Summary Of Exposure |
A) USES: Adalimumab is indicated for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa.
B) PHARMACOLOGY: Adalimumab is a recombinant human IgG1 monoclonal antibody that binds to tumor necrosis factor (TNF) alpha and blocks its interaction with endogenous cell surface TNF receptors.
C) EPIDEMIOLOGY: Overdose is very rare.
D) WITH THERAPEUTIC USE
1) ADVERSE EFFECTS: COMMON (greater than 10%) - Infections (eg; upper respiratory, sinusitis), injection site reaction, headache, and rash. LESS COMMON (5% to 10%): Nausea, abdominal pain, hematuria, hypercholesterolemia, increased alkaline phosphatase, and back pain. Although the causal relationship to adalimumab is not clear, the following adverse reactions were also reported during studies: New onset or worsening congestive heart failure, leucocytoclastic vasculitis, hypertension, angioneurotic edema, cellulitis, psoriasis, erysipelas, cutaneous vasculitis, Stevens-Johnson syndrome, erythema multiforme, optic neuritis, pancytopenia, aplastic anemia, thrombocytopenia, leukopenia, polycythemia, anaphylaxis, paresthesia, tremor, hepatic necrosis, elevated liver enzymes, and interstitial lung disease, including pulmonary fibrosis.
E) WITH POISONING/EXPOSURE
1) TOXICITY: There are no reports of toxicity following acute overdose. Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses.
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) OPTIC NEURITIS - Two cases of optic neuritis associated with adalimumab have been reported (Chung et al, 2006). a) The first was a case report of a 55-year-old man with no previous history of ocular disease who presented with a decrease in central vision in his right eye after adalimumab 40 mg injections every other week for a total of eight injections over four months to treat a severe psoriatic rash on his trunk, legs and elbows as well as tenderness and swelling in wrists and fingers. The patient previously tried oral methotrexate 15 mg weekly which was reduced to 10 mg weekly when adalimumab was initiated. Ocular coherence tomography revealed abnormally thickened circumpapillary nerve fiber layer and an MRI of the brain and orbits revealed enhancement in the intracanalicular portion of the right optic nerve. The patient was diagnosed with drug associated retrobulbar optic neuritis and adalimumab was discontinued. The patient's visual acuity improved within a week with 250 mg methylprednisolone intravenously four times daily for 3 days followed by an oral prednisone taper. The patient suffered no further neurologic events one year later (Chung et al, 2006).
b) A 40-year-old man with rheumatoid arthritis presented with gradual right eye visual loss with pain on movement. The patient had been taking adalimumab 40 mg subcutaneously every other week for the past year. The patient had no previous ocular or neurologic disease history. A diagnosis of demyelinating optic neuritis was made after an MRI revealed mild enhancement of the intra-orbital right optic nerve and several predominantly periventricular hyperintense lesions and two non-enhancing demyelinating plaques. The patient's vision gradually recovered spontaneously 4 months after visual loss onset. Visual tests showed a mild central scotoma in the right eye with a mild temporal atrophy of the affected optic disc. Adalimumab was not discontinued due to good control of his rheumatoid arthritis (Chung et al, 2006).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) CONGESTIVE HEART FAILURE 1) WITH THERAPEUTIC USE a) New onset or worsening congestive heart failure (CHF) has been reported in patients treated with tumor necrosis factor (TNF) blockers. Although adalimumab has not been studied in patients with CHF, cases of worsening CHF have been observed with adalimumab treatment (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) HYPERTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), hypertension was reported in 5% of the adalimumab group compared with 3% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) ANGIOEDEMA 1) WITH THERAPEUTIC USE a) During postmarketing surveillance, angioneurotic edema was reported with adalimumab use; however, the causal relationship to adalimumab is not clear (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) UPPER RESPIRATORY INFECTION 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), upper respiratory infection was reported in 17% of the adalimumab group compared with 13% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) SINUSITIS 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), sinusitis was reported in 11% of the adalimumab group compared with 9% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) INTERSTITIAL LUNG DISEASE 1) WITH THERAPEUTIC USE a) Interstitial lung disease, including pulmonary fibrosis, has been reported with adalimumab use during postmarketing surveillance; however, causality to adalimumab has not been established (Prod Info HUMIRA(R) subcutaneous injection, 2009).
