Inflamm. res. 50, Supplement 1 (2001) S5 S9 1023-3830/01/01S5-05 $ 1.50+0.20/0 Birkhäuser Verlag, Basel, 2001 Inflammation Research Meloxicam: a review of its pharmacokinetics, efficacy and tolerability following intramuscular administration L. Euller-Ziegler 1, P. Velicitat 2, E. Bluhmki 3, D. Türck 3, S. Scheuerer 3 and B. Combe 4 1 Service de Rhumatologie, Hôpital de l Archet, CHU de Nice, BP 3079, 06202 Nice Cédex, France, e-mail: Lziegler@unice.fr 2 Medical Department, Boehringer Ingelheim, Reims, France 3 Boehringer Ingelheim GmbH, Biberach, Germany 4 Fédération de Rhumatologie, Hôpital Lapeyronie, Montpellier, France Received 21 March 2000; returned for revision 22 March 2000; accepted 27 October 2000 Abstract. This paper reviews published studies on the intramuscular use of meloxicam in acute rheumatic conditions. Data were obtained from 68 healthy volunteers and >800 patients with conditions such as arthritis, sciatica and lumbago who were treated with intramuscular injections of meloxicam compared with oral formulations. Intramuscular meloxicam appears to have a more rapid onset of action than oral meloxicam in acute inflammatory rheumatism. Local tolerance of im meloxicam was consistently good in both volunteers and patients, with respect to creatine phosphokinase levels and local reactions. Meloxicam im was also superior to other drugs such as piroxicam with respect to local tolerance. The incidence of adverse events, including gastrointestinal events, was low. Therefore, im meloxicam is an alternative to achieve rapid relief of acute pain in patients with acute inflammatory rheumatism. However, the recurrent use of im meloxicam is not recommended and patients should be switched to the oral formulation for chronic use. Key words: Meloxicam Intramuscular Rheumatoid arthritis Non-steroidal anti-inflammatory drugs Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively used to reduce inflammation and associated pain in rheumatic diseases and other disorders. During acute, painful exacerbations of rheumatoid arthritis and sciatica, rapid pain relief is required. In such cases, NSAID therapy may initially be administered intramuscularly (im) so that maximum plasma concentrations, which may equate with the onset of therapeutic effect, are achieved more rapidly than after oral administration. However, treatment with im formulations of NSAIDs should only be used for the first few days and patients should be switched to an oral formulation as soon as possible. Correspondence to: L. E. Ziegler In order to realise the therapeutic benefits of the im route, it is vital that both the systemic and local tolerability of the NSAID are good. The systemic tolerability of a NSAID is independent of the route of administration, although some patients may tolerate an im NSAID but not the same drug given orally, possibly due to psychological factors [1]. However, local tolerance of the im formulations of traditional NSAIDs is often poor, resulting in local tissue irritation and necrosis [1 3]. Meloxicam is a novel NSAID which inhibits cyclooxygenase (COX)-2 more potently than COX-1 and has been extensively evaluated in rheumatic disorders. When administered orally at a daily dose of 7.5 mg in osteoarthritis or 15 mg for chronic inflammatory rheumatism (rheumatoid arthritis or ankylosing spondylitis), meloxicam is as effective as traditional NSAIDs and is associated with superior gastrointestinal tolerability [4 7]. This article will examine the use of im meloxicam in the acute situation, particularly with respect to onset of action, and will also assess the local and overall tolerability of im meloxicam. Preclinical studies The preclinical pharmacology of meloxicam (Fig. 1) has been extensively reviewed [8, 9]. In animal models, meloxicam showed potent anti-inflammatory and anti-arthritic activity combined with a low propensity to induce stomach ulceration. Fig. 1. Structure of meloxicam.
