431004 TAB411759720X11431004F Striesow and A BrandtTherapeutic Advances in Musculoskeletal Disease
`
`2012
`
`Therapeutic Advances in Musculoskeletal Disease
`
`Original Research
`
`Preference, satisfaction and usability of
`subcutaneously administered methotrexate
`for rheumatoid arthritis or psoriatic
`arthritis: results of a postmarketing
`surveillance study with a high-concentration
`formulation
`
`Ther Adv Musculoskel Dis
`
`(2012) 4(1) 3 –9
`
`DOI: 10.1177/
`1759720X11431004
`
`© The Author(s), 2012.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Frank Striesow and Andreas Brandt
`
`Abstract:
`Background/objectives: This postmarketing surveillance study assessed the preference,
`satisfaction, usability, and tolerability of subcutaneous self-administration of a high-
`concentration (50 mg/ml) ready-to-use formulation of methotrexate (MTX) in patients with
`rheumatoid arthritis or psoriatic arthritis.
`Methods: The study enrolled 403 patients with rheumatoid or psoriatic arthritis. The first
`injection was administered by the attending physician or nurse, followed by five self-
`administered injections at weekly intervals. The high-concentration formulation consisted of a
`prefilled syringe with MTX 50 mg/ml solution and a pre-attached needle. Questionnaires were
`used to document outcomes.
`Results: The overall assessment was ‘very good’ and ‘good’ in 87.6% of the patients and
`in 92.8% of the physicians/study nurses. Availability and use of a pre-attached needle was
`considered as very advantageous and advantageous by 91.8% of the patients and 88.8%
`of the physicians/study nurses. A total of 96% of the patients described the feeling of the
`injection as comfortable or tolerable. Patients reported that self-administration led to a
`feeling of more independence (89.1%) and an improved quality of life (83.6%). A total of 109
`patients reported previous self-administration of low-concentration MTX formulations;
`94.5% of them stated that they would prefer the high-concentration MTX formulation in the
`future. The formulation was generally well tolerated. Physicians’ expectations concerning
`the benefit of switching to MTX self-administration was met in 92.8% of the patients. A total
`of 96.3% of the patients were considered suitable for subcutaneous self-administration of
`the MTX formulation.
`Conclusions: The 50 mg/ml prefilled syringe appears to be a valuable treatment option for
`patients with rheumatoid and psoriatic arthritis in need of MTX. This is supported by the
`strong appreciation of the patients as well as their attending healthcare professionals for its
`convenience and tolerability. The results confirm the findings and experience from a clinical
`study performed in Germany in 2009, which showed that 93% of the patients prefer the 50 mg/
`ml prefilled syringe with a pre-attached needle.
`
`Keywords: methotrexate, parenteral, postmarketing surveillance study, pre-attached needle,
`prefilled syringe, psoriatic arthritis, rheumatoid arthritis, self-administration, subcutaneous
`injection
`
`Correspondence to:
`Andreas Brandt, PhD
`medac Gesellschaft für
`klinische Spezialpräparate
`mbH, Hamburg, Germany
`a.brandt@medac.de
`Frank Striesow, MD
`Rheumatologische
`Schwerpunktpraxis,
`Quirinstrasse 7, D-53129
`Bonn, Germany
`
`http://tab.sagepub.com
`
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`Medac Exhibit 2091
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
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`Therapeutic Advances in Musculoskeletal Disease 4 (1)
`
`Introduction
`Methotrexate (MTX) has been established as a
`gold standard in the first-line medical treatment
`of rheumatoid arthritis (RA) [Ahern and
`Chandran, 1995; Sieper and Braun, 1996; Ward
`and Fries, 1998]. MTX is a disease-modifying
`antirheumatic drug that in the past has been
`mainly administered orally at doses between 7.5
`and 30 mg once a week. Clinical data support the
`use of subcutaneously (SC) administered MTX
`that is well absorbed, well tolerated, and appears
`to solve some of the issues encountered with oral
`administration, e.g. variable absorption and satu-
`ration of the absorption mechanism with increas-
`ing doses [Balis et al. 1988]. A 24-week SC
`administration of MTX at a dose of 15 mg/week
`was significantly more effective than oral adminis-
`tration [Braun et al. 2008]. In comparison to
`intramuscular injection, SC administration has
`been shown to be better tolerated with improved
`usability [Brooks et al. 1990]. In addition, SC
`administration of MTX was associated with a sig-
`nificant reduction in gastrointestinal side effects
`compared with oral administration of the same
`MTX dose [Rutkowska-Sak et al. 2009].