D) TUBERCULOSIS 1) WITH THERAPEUTIC USE a) Tuberculosis, frequently disseminated or extrapulmonary at clinical presentation, has been reported in some patients. The incidence of tuberculosis was 0.07 to 0.26 per 100 patient-years from collective study data in global trials (n=13,000), and US and Canadian trials (n=4500). This included reports of miliary, lymphatic, peritoneal, and pulmonary tuberculosis, with some fatalities. Most cases occurred within the first 8 months following initiation of therapy, and may reflect recrudescence of latent disease. There was some evidence of a greater occurrence of tuberculosis reactivation at higher than recommended doses. Antituberculosis treatment of patients with latent tuberculosis infection may reduce the risk of reactivation in patients treated with adalimumab. However, there have been cases in which patients developed active tuberculosis while being treated with adalimumab following a screening for latent tuberculosis that was negative (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), headache was reported in 12% of the adalimumab group compared with 8% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) DEMYELINATING DISEASE OF CENTRAL NERVOUS SYSTEM 1) WITH THERAPEUTIC USE a) Rare cases of new-onset or exacerbation of clinical and/or radiologic evidence of demyelinating disease have been reported in association with tumor necrosis factor (TNF) blockers, including adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) PARESTHESIA 1) WITH THERAPEUTIC USE a) In clinical trials, paresthesia occurred in less than 5% of patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) subcutaneous injection, 2009).
D) TREMOR 1) WITH THERAPEUTIC USE a) In clinical trials, tremor occurred in less than 5% patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), nausea was reported in 9% of the adalimumab group compared with 8% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) ABDOMINAL PAIN 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), abdominal pain was reported in 7% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) TYPE B VIRAL HEPATITIS 1) WITH THERAPEUTIC USE a) Hepatitis B virus (HBV) reactivation has been reported with tumor necrosis factor (TNF) blocker therapy, including adalimumab, in patients who are chronic carriers of the virus. Some cases have been fatal. The majority of these cases occurred in patients who were concomitantly treated with other drugs that suppress the immune system (Prod Info HUMIRA(R) solution for subcutaneous injection, 2007).
B) HEPATIC NECROSIS 1) WITH THERAPEUTIC USE a) In clinical trials, hepatic necrosis occurred in less than 5% of patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) TOXIC LIVER DISEASE 1) WITH THERAPEUTIC USE a) CASE REPORT - A 46-year-old man with psoriatic arthritis developed elevated liver enzymes (AST 66 mUnits/mL; ALT 252 mUnits/mL) after receiving adalimumab (40 mg SubQ every other week) for 3 months. The liver enzymes gradually normalized following the discontinuation of adalimumab. He was subsequently treated successfully with etanercept (Massarotti & Marasini, 2009).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) BLOOD IN URINE 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), hematuria was reported in 5% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) URINARY TRACT INFECTIOUS DISEASE 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), urinary tract infection was reported in 8% of the adalimumab group compared with 5% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) PANCYTOPENIA 1) WITH THERAPEUTIC USE a) Pancytopenia including aplastic anemia has been reported rarely in association with the use of TNFalpha-blocking agents. Adverse hematologic events, including clinically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been reported infrequently following the administration of adalimumab. The causal relationship of these events to adalimumab is not clear (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) Thrombocytopenia has been reported infrequently with the use of tumor necrosis factor (TNF) blockers. Thrombocytopenia has also been reported with adalimumab use during postmarketing surveillance. Causality to adalimumab has not been established (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) APLASTIC ANEMIA 1) WITH THERAPEUTIC USE a) Rare cases of pancytopenia, including aplastic anemia have been reported with the use of tumor necrosis factor (TNF) blockers. Causality to adalimumab has not been established (Prod Info HUMIRA(R) subcutaneous injection, 2009).
