" of the European Medicines Evaluation Agency, German version of October 20, 1999.