`
`In a 6-month, multicenter, prospective, rand-
`omized, double-blind, two-arm phase IV trial, SC
`and oral MTX administrations were compared in
`384 patients with RA [Braun et al. 2008]. MTX
`doses were 15 mg/week either orally (two 7.5 mg
`tablets) or SC (prefilled syringe containing a
`medium-concentrated formulation of 10 mg/ml).
`Tolerability between treatments was similar.
`However, significantly more patients receiving SC
`MTX than with oral MTX showed ACR20 (78%
`versus 70%) and ACR70 (41% versus 33%)
`responses. Patients with a disease duration (cid:116)12
`months had even higher ACR20 response rates
`(89% for SC administration and 63% for oral).
`
`In a pharmacokinetic study in 12 healthy male
`subjects, 15 mg of MTX was administered SC at
`concentrations of either 50 mg/ml or 10 mg/ml
`solution. Both concentrations were shown to be
`bioequivalent with regard to area under the
`curve (AUC; medac, data on file). However, the
`rate of absorption (Cmax) was higher after admin-
`istration of the higher concentrated solution.
`Rate and extent of absorption after SC adminis-
`tration with the two solutions was similar for the
`metabolite 7hydroxy-MTX. Since both concen-
`trations were bioequivalent, no difference in the
`efficacy and the safety of the two formulations
`was expected.
`
`Two MTX formulations for SC use were tested in
`an open-label, comparative, within-patient con-
`trolled, multicenter study in 132 patients with
`RA [Müller-Ladner et al. 2010]. MTX treat-
`ment consisted of 20 mg/week administered as
`a medium-concentration formulation (2.0 ml of
`10 mg/ml solution in prefilled syringe; separate
`needle) which was compared to a novel high-con-
`centration formulation (0.4 ml of 50 mg/ml in
`prefilled syringe; pre-attached needle). Each
`treatment was given for 3 weeks. Questionnaires
`and visual analog scales were used to measure
`outcomes. The total smaller volume of adminis-
`tered drug and the improved usability of a pre-
`attached needle in combination with a smaller
`prefilled syringe resulted in preference of the
`patients for the high-concentration formulation.
`In addition, local tolerability was slightly better
`compared with the medium-concentration for-
`mulation. These assessments were confirmed by
`the attending healthcare professionals.
`
`This postmarketing surveillance study assessed
`preference, satisfaction, and usability of SC self-
`administration of a high-concentration (50 mg/ml)
`ready-to-use MTX formulation (Metex®/Metoject®
`50 mg/ml; medac GmbH, Wedel, Germany) in
`patients with RA or psoriatic arthritis.
`
`Patients and methods
`This postmarketing surveillance study (Anwen-
`dungsbeobachtung) was conducted between June
`2009 and May 2010 in 52 outpatient rheumatol-
`ogy practices in Germany and enrolled patients
`with a diagnosis of RA or psoriatic arthritis.
`Decisions about medical treatment were exclu-
`sively made by the treating physicians. The physi-
`cians selected appropriate patients, i.e. patients
`suffering from RA or psoriatic arthritis, for whom
`therapy (Metex®/Metoject® 50 mg/ml;
`MTX
`medac GmbH, Wedel, Germany) was indicated.
`MTX was contained in a prefilled syringe that
`included a pre-attached needle. Physicians
`recorded patient history, previous and concomi-
`tant MTX therapy, and the Metex®/Metoject®
`50 mg/ml dose administered. They also recorded
`physicians’/patients’ assessments of usability and
`preference as well as assessments of local tolera-
`bility by the patient at the respective visits. Adverse
`drug reactions were to be reported.