D) LEUKOPENIA 1) WITH THERAPEUTIC USE a) Leukopenia has been reported infrequently with the use of tumor necrosis factor (TNF) blockers. Causality to adalimumab has not been established (Prod Info HUMIRA(R) subcutaneous injection, 2009).
E) ERYTHROCYTOSIS 1) WITH THERAPEUTIC USE a) In clinical trials, polycythemia occurred in less than 5% of patients treated with adalimumab for rheumatoid arthritis (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) PSORIASIS 1) WITH THERAPEUTIC USE a) A review of 69 cases of new onset psoriasis included 17 cases of pustular and 15 cases of palmoplantar psoriasis in patients using tumor necrosis factor (TNF) blockers, including adalimumab, to treat autoimmune and rheumatic conditions other than psoriasis or psoriatic arthritis. Two cases occurred in pediatric patients. The onset of psoriasis occurred from weeks to years after initiating treatment with TNF blockers. Twelve cases required hospitalization. None of the cases had a history of psoriasis prior to beginning TNF blocker therapy (US Food and Drug Administration, 2009).
B) CELLULITIS 1) WITH THERAPEUTIC USE a) In clinical trials, cellulitis was reported in less than 5% of patients with rheumatoid arthritis who received adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) VASCULITIS 1) WITH THERAPEUTIC USE a) During postmarketing surveillance, cutaneous vasculitis was reported with adalimumab use; however, the causal relationship to adalimumab is not clear (Prod Info HUMIRA(R) subcutaneous injection, 2009).
b) CASE REPORT - A 44-year-old woman with a 16-year medical history of rheumatoid arthritis developed leucocytoclastic vasculitis within 24 hours of her second dose of subcutaneous adalimumab 40 mg. She presented with a pruritic eruption on the dorsal aspect of both feet and around both medial malleoli. The rash subsided after 5 days. There was no evidence of an infectious cause for the eruption. The only other abnormality was an increased C-reactive protein. The patient's underlying rheumatoid arthritis could have been a trigger for the eruption or it may have been the adalimumab. The only medication the patient was currently taking was oral prednisone 5 mg daily. The patient was not rechallenged with adalimumab (Orpin et al, 2006).
D) ERYSIPELAS 1) WITH THERAPEUTIC USE a) In clinical trials, erysipelas was reported in less than 5% of patients with rheumatoid arthritis who received adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2009).
E) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) Serious skin reactions, including Stevens-Johnson syndrome (SJS), have been reported rarely with the use of tumor necrosis factor-alpha antagonists, including adalimumab. In general, presenting symptoms of the serious skin reactions were mainly rash and skin lesions on the trunk, legs, arms, shoulder, back, hands, and face. Additionally, oral mucositis or ulceration, genital ulceration, and/or fever were present in some SJS cases (United States Food and Drug Administration, 2008).
b) The United States Food and Drug Administration has received postmarketing reports of 7 cases of serious skin reactions following adalimumab administration, including 4 cases of erythema multiforme (EM), 2 cases of Stevens-Johnson syndrome (SJS), and 1 case of both EM and SJS. The majority of patients affected were female (85%) and were being treated for rheumatoid arthritis (71%). Two patients were also receiving methotrexate therapy. The median time to skin reaction onset was 60 days, with 3 cases reported within the first 2 months of adalimumab therapy. There were no fatalities, although hospitalization was required in one case. The skin reactions resolved with drug discontinuation in 4 patients and no attempts at rechallenge were reported. (United States Food and Drug Administration, 2008).