S6 L. Euller-Ziegler et al. Inflamm. res., Supplement 1 (2001) The tolerance of im meloxicam at the injection site was investigated in two studies in Chbb:HM rabbits [10]. The first study compared a single im injection of either placebo solution, saline solution or meloxicam solution (5 mg in 0.5 ml). The second study compared meloxicam with piroxicam and diclofenac administered as a single im injection. The test drugs were injected according to their relative volume ratio in humans (meloxicam 0.5 ml, piroxicam 0.33 ml, diclofenac 1 ml). Both studies showed the local tolerance of meloxicam to be very good, with only small, transient microscopic changes at the site of administration. In the first study meloxicam showed equivalent local tolerance to placebo. In the second study meloxicam demonstrated better local tolerance than im piroxicam and diclofenac as, unlike meloxicam, im administration of both piroxicam and diclofenac resulted in the development of an extensive solitary necrotic area. Pharmacokinetics of im meloxicam The pharmacokinetics of im meloxicam have been investigated in four volunteer studies. A dose-escalating study was conducted in which 32 volunteers were randomised to receive either meloxicam (5, 10, 20 or 30 mg) or placebo. Dose proportionality was demonstrated over the dose range 5 30 mg for C max and AUC. The maximum plasma concentration was reached within 1.5 h of administration and 90% of the C max was achieved within 30 50 min for all four doses of meloxicam [11]. In comparison, C max was not attained until 5 6 h after the administration of oral meloxicam [12]. A two-way cross-over randomised, open study (Boehringer Ingelheim, data on file, study 107.217) directly compared the pharmacokinetics of a single 15 mg im dose of meloxicam with a single 15 mg oral dose in 12 healthy subjects. Results showed C max values were reached at approximately 1.5 h after im injection and at about 6 h after oral administration (Fig. 2). Twelve volunteers received single doses of meloxicam (15 mg) im and intravenously (iv) in a two-way cross-over design study, with a 2-week washout period between doses (Boehringer Ingelheim, data on file, study 107.56). Meloxicam was rapidly and completely absorbed following im administration; C max was reached within 1.5 h and absolute bioavailability was 102% [11]. The elimination half-life was comparable between im and iv administration (16.2 h vs Fig. 2. Plasma concentration/time curve for 15 mg meloxicam im versus 15 mg meloxicam tablets in 12 healthy volunteers. 15.3 h, respectively) [11]. Plasma clearance was also similar, irrespective of route of administration, at 7 9 ml/min. Table 1 compares the mean pharmacokinetic parameters for meloxicam im, iv and oral formulations. The complete absorption of meloxicam was confirmed (absolute bioavailability 97%) in a similar study of meloxicam 7.5 mg involving 12 healthy volunteers (Boehringer Ingelheim, data on file, study 107.171). C max (0.99 mg/l) was reached within approximately 1 h and the mean elimination half-life was 18 h, consistent with results observed with im meloxicam 15 mg [11]. Efficacy of intramuscular meloxicam The clinical efficacy of im and oral meloxicam have been compared in two studies in patients with acute sciatica [13] and rheumatoid arthritis [14]. Both trials used a doubledummy design in order to ensure the trial was double blinded. This design also reduced the potential psychological injection effect [1] which may influence the efficacy of im agents. The onset and intensity of action of im and oral meloxicam (15 mg) were compared in patients with acute sciatica [13]. Global efficacy assessments demonstrated that both im and oral meloxicam (15 mg) were effective in relieving pain in patients with acute sciatica. The mean time to onset of analgesic action was not significantly different between patients receiving im and oral meloxicam (mean 80 min vs 89 min, respectively). Furthermore, both im and oral meloxicam (15 mg) significantly reduced spontaneous pain compared with baseline, although no significant difference was Table 1. Comparison of the mean pharmacokinetics parameters after single im, iv and oral administration. Route of Meloxicam C max t max t 1/2 AUC 0 CL/f MRT V z /f administration dose (mg) (mg/l) (h) (h) (mg.h/l) (ml/min) (h) (l) iv (infusion) 7.5 1.2 0.5 18.2 18.4 6.9 24.9 10.7 iv (bolus) 15 3.0 0.05 15.3 30.6 8.6 21.1 11.0 im 7.5 0.99 1.0 18.4 18.1 7.2 25.5 11.3 15 1.6 1.4 16.2 30.6 8.5 22.5 11.6 Oral (capsule) 7.5 0.57 5.1 21.4 15.9 8.3 33.2 14.8 15 0.93 6.0 19.3 28.8 9.4 31.3 14.7 [9, 11, 12].