`
`Table 1 summarizes questions and answers con-
`cerning patient-, physician-, and study-nurse-
`reported outcomes.
`
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` F Striesow and A Brandt
`
`Table 1. Preference, usability, and tolerability outcomes*.
`
`Patient-, physician-, and study-nurse-reported outcomes
`Visibility of information ‘Dose strength of ready-to-use syringe’ printed on outer package
`Four categories were suggested: ‘very good’, ‘good’, ‘mediocre’, and ‘poor’.
`Visibility of information ‘Application once a week’ printed on outer package
`Four categories were suggested: ‘very good’, ‘good’, ‘mediocre’, and ‘poor’.
`Usability concerning (1) removal of ready-to-use syringe from package; (2) removal of the rubber
`stopper; (3) handling of syringe at time of prick; (4) handling of syringe during injection; and (5)
`easiness of depressing the syringe plunger
`Three categories were suggested: ‘very satisfactory’, ‘satisfactory’, ‘less satisfactory’.
`Patient’s tolerability of the subcutaneous injection
`Three categories were suggested: ‘comfortable’, ‘tolerable’, ‘intolerable’.
`Occurrence of pain at injection site‘Yes/no’; if ‘yes’: Three categories were suggested: ‘slight’,
`‘moderate’, ‘severe’.
`Overall assessment of therapy with MTX ready-to-use syringe at the end of a 5-week treatment
`Five categories were suggested: ‘very poor’, ‘poor’, ‘satisfactory’, ‘good’ and ‘very good’.
`Syringe with or without pre-attached needle in patients with previous use of the low-concentration
`(10 mg/ml) MTX ready-to-use syringe‘How do you like the pre-attached needle (small syringe) in
`comparison to the one which still has to be attached (large syringe)?’
`Five categories were suggested: ‘great disadvantage’, ‘disadvantage’, ‘no difference’, ‘advantage’, and
`‘great advantage’.
`Physician- and study-nurse-reported outcomes
`Patient’s suitability for subcutaneous self-injection with MTX ready-to-use syringe
`Three categories were suggested: ‘very suitable’, ‘suitable’, ‘less suitable’.
`Expectations met for switch to self-administration of MTX ready-to-use syringe
`Five categories were suggested: ‘fully met’, ‘largely met’, ‘partly met’, ‘less met’ and ‘not met’.
`Improved patient compliance expected with smaller injection volume of MTX ready-to-use syringe
`Two categories were suggested: ‘yes’, ‘no’.
`Continuation of treatment with MTX ready-to-use syringe
`Two categories were suggested: ‘yes’, ‘no’.
`Patient-reported outcomes
`Effort needed for self-injection
`Three categories were suggested: ‘little’, ‘moderate’, ‘great’.
`More patient independence through self-administration
`Three categories were suggested: ‘yes’, ‘no’, ‘not yet assessable at this time’.
`Improved patient quality of life through self-administration
`Three categories were suggested: ‘yes’, ‘no’, ‘not yet assessable at this time’.
`Patient-reported outcomes in patients with previous use of the low-concentration (10 mg/ml) MTX
`ready-to-use syringe
`Smaller injection volume
`Five categories were suggested: ‘very unpleasant’, ‘unpleasant’, ‘no difference’, ‘pleasant’ and ‘very pleasant’.
`Preference of smaller, high-concentration (50 mg/ml) versus larger, low-concentration (10 mg/ml)
`MTX ready-to-use syringe
`Two categories were suggested: ‘smaller syringe’, ‘larger syringe’.
`
`*Original in German
`
`Treatment duration was 5 weeks, during which
`patients received a total of six MTX injections
`administered subcutaneously. At baseline, the
`first MTX treatment was administered by the
`physician/nurse to instruct the patient. One
`week later (week 1), the patients self-injected
`the second MTX dose under the supervision of
`the physician/nurse. The next 3 MTX injec-
`tions at week 2, 3, and 4 were performed by the
`
`patients at their homes. The sixth and last
`MTX injection was self-administered by the
`patient at the physician’s office (see Table 2).
