Safety

The safety profile of adalimumab has been studied extensively in randomized clinical trials and in long-term OLE trials (Weinblatt et al. 2003; Keystone et al. 2004a, 2004b; Furst et al. 2003; van de Putte et al. 2004). At least 10,050 patients with moderate to severe RA have been evaluated, representing 12,506 patient-years (PYs) of adalimumab exposure (Schiff et al. 2006). Adalimumab is generally well tolerated, with less than 10 % of the patients discontinuing treatment due to AEs in RA trials (Furst et al. 2003; Keystone et al. 2004a). Additionally, data from a national registry demonstrated a high adherence rate (82%) after 12 months of adalimumab therapy (Kristensen et al. 2004).

The most common AE associated with adalimumab treatment is injection site reactions, occurring in 20.3 % of adalimumab-treated patients versus 13.8 % of placebo-treated patients across RA trials. Most injection site reactions were mild and nonrecurrent and rarely led to drug discontinuation (Wells et al. 2003). Phase Illb studies of adalimumab in RA (Burmester et al. 2004, 2005) and in studies for other approved or potential indications (e.g., PsA, psoriasis, AS, Crohn's

Table 3.4. Adverse events reported by a 5% of patients treated with adalimumab during placebo-controlled periods of rheumatoid arthritis studies (Abbott Laboratories 2006)

Adverse event

Adalimumab

Placebo

40 mg e.o.w.

(n = 690) (<%)

(n = 705) (%)

Respiratory

Upper respiratory infection

17

13

Sinusitis

11

9

Flu syndrome

7

6

Gastrointestinal

Nausea

9

8

Abdominal pain

7

4

Laboratory testsa

Laboratory test abnormal

8

7

Hypercholesterolemia

6

4

Hyperlipidemia

7

5

Hematuria

5

4

Alkaline phosphatase

5

3

increased

Other

Injection site pain

12

12

Headache

12

8

Rashb

12

6

Accidental injury

10

8

Injection site reactionb,c

8

1

Back pain

6

4

Urinary tract infection

8

5

Hypertension

5

3

a Laboratory test abnormalities were reported as adverse events in European trials b Statistically significant c Does not include erythema and/or itching, hemorrhage, pain, or swelling e.o.w. every other week a Laboratory test abnormalities were reported as adverse events in European trials b Statistically significant c Does not include erythema and/or itching, hemorrhage, pain, or swelling e.o.w. every other week disease) have revealed no new safety signals (Langley et al. 2005; Hanauer et al. 2006; Mease et al. 2005a, 2005b; Sandborn et al. 2005a; Schiff et al. 2003, 2006; van der Heijde et al. 2006).

Retrospective analysis of combined data from all clinical trials in RA patients treated with adalimumab determined that the rates of serious and nonserious infections were similar to those reported with traditional DMARDs, and other TNF antagonists, and did not increase over time (Schiff et al. 2005, 2006). During the pivotal trials, the rate of infection was 1.0/PY in the ada-limumab-treated patients and 0.9/PY in the placebo-treated patients. The most frequently reported infections were upper respiratory tract infections, rhinitis, bronchitis, and urinary tract infections (Abbott Laboratories 2006). As of April 2005, the rate of serious infections among adalimumab-treated patients was 5.1/ 100 PYs, which is consistent with that of the previous assessment in August 2002 of 4.9/100 PYs. These rates are similar to those observed for the general RA population naïve to TNF antagonists (Schiff et al. 2006).

Cases of tuberculosis (TB) have been documented in patients treated with TNF inhibitors. Most of these cases are a result of reactivation of latent TB and occur within the first few months of therapy (Bieber and Kavanaugh 2004; Schiff et al. 2003). During the first 534 PYs of adalimumab exposure in clinical trials, screening for TB was not required and 7 TB cases were reported, all in Europe (1.3/100 PYs); however, the rate of TB decreased by 75 % (0.33/100 PYs) after the introduction of routine TB screening in European clinical trials (Schiff et al. 2006). In North American clinical RA trials, 4 cases had been reported after 4,914 PYs of exposures (0.08/100 PYs). In the postmarketing period from 31 December 2002 through 30 June 2005, there were 17 cases of TB (0.02/100 PYs) reported in the United States, of which 5 had extrapulmonary involvement (Schiff et al. 2006). These data are consistent with those for other TNF inhibitors and the decrease in cases seen after screening was introduced prior to beginning TNF antagonist therapy highlights the importance of screening for latent TB prior to commencing therapy with adalimumab or other TNF antagonists (Lee and Kavanaugh 2005).

Reports in the literature suggest that RA patients have an approximately twofold increased risk of lymphoma than the general population, which may be further increased in patients with highly active disease (Gridley et al. 1993; Isomaki et al. 1978; Mellemkjaer et al. 1996). After 12,506 PYs of adalimumab exposure, 15 cases of lymphoma were observed (0.12/100 PYs). Most patients in adalimumab clinical trials had moderately to severely active RA at study entry, increasing their risk for lymphoma. The Standardized Incidence Ratio of 3.19 for lymphoma in adalimumab-treated patients is consistent with that expected in RA patients naïve to TNF antagonists (Schiff et al. 2006).

Ten cases of demyelinating conditions were observed among RA patients who had received adalimumab after 12,506 PYs of exposure (0.08/100 PYs). Six of these were cases of multiple sclerosis (MS) (Schiff et al. 2006). This rate is consistent with the background rate of MS in society as a whole and with that of other TNF inhibitors. The literature suggests that patients with MS have a statistically significantly higher coexistence of RA, psoriasis, and goiter than matched controls (Heinzlef et al. 2000). Patients with RA and Crohn's disease who develop neurologic signs after exposure to TNF inhibitors may innately be at increased risk of developing MS as compared with the general population (Magnano et al. 2004). The true impact of TNF inhibitors on the development of this disorder is unknown (Lee and Kavanaugh 2005; Mag-nano et al. 2004).

Approximately 3 -12 % of patients treated with ada-limumab develop autoantibodies to antinuclear antigen and double-stranded DNA. The clinical implications of these antibodies remain to be defined, because progression to lupuslike illness appears to be uncommon. After 12,506 PYs of adalimumab exposure, 13 cases of systemic lupus erythematosus and lupuslike syndromes have been reported. None of these cases had significant internal organ involvement.

Other rare reports include aggravation of congestive heart failure (CHF) (Kavanaugh et al. 2003). During adalimumab trials, 44 patients reported a medical history of CHF, and 3 (7 %) of these patients reported CHF events during the trials. Thirty-two cases of CHF were observed among 10,006 (0.3%) patients who did not report a medical history of CHF. Over the 2.5 years in which the rate of CHF was evaluated, the frequency of these conditions appears to have remained stable (Schiff et al. 2006).

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