F) ERYTHEMA MULTIFORME 1) WITH THERAPEUTIC USE a) During postmarketing surveillance, erythema multiforme was reported with adalimumab use (Prod Info HUMIRA(R) solution for subcutaneous injection, 2008; United States Food and Drug Administration, 2008). In general, presenting symptoms of the serious skin reactions were mainly rash and skin lesions on the trunk, legs, arms, shoulder, back, hands, and face (United States Food and Drug Administration, 2008).
b) The United States Food and Drug Administration (FDA) has received postmarketing reports of 7 cases of severe skin reactions following adalimumab administration, including 4 cases of erythema multiforme (EM), 2 cases of Stevens-Johnson syndrome (SJS), and 1 case of both EM and SJS. The majority of patients affected were female (85%) and were being treated for rheumatoid arthritis (71%). Two patients were also receiving methotrexate therapy. The median time to skin reaction onset was 60 days, with 3 cases reported within the first 2 months of therapy. There were no fatalities, although hospitalization was required in one case. The skin reactions resolved with drug discontinuation in 4 patients and no attempts at rechallenge were reported (United States Food and Drug Administration, 2008).
c) CASE REPORT - Erythema multiforme (EM) was diagnosed in a 49-year-old man with rheumatoid arthritis one month after beginning adalimumab therapy. The patient was also taking methadone, prednisone, multivitamins, and iron, although the start/stop times in relation to the adalimumab were not reported. After receiving the second adalimumab injection, red skin lesions on the arms and body developed and were identified as EM following a skin biopsy. The patient recovered upon discontinuation of adalimumab (United States Food and Drug Administration, 2008).
G) INJECTION SITE REACTION 1) WITH THERAPEUTIC USE a) In clinical trials, the most common adverse event associated with adalimumab was mild injection site reaction. In placebo-controlled trials, injection-site reaction, which included erythema and/or itching, hemorrhage, pain or swelling, was reported in 20% of the adalimumab-treated patients compared with 14% of the placebo-treated patients (Prod Info HUMIRA(R) subcutaneous injection, 2009).
b) In a large, placebo-controlled clinical study in patients with rheumatoid arthritis, injection-site reaction (not including erythema and/or itching, hemorrhage, pain or swelling) was reported in 8% of patients in the adalimumab group (n=705) compared to 1% of patients in the placebo group (n=690) (Prod Info HUMIRA(R) subcutaneous injection, 2009).
c) In clinical trials in pediatric patients (aged 4 to 17 years) with polyarticular juvenile idiopathic arthritis (n=171), injection-site reaction was reported in 16% of patients treated with adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2009).
d) Injection-site reactions were reported in 15% of patients receiving repeat doses of subcutaneous adalimumab in one trial compared with 3% of placebo recipients (Keystone et al, 2001).
H) INJECTION SITE PAIN 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in patients with rheumatoid arthritis, injection-site pain was reported in 12% of patients in the adalimumab group (n=705) and 12% of patients in the placebo group (n=690) (Prod Info HUMIRA(R) subcutaneous injection, 2009).
b) In clinical trials in pediatric patients (aged 4 to 17 years) with polyarticular juvenile idiopathic arthritis (n=171), injection-site pain was reported in 19% of patients treated with adalimumab (Prod Info HUMIRA(R) subcutaneous injection, 2009).
I) ERUPTION 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in patients with rheumatoid arthritis, rash was reported in 12% of patients in the adalimumab group (n=705) compared to 6% of patients in the placebo group (n=690) (Prod Info HUMIRA(R) subcutaneous injection, 2009).