`No diagnostic and therapeutic measures were
`requested for the conduct of the study. This
`postmarketing surveillance study did not
`require any additional diagnostic or therapeu-
`tic measures beyond usual standard medical
`procedures.
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`Therapeutic Advances in Musculoskeletal Disease 4 (1)
`
`Table 2. Study procedures.
`
`Start of therapy
`
`Week 1
`
`Weeks 2, 3 and 4
`
`Week 5
`
`(cid:153)(cid:21) (cid:66)(cid:90)(cid:89)(cid:94)(cid:88)(cid:86)(cid:97)(cid:21)(cid:93)(cid:94)(cid:104)(cid:105)(cid:100)(cid:103)(cid:110)
`(cid:153)(cid:21)
`(cid:62)(cid:99)(cid:104)(cid:105)(cid:103)(cid:106)(cid:88)(cid:105)(cid:94)(cid:100)(cid:99)(cid:104)(cid:21)(cid:100)(cid:99)(cid:21)
`subcutaneous self-
`administration
`(cid:62)(cid:99)(cid:95)(cid:90)(cid:88)(cid:105)(cid:94)(cid:100)(cid:99)(cid:21)(cid:24)(cid:38)
`(cid:153)(cid:21)
`(cid:153)(cid:21) (cid:57)(cid:100)(cid:88)(cid:106)(cid:98)(cid:90)(cid:99)(cid:105)(cid:86)(cid:105)(cid:94)(cid:100)(cid:99)
`
`(cid:153)(cid:21) (cid:72)(cid:106)(cid:87)(cid:88)(cid:106)(cid:105)(cid:86)(cid:99)(cid:90)(cid:100)(cid:106)(cid:104)(cid:21)(cid:104)(cid:90)(cid:97)(cid:91)(cid:34)
`administration
`under supervision of
`physician/study nurse
`(cid:62)(cid:99)(cid:95)(cid:90)(cid:88)(cid:105)(cid:94)(cid:100)(cid:99)(cid:21)(cid:24)(cid:39)
`(cid:153)(cid:21)
`(cid:153)(cid:21) (cid:57)(cid:100)(cid:88)(cid:106)(cid:98)(cid:90)(cid:99)(cid:105)(cid:86)(cid:105)(cid:94)(cid:100)(cid:99)
`
`(cid:153)(cid:21) (cid:72)(cid:106)(cid:87)(cid:88)(cid:106)(cid:105)(cid:86)(cid:99)(cid:90)(cid:100)(cid:106)(cid:104)(cid:21)
`self-
`administration at
`home
`(cid:62)(cid:99)(cid:95)(cid:90)(cid:88)(cid:105)(cid:94)(cid:100)(cid:99)(cid:104)(cid:21)(cid:24)(cid:40)(cid:33)(cid:21)(cid:24)(cid:41)(cid:21)
`(cid:86)(cid:99)(cid:89)(cid:21)(cid:24)(cid:42)
`
`(cid:153)(cid:21)
`
`(cid:153)(cid:21) (cid:72)(cid:106)(cid:87)(cid:88)(cid:106)(cid:105)(cid:86)(cid:99)(cid:90)(cid:100)(cid:106)(cid:104)(cid:21)
`self-administration
`under supervision of
`physician/study nurse
`(cid:62)(cid:99)(cid:95)(cid:90)(cid:88)(cid:105)(cid:94)(cid:100)(cid:99)(cid:21)(cid:24)(cid:43)
`(cid:153)(cid:21)
`(cid:153)(cid:21) (cid:57)(cid:100)(cid:88)(cid:106)(cid:98)(cid:90)(cid:99)(cid:105)(cid:86)(cid:105)(cid:94)(cid:100)(cid:99)
`
`Patients
`Physicians / study nurses
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Very good
`
`Good
`
`Satisfactory
`
`Poor /
`very poor
`
`No
`information
`
`Figure 1. Overall assessment of MTX prefilled syringe 50 mg/ml (n = 403).