Inflamm. res., Supplement 1 (2001) Intramuscular administration of meloxicam S7 Fig. 3. Time to maximum improvement (degree of elevation in the straight-leg-raising test) in induced pain after treatment with im or oral meloxicam 15 mg in patients with acute sciatica. Adapted from Auvinet et al., 1995 [13], with kind permission of Excerpta Medica Inc. observed for this parameter between the two treatment groups. However, im meloxicam significantly reduced the time to maximum improvement in induced pain (as assessed by the straight-leg-raising test) compared with oral meloxicam (p < 0.01) (Fig. 3), a measure which is clinically more meaningful than spontaneous pain [13]. This occurred during the first hour in 43.5% of patients treated with the im formulation compared with 15.1% of patients given oral meloxicam (p = 0.002) [13]. Oral and im formulations of meloxicam were also both effective in the treatment of acute exacerbations of rheumatoid arthritis [14]. Significant improvements in overall pain and disease activity were observed for both formulations, with no significant difference in terms of whether the patients received im or oral meloxicam. Intramuscular meloxicam was significantly better than oral meloxicam with respect to time to onset of action (p = 0.012) (Fig. 4), as well as global efficacy assessed by patient (p = 0.03) and the duration of morning stiffness (p = 0.026) [14]. Fig. 5. Global efficacy (good and satisfactory) as assessed on a 4-point verbal rating sale by the clinician in patients with rheumatoid arthritis and osteoarthritis receiving im meloxicam (15 mg) or piroxicam (20 mg). Adapted from Ghozlan et al., 1996 [16], with kind permission of Oxford University Press. The comparative efficacy of a single dose of im meloxicam and piroxicam has been evaluated in two studies [15, 16]. Bosch et al. [15] investigated the efficacy of im meloxicam (15 mg), followed by 7 days of oral meloxicam (15 mg/ day) compared with an im dose of piroxicam (20 mg) followed by 7 days of oral piroxicam (20 mg/day) in 169 patients with acute lumbago. The median time to onset of pain relief was comparable in the meloxicam and piroxicam groups (45 and 40 min, respectively) following im injection [15]. Improvement in pain was rapid in both groups with severe or very severe pain being reported by only 6% of meloxicam-treated patients and 10% of patients receiving piroxicam 90 min after the injection. A comparative study involving 210 patients with osteoarthritis or rheumatoid arthritis was conducted to compare im meloxicam (15 mg) with im (20 mg) [16]. Assessment of global efficacy by the investigator showed a significant advantage for im meloxicam over im piroxicam in patients with rheumatoid arthritis (Fig. 5). In addition, the overall pain intensity was significantly improved in patients with osteoarthritis receiving meloxicam in comparison to those receiving piroxicam (p = 0.02). Tolerability of intramuscular meloxicam Fig. 4. Survival distribution curve for im and oral meloxicam regarding onset of analgesic action within the first 6 h in patients with rheumatoid arthritis. Adapted with kind permission from Combe et al, this supplement. Creatine phosphokinase (CPK) levels are widely used as an indicator of local tissue damage after im injections [2, 17]. No rise in CPK (or the CPK isoenzyme selective for skeletal muscle) levels was detected after im injections of meloxicam (5, 10, 15, 20 and 30 mg) in any of the volunteer studies [11] or the clinical studies [13 16, 18]. Figure 6 shows the maximum changes in CPK-MM compared with baseline during volunteer studies.