J) URTICARIA 1) WITH THERAPEUTIC USE a) CASE REPORT - A 41-year-old woman with a 15-year history of plaque-type psoriasis was started on adalimumab 40 mg subcutaneously twice a week for two weeks, weekly for the next 10 weeks, and then every other week. The patient reported a wheel-like flare with each injection followed by a pruritic, urticarial eruption (primarily on neck and arms) 10 hours post-injection. The reactions became less severe with each injection and required no treatment. After her tenth injection, the only skin reaction was at the injection site and the psoriasis responded dramatically to therapy (George et al, 2006).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) BACKACHE 1) WITH THERAPEUTIC USE a) In a placebo-controlled clinical study in which patients with rheumatoid arthritis were treated with adalimumab 40 milligrams subcutaneously every other week (n=705) or placebo (n=690), back pain was reported in 6% of the adalimumab group compared with 4% of the placebo group (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) ANAPHYLAXIS 1) WITH THERAPEUTIC USE a) During postmarketing surveillance, anaphylaxis was reported with adalimumab use (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) HYPERSENSITIVITY REACTION 1) WITH THERAPEUTIC USE a) In clinical trials, allergic reactions (eg, allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) LUPUS ERYTHEMATOSUS 1) WITH THERAPEUTIC USE a) In rheumatoid arthritis controlled trials including 3046 patients treated with adalimumab, 2 patients developed clinical symptoms suggestive of a new onset lupus-like syndrome after 24 weeks of therapy with adalimumab. The patients improved clinically after the drug was discontinued, and no signs of lupus nephritis or central nervous system symptoms were reported (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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Reproductive |
3.20.1) SUMMARY
A) Adalimumab is classified as FDA pregnancy category B. There are no adequate and well-controlled studies with adalimumab in pregnant women. In a clinical study in 10 pregnant women who received adalimumab for inflammatory bowel disease and their 8 newborn infants, adalimumab serum concentrations measured on the day of birth suggest the drug actively crosses the placenta. During an observational study of 212 pregnancy outcomes in women with inflammatory bowel disease, exposure to infliximab or adalimumab did not lead to an increased risk of fetal anomalies compared with untreated women; however, premature deliveries were observed more frequently in women with direct exposure to infliximab or adalimumab (27 out of 161 live births) compared with the control group (3 out of 48 live births). In an observational study of the general in vitro fertilization (IVF) population, the rate of congenital anomalies did not exceed the expected rate in either adalimumab-treated (31 cycles of IVF) or control groups (63 cycles of IVF) with up to 8 doses of adalimumab 40 mg and IV immunoglobulin administered before in vitro transfer.
3.20.2) TERATOGENICITY
A) LACK OF EFFECT 1) The rate of congenital anomalies did not differ from the expected rate among the general in vitro fertilization (IVF) population in either adalimumab-treated or control groups in an observational study of 31 women treated during 31 IVF cycles with up to 8 doses of adalimumab 40 mg and intravenous immunoglobulin (IVIG) before in vitro transfer. Controls received 69 cycles of IVF without exposure to adalimumab or IVIG. Adalimumab treatments concluded an average of 65.3 days before in vitro transfer. In the adalimumab-treated group, one fetus with DiGeorge syndrome (chromosome 22 deletion) was electively terminated (n=41; congenital anomaly rate 2.44%), while the control group experienced 2 neonatal deaths from a severe heart defect and Edwards syndrome (Trisomy 18), respectively (n=95; congenital anomaly rate 2.11%) (Winger et al, 2011).
2) During an observational study of 212 pregnancy outcomes in women with inflammatory bowel disease (IBD) aged 18 to 40 years, exposure to infliximab (IFX) or adalimumab (ADA) did not lead to an increased risk of fetal anomalies compared with untreated women; however, premature deliveries were observed more frequently in women with direct exposure to IFX or ADA (27 out of 161 live births) compared with the control group (3 out of 48 live births). There were a total of 42 pregnancies with direct exposure to IFX (n=35) or ADA (n=7), 23 pregnancies prior to IBD diagnosis, 78 pregnancies after diagnosis of IBD and before IFX implementation, 53 pregnancies with indirect IFX exposure, and 56 pregnancies in healthy women. Thirty-two of the 42 direct IFX exposure pregnancies resulted in live births, although one child died after 13 days due to necrotizing enterocolitis. Seven premature deliveries, 6 children with low birth weight, and one stillbirth were observed. Of the 42 pregnancies, one was terminated due to trisomy 18. There were a total of 44 live births from 53 pregnancies with indirect exposure to IFX and one elective abortion due to trisomy 21. Additionally, there were a total of 65 live births from 78 pregnancies after diagnosis of IBD but prior to IFX implementation and a total of one elective abortion due to karyotype45/XO. There were a total of 48 live births from 56 pregnancies in the control group and no reports of neonatal malformations resulting in an elective abortion (Schnitzler et al, 2011).