`
`Patients
`Physicians / study nurses
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Great
`advantage
`
`Advantage
`
`No
`difference
`
`Disadvantage
`
`Great
`disadvantage
`
`No
`information
`
`Figure 2. Overall assessment of pre-attached needle in patients with previous experience of low-
`concentration MTX 10 mg/ml (n = 109).
`
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`Since no statistical hypotheses were prespecified
`only descriptive statistical methods were employed
`and no confirmatory analyses of the data were
`performed. In accordance with confidentiality
`regulations, no data were recorded which could
`be directly assigned to patients.
`
`in compliance
`The study was conducted
`with German Drug Law regulations (§ 67
`Section 6) applicable to postmarketing surveil-
`lance studies.
`
`Results
`
`Demographics and baseline characteristics
`A total of 71 physicians enrolled 403 patients into
`the study: 122 (30.3%) were men, 275 (68.2%)
`were women; information on gender was missing
`in 6 (1.5%) patients. Mean weight was 76.5 kg,
`median height 168.4 cm, and mean body mass
`index 27.8 kg/m2. A total of 310 (76.9%) patients
`had RA, 59 (14.6%) psoriatic arthritis, 28 (6.9%)
`other rheumatic diseases/arthritis, and no infor-
`mation was available for 6 (1.5%) patients. Of
`these, 221 (54.8%) patients had previously
`received MTX treatment at dosages ranging
`between 7.5 and 25 mg/week and a treatment
`duration for up to 23 years, and 92 (41.6%) of
`these patients had received MTX as subcuta-
`neous injections. The most common reasons
`for a change to MTX self-administration were
`improved efficacy due to better bioavailability
`(43.0%) compared with previous treatments,
`improved usability (25.3%) and dislike to MTX
`tablets (13.6%). Table 3 summarizes demograph-
`ics and baseline characteristics.
`
`Patient-, physician-, and study-nurse-
`reported outcomes
`At the end of the study after a 5-week self-admin-
`istered treatment with MTX ready-to-use syringe
`(50 mg/ml), the overall assessment was ‘very
`good’ and ‘good’ in 87.6% of the patients com-
`pared with 2.7% with a ‘poor’ and ‘very poor’
`assessment. The corresponding assessments by
`physicians/study nurses were 92.8% (‘very good’
`and ‘good’) and 1.2% (‘poor’ and ‘very poor’)
`(see Figure 1).
`
` F Striesow and A Brandt
`
`Table 3. Demographics and baseline characteristics
`(n = 403).
`
`122 (30.3)
`275 (68.2)
`6 (1.5)
`76.5 ± 16.6
`168.4 ± 11.1
`27.8 ± 16.6
`
`310 (76.9)
`59 (14.7)
`28 (6.9)
`6 (1.5)
`
`221 (54.8)
`180 (44.7)
`2 (0.5)
`
`Gender, n (%)
` Men
` Woman
`
`Information missing
`Weight, mean ± SD (kg)
`Height, mean ± SD (cm)
`Body mass index, mean ± SD
`(kg/m2)
`Diagnosis of rheumatic disease, n (%)
` Rheumatoid arthritis
` Psoriatic arthritis
` Others
`
`Information missing
`Pretreatment with MTX, n (%)
` Yes
` No
`
`Information missing
`Previous MTX dose, n (%)
`10 (4.5)
` 7.5 mg
`53 (24.0)
` 10 mg
`112 (50.7)
` 15 mg
`34 (15.4)
` 20 mg
`6 (2.7)
` 25 mg
`6 (2.7)
`
`Information missing
`14.5 ± 3.9 mg
` Mean dose
`15 mg (7.5–25 mg)
` Median dose (range)
`Previous mode of MTX administration, n (%)
` Oral
`106 (48.0)
` Parenteral
`115 (52.0)
`Start of MTX treatment, n (%)
` (cid:33)20 years ago
`3 (1.3)
` (cid:33)10 to 20 years ago
`22 (9.9)
` (cid:33)5 to 10 years ago
`62 (28.2)
`132 (59.7)
` 0 to 5 years ago
`2 (0.9)
`
`Information missing
`Reasons for change to MTX self-administration, n (%)
`
`Improved bioavailability
`95 (43.0)
`
`Improved usability
`56 (25.3)
`
` Low bioavailability of
`32 (14.5)
`previous MTX treatment
` Dislike to MTX tablets
`
` Adverse events of previous
`MTX treatment
` Others
`
`30 (13.6)
`23 (10.4)
`
`25 (11.3)
`
`MTX, methotrexate; SD, standard deviation
`
`Availability and use of a pre-attached needle
`was considered as advantageous by 91.8% of
`the patients and physicians/study nurses (see
`Figure 2).