S8 L. Euller-Ziegler et al. Inflamm. res., Supplement 1 (2001) In two comparative studies with im piroxicam (20 mg), the overall tolerability of im meloxicam (15 mg) [as assessed by clinician and patient] was rated as very good by the majority of patients in both groups [15, 16]. There were no significant differences between the groups in relation to the incidence of adverse events in either study. Furthermore, the incidence of gastrointestinal adverse events were low for both groups in both studies, with no significant differences between the groups [15, 16]. Discussion and conclusions Fig. 6. Maximum changes to baseline of CPK-MM in the time range > 0 to 24 h for meloxicam im at different dose levels. [Data on file, study 107.050]. In contrast, in a comparative study of im meloxicam versus im piroxicam, CPK levels showed a significant increase from baseline to 59% in the piroxicam group (p = 0.01), but there was no mean change in CPK levels in the meloxicam group [16]. Furthermore, CPK levels increased from baseline by > 30 IU/l in 22.6% of the piroxicam group compared with only 3.8% of the meloxicam group (p = 0.0001). Local tolerability of im meloxicam in both volunteer and clinical studies has been good, confirming the CPK findings [11, 13 16, 18]. In the comparative studies against oral meloxicam, which had double-dummy designs, local tolerability ratings for im meloxicam were similar to those for im placebo [13, 18]. Furthermore, in a comparative study against piroxicam, im meloxicam was associated with significantly less local reddening (p = 0.03) and improved global local tolerability as assessed both by the physician (p = 0.045) and the patient (p = 0.029) [16] (Fig. 7). Fig. 7. Clinician s assessment of local tolerability after the first injection of meloxicam or piroxicam. Adapted with kind permission from Ghozlan et al., 1996 [16], with kind permission of Excerpta Medica Inc. Intramuscular injections of NSAIDs are usually used for the short-term treatment of acute pain as they generally provide a more rapid onset of action. However, the im route has no further advantages over oral administration it is not more efficacious or better tolerated. Therefore there is usually no medical rationale to extend the use of the im formulation beyond the very first days of treatment. Several clinical studies have demonstrated that, even after allowing for the psychological advantages of the im route, im meloxicam has a more rapid onset of action than oral meloxicam in acute inflammatory rheumatism. This is specifically noted in efficacy endpoints such as time to maximum improvement in induced pain, which is considered to be clinically more meaningful than spontaneous pain [13]. This confirms the theoretical pharmacokinetic advantages of using the im route for initiation of treatment. CPK is an indicator of muscle fibre damage; therefore changes in CPK levels are an important factor in the evaluation of local tolerability. Intramuscular injections traditionally result in elevated CPK levels, which may be due to several factors such as chemotoxicity, stimulation of histamine release and direct muscle trauma [2]. There are reports of marked increases in CPK levels after im administration of several of the classical NSAIDs [3, 16]. Mean increases in CPK from baseline of 147% with piroxicam and 922% with diclofenac have been reported in previous trials [3]. However, local tolerance of im meloxicam has been consistently good in both volunteers and patients, both with respect to CPK levels and local reactions. This confirms the results of animal studies where rabbits treated with im diclofenac and piroxicam developed necrotic areas in their muscles but no necrotic areas were seen in rabbits treated with im meloxicam [10]. Clinical comparator studies with im piroxicam have also shown im meloxicam to have superior local tolerance. CPK levels increased in the piroxicam group while they were stable in the meloxicam group, and meloxicam was associated with significantly less local reddening and improved global local tolerability. This finding reflects earlier studies on local reactions to im NSAIDs where, although clinically superior to that of im diclofenac, im piroxicam exhibited unacceptable local reactions with injections causing burning, pain, redness and induration [2, 3]. Overall, the tolerability of im meloxicam was very good in the majority of patients with rheumatic diseases and the incidence of adverse events, including gastrointestinal events, were low. This tolerability profile was comparable with im piroxicam and is typical of the superior tolerability profile exhibited by NSAIDs which are less toxic and better