3) CASE REPORT: A 37-year-old pregnant woman who received a single dose of adalimumab during the first 5 weeks of gestation had an uneventful pregnancy and gave birth to a healthy baby who was developing normally 25 months later. The patient was treated with adalimumab 40 mg twice per month for rheumatoid arthritis. Five weeks after initiating adalimumab, the patient became pregnant. She had received a single injection of adalimumab during the 5 weeks and decided to continue with the pregnancy. Fetal growth progressed normally and no fetal anomalies were detected (Roux et al, 2007).
B) ANIMAL STUDIES 1) In animal studies of cynomolgus monkeys, no fetal adverse effects occurred with doses up to 100 mg/kg (systemic exposures of 266 times the human AUC when given 40 mg/week subQ with methotrexate or 373 times the human AUC at 40 mg/week subQ without methotrexate) (Prod Info HUMIRA(R) subcutaneous injection, 2014).
3.20.3) EFFECTS IN PREGNANCY
A) LACK OF INFORMATION 1) There are no adequate and well-controlled studies with adalimumab in pregnant women (Prod Info HUMIRA(R) subcutaneous injection, 2014).
B) PREGNANCY CATEGORY 1) Adalimumab is classified as FDA pregnancy category B (Prod Info HUMIRA(R) subcutaneous injection, 2014).
C) PLACENTAL TRANSFER 1) In a clinical study in 10 pregnant women who received adalimumab for inflammatory bowel disease and their 8 newborn infants, adalimumab serum concentrations suggested that the drug actively crosses the placenta. The last dose of adalimumab was administered between 1 and 56 days before delivery. Adalimumab concentrations measured on the day of birth were 0.16 to 19.7 mcg/mL in cord blood, 4.28 to 17.7 mcg/mL in infant blood, and 0 to 16.1 mcg/mL in maternal blood. The adalimumab levels in cord blood were higher than the maternal levels in all but 1 case. Furthermore, adalimumab was detected in 1 infantfor 3 months postpartum: 6 weeks (1.94 mcg/mL), 7 weeks (1.31 mcg/mL), 8 weeks (0.93 mcg/mL), and 11 weeks (0.53 mcg/mL) (Prod Info HUMIRA(R) subcutaneous injection, 2014).
D) PREMATURE DELIVERY 1) During an observational study of 212 pregnancy outcomes in women with inflammatory bowel disease (IBD) aged 18 to 40 years, exposure to infliximab (IFX) or adalimumab (ADA) did not lead to an increased risk of fetal anomalies compared with untreated women; however, premature deliveries were observed more frequently in women with direct exposure to IFX or ADA (27 out of 161 live births) compared with the control group (3 out of 48 live births). Thirty-two of the 42 direct IFX exposure pregnancies resulted in live births, although one child died after 13 days due to necrotizing enterocolitis. Seven premature deliveries, 6 children with low birth weight, and one stillbirth were observed (Schnitzler et al, 2011).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) While limited data from published literature show that adalimumab is present in breast milk at levels unlikely to be absorbed by a breastfed infant, no data are available on its absorption. Therefore, exercise caution when administering adalimumab to a nursing woman. (Prod Info HUMIRA(R) subcutaneous injection, 2014).
B) LACK OF EFFECT 1) CASE REPORT: Adalimumab levels in breast milk were 1/100th of corresponding serum blood levels in a 26-year-old woman receiving treatment for Crohn disease. While the drug had been discontinued by the thirtieth week of gestation, the patient sought to continue breastfeeding when adalimumab 40 mg subQ was resumed for a flare-up 4 weeks postpartum. Breast milk samples were obtained at baseline and every 2 days after adalimumab administration. Serum adalimumab levels peaked by day 3 at 4300 nanogram/mL and then continued to decline. Breast milk drug levels were undetectable initially, but were at 31 nanograms/mL by day 6 post-injection (Ben-Horin et al, 2010).