`
`A total of 96% of the patients described the feel-
`ing of the injection as comfortable or tolerable
`between the first and sixth injection; severe pain
`occurred only once.
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`Therapeutic Advances in Musculoskeletal Disease 4 (1)
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`Safety
`No serious adverse drug reactions were reported.
`
`Discussion
`This was a postmarketing surveillance study that
`evaluated preference, satisfaction, and usability of
`subcutaneous self-administration of a high-con-
`centration (50 mg/ml) ready-to-use formulation of
`MTX in 403 patients with RA or psoriatic arthri-
`tis. The results show a high acceptance by patients
`(87.6%) and healthcare professionals (92.8%) of
`the MTX prefilled syringe with a pre-attached
`needle. In particular, 91.8% of the patients and
`physicians/study nurses valued the availability and
`use of a pre-attached needle as high. The formula-
`tion was generally well tolerated. In addition, self-
`administration of the MTX formulation was
`associated with an improved quality of life in 84%
`of the patients. Physicians considered 96.3% of
`the patients suitable for SC self-administration of
`the MTX formulation.
`
`A total of 109 patients had previous experience in
`using medium-concentration MTX formulations.
`Of these, 94.5% preferred to use the new high-
`concentration MTX formulation in the future.
`These results are similar to those reported previ-
`ously in a study comparing a medium-concentra-
`tion with a high-concentration MTX formulation
`for SC self-administration [Müller-Ladner et al.
`2010]. The smaller injection volume may improve
`the comfort of injection and the pre-attached
`needle makes the handling of the syringe safer,
`both contributing to the patients’ preference for
`this MTX formulation [Müller-Ladner et al.
`2010]. In addition, other studies have confirmed
`the improved convenience and tolerability of sub-
`cutaneous administration of MTX also in com-
`parison with intramuscular injection [Brooks et al.
`1990; Sander et al. 1996; Zackheim, 1992].
`
`This postmarketing surveillance study focused on
`subjective assessments of preference, satisfaction,
`and usability of the high-concentration MTX for-
`mulation and does not address safety and efficacy.
`However, with regard to efficacy, a recently per-
`formed 6 month, multicenter, randomized, dou-
`ble-blind, controlled trial compared oral MTX in
`384 MTX-naïve patients with active RA to sub-
`cutaneously administered MTX [Braun et al.
`2008]; the latter formulation showed superior
`efficacy over the oral MTX formulation and
`thus similar clinical results may be expected for
`the high-concentration MTX formulation. In
`addition, current practice guidelines support the
`
`Figure 3. Different volumes of a 20 mg dose
`comparing the concentrations 10 mg/ml (2 ml to
`inject), 20 mg/ml (1 ml to inject) or 50 mg/ml (0.4 ml
`to inject).