Inflamm. res., Supplement 1 (2001) Intramuscular administration of meloxicam S9 tolerated than traditional analgesic/anti-inflammatory agents such as aspirin. In conclusion, in patients with acute inflammatory rheumatism, meloxicam may be given im as an alternative to the oral route in order to achieve rapid pain relief, with excellent local and systemic tolerability comparable with oral formulations of meloxicam. However, there is no medical rationale to extend the use of im formulation beyond the very first days of treatment for the acute flare, and patients should be switched to the oral formulation as soon as possible. References [1] Avouac B. Intramuscular use of NSAIDs. In: Famely JP, Paulus HE (eds). Therapeutic applications of NSAIDs. New York: Marcel Dekker 1992; 401 12. [2] Cacace L. Elevated serum CPK after drug injections. N Engl J Med 1972; 287: 309 10. [3] Vaccarino V, Sirtoni R, Bufalino L. Local and systemic tolerability of piroxicam after intramuscular administration in healthy volunteers. Curr Ther Res 1989; 45: 1 13. [4] Barner A. Review of clinical trials and benefit/risk ratio of meloxicam. Scand J Rheumatol 1996; 25 (Suppl 102): 29 37. [5] Distel M, Mueller C, Bluhmki E, Fries J. Safety of meloxicam: a global analysis of clinical trials. Br J Rheumatol 1996; 35 (Suppl 1): 68 77. [6] Dequeker J, Hawkey C, Kahan A, Steinbrück K, Alegre C, Baumelou E, et al. On behalf of the SELECT Study Group. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large Scale Evaluation of COX inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998; 37: 946 51. [7] Hawkey C, Kahan A, Steinbrück K, Alegre C, Baumelou E, Begaud B, et al. and the international MELISSA Study Group. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatol 1998; 37: 937 45. [8] Engelhardt G. Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibition of COX-2. Br J Rheumatol 1996; 35 (Suppl 1): 4 12. [9] Degner F, Türck D, Pairet M. Pharmacological, pharmacokinetic and clinical profile of meloxicam. Drugs of Today 1998; 34 (Suppl A): 1 22. [10] Stei P, Kruss B, Wiegleb J, Trach V. Local tissue tolerability of meloxicam, a new NSAID: indications for parenteral, dermal and mucosal administration. Br J Rheumatol 1996; 35 (Suppl 1): 44 50. [11] Narjes H, Türck D, Busch U, Heinzel G, Nehmiz G. Pharmacokinetics and tolerability of meloxicam after im administration. Br J Clin Pharmacol 1996; 41: 135 9. [12] Türck D, Roth W, Busch U. A review of the clinical pharmacokinetics of meloxicam. Br J Rheumatol 1996; 35 (Suppl 1): 13 6. [13] Auvinet B, Ziller R, Appelboom T, Velicitat P. Comparison of the onset and intensity of action of intramuscular meloxicam and oral meloxicam in patients with acute sciatica. Clin Ther 1995; 17: 1078 90. [14] Combe B, Velicitat P, Garzon N, Koneke N, Bluhmki E. Comparison of intramuscular and oral meloxicam in rheumatoid arthritis patients. [This supplement]. [15] Bosch H-C, Sigmund R, Hettich M. Efficacy and tolerability of intramuscular and oral meloxicam in patients with acute lumbago: a comparison with intramuscular and oral piroxicam. Curr Med Res Opin 1997; 14: 29 38. [16] Ghozlan POR, Bernhardt M, Velicitat P, Bluhmki E. Tolerability of multiple administration of intramuscular meloxicam: a comparison with intramuscular piroxicam in patients with rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1996; 35 (Suppl 1): 51 5. [17] Steiness E, Rasmussen F, Svendsen O, Nielsen P. A comparative study of serum creatine phosphokinase (CPK) activity in rabbits, pigs and humans after intramuscular injection of local damaging drugs. Acta Pharmacol Toxicol 1978; 42: 357 64. [18] Baturone M, Euller-Ziegler L, Kneer W, Bluhmki E, Morene J. The intramuscular formulation of the COX-2 inhibitor meloxicam is effective and safe in osteoarthritis. Presented at 3rd APLAR congress, The Philippines, January 1998.