`
`Patient-reported outcomes
`Most patients got used to the effort in applying
`self-injection of MTX. Twenty (5.0%) patients
`reported administration errors with regard to
`administration sites and disinfection. A total of
`89.6% of the patients evaluated the labeling of
`the dosage as ‘very good’ and ‘good’, which con-
`firms the usefulness of the color-coded backstop
`matching to the carton. Patients reported that
`self-administration led to a feeling of more inde-
`pendence (89.1%) and an improved quality of life
`(83.6%). A total of 109 patients reported previ-
`ous self-administration of medium-concentration
`MTX formulations; 94.5% of them stated that
`they would prefer the high-concentration MTX
`formulation with 50 mg/ml in the future. This was
`mostly due to a better tolerated injection with
`reduced volume (93.6%) and the pre-attached
`needle (91.8%).
`
`Physician- and study-nurse-reported outcomes
`Physicians’ expectations concerning the benefit
`of switching to MTX self-administration were
`met in 92.8% of the patients and 96.3% of
`the patients were considered suitable for
`subcutaneous self-administration of the MTX
`formulation.
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` F Striesow and A Brandt
`
`use of parenteral MTX treatment in patients with
`poor compliance, inadequate effectiveness, or
`gastrointestinal side effects [Pavy et al. 2006;
`Tarner et al. 2009].
`
`References
`Ahern, M.J. and Chandran, G. (1995) Category
`III symptom-modifying antirheumatic drugs. Clin
`Immunother 3: 196–217.
`
`Conclusions
`The 50 mg/ml prefilled syringe appears to be a
`valuable treatment option for patients with RA
`and psoriatic arthritis in need of MTX. This is
`supported by the strong appreciation of the
`patients as well as their attending healthcare pro-
`fessionals for its convenience and tolerability. The
`results confirm the findings and experience from
`a previously performed clinical study.
`
`Acknowledgements
`The authors wish to thank all participating cent-
`ers who enrolled at least one patient:
`
`H. Schmidt, Berlin; C. Busch-Mauz and T. Busch,
`Ilvesheim; I. Dahmann, Göttingen; R. Dockhorn,
`Weener; C. Eisterhues, Braunschweig; J. Frey,
`Neuburg a. d. Donau; A. Göbel, Lippstadt; W.
`Harmuth, Marktredwitz; H. Heintz, Hamburg; M.
`Hesse, Bad Kreuznach; T. Karger, Köln; M. Lei-
`dert, Lüneburg; A. Liebhaber, Halle; T. Marycz,
`Amberg; A. Melzer, Sessen; A. Reck, Mittelher-
`wigsdorf; S. Remstedt, Berlin; U. Schoo, Rheine;
`H. Schulte and Partner, Hamburg; F. Schumann,
`Reken; M. Schürmann, Mülheim; F. Striesow,
`Bonn; W. Thies, Herrsching; C. Weimann, Magde-
`burg; S. Worsch, Mühlhausen; W.-D. Wörth, Wies-
`baden; P. Veress, Mönchengladbach; K. Babinsky,
`Halle; C. Stille, Hannover; C. Baumann, Plauen;
`S. Bödeker, Marl; A. Rittstieg, Gelsenkirchen; E.
`Bräuning, Kahla; H.-E. Langer, Düsseldorf; B.
`Proba, Lüdenscheid; B. Heilig, Heidelberg; U.
`Kaeding, Parchim; V. Kubitza, Aschaffenburg; D.
`Lassak-Siedl, Heidelberg; D. Nottarp, Hanau;
`G. Hübner, Rheine; M. Linke, Stadtbergern; M.
`Reichardt, Berlin; J.-C. Nolde, Hannover; R. Haux,
`Berlin; S. Kupka, Altenburg; H.-J. Menne, Dort-
`mund; B. Pech, Eberswalde; A. Stein, München;
`G. Donath, Freystadt; and N. Rinaldi, Ulm..
`
`Martin Bornemann MD provided medical writ-
`ing support on behalf of medac GmbH, Germany.
`
`Funding
`This postmarketing surveillance study was
`sponsored by medac Gesellschaft für klinische
`Spezialpräparate mbH.
`
`Conflict of interest statement
`FS has no conflicts of interest to declare. AB is an
`employee of medac GmbH.
`
`http://tab.sagepub.com
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