3.20.5) FERTILITY
A) LACK OF INFORMATION 1) Long-term studies have not been done on adalimumab to evaluate its effect on fertility (Prod Info HUMIRA(R) subcutaneous injection, 2014).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) More cases of malignancies have occurred in patients receiving adalimumab than in controls; however, the number and type are similar to what would be expected in the general population. An increased risk of lymphoma and other malignancies was reported in children and adolescents receiving tumor necrosis factor (TNF) blockers. Results from meta analyses and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of lymphoma or non-cutaneous cancers plus melanoma associated with recommended doses of adalimumab, etanercept, or infliximab.
3.21.3) HUMAN STUDIES
A) CARCINOMA 1) Merkel cell carcinoma has been reported during postmarketing surveillance of adalimumab (Prod Info HUMIRA(R) subcutaneous injection solution, 2012).
2) More cases of malignancies have occurred in patients receiving adalimumab than in controls; however, the number and type are similar to what would be expected in the general population. In controlled portions of adalimumab trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, malignancies other than lymphoma and non-melanoma skin cancer including, breast, colon, prostate, lung, and melanoma, were observed at a rate of 0.6 per 100 patient-years (95% confidence interval (CI), 0.3 to 1) among 3853 adalimumab-treated patients (median treatment duration of 5.5 months) compared with a rate of 0.4 per 100 patient-years (95% CI, 0.2 to 1) for 2183 control-treated patients (median treatment duration of 3.9 months) (Prod Info HUMIRA(R) subcutaneous injection, 2009).
B) HEMATOLOGIC CANCER 1) An increased risk of lymphoma and other malignancies was reported in children and adolescents receiving tumor necrosis factor (TNF) blockers. An 8-year review identified 48 US and non-US cases of malignancies in children and adolescents receiving TNF blockers with approximately half of the cases reported as lymphomas, including hepatosplenic T-cell (10 cases), Hodgkin's (6 cases), and non-Hodgkin's (7 cases) lymphoma. Leukemia (6 cases), malignant melanoma (3 cases), and solid organ cancers were also reported. Most of the cases (88%) were also receiving concurrent immunosuppressive therapy with agents such as azathioprine and methotrexate. Rare malignancies included leiomyosarcoma (1 case), hepatic malignancy (1 case), and renal cell carcinoma (1 case). Of the cases reported, 31 cases were associated with infliximab (5 cases with rheumatic conditions), 15 cases were associated with etanercept (14 cases with rheumatic conditions), and 2 cases were associated with adalimumab (1 case with rheumatic conditions). Overall, 11 cases of malignancy were fatal, and causes of death included hepatosplenic T-cell lymphoma (9 cases), T-cell lymphoma (1 case), and sepsis following remission of the lymphoma (1 case). No specific dose was identified as being associated with the development of the malignancies (US Food and Drug Administration, 2009; US Food and Drug Administration, 2009). 2) LEUKEMIA a) A review of 147 postmarketing reports of leukemia in all patients using tumor necrosis factor (TNF) blockers included 44 cases of acute myeloid leukemia, 31 cases of chronic lymphocytic leukemia and 23 cases of chronic myeloid leukemia. Four cases of leukemia were reported in pediatric patients. Concomitant immunosuppressive therapies were used in 61% of the cases. In 26 of the 30 deaths reported, the cause was attributed to leukemia and was associated with the use of TNF blockers. Leukemia occurred within the first 1 to 2 years of therapy (US Food and Drug Administration, 2009).
3) LYMPHOMA a) Results from meta analyses and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of lymphoma associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for lymphoma using the unadjusted meta-analytic method was 1.26 (95% confidence interval, 0.52 to 3.06). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).
b) Lymphoma has occurred more frequently in patients treated with adalimumab than in patients treated with placebo, and at an approximately 3-fold higher rate than expected in the general population. In controlled trials of patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, 2 lymphomas occurred in the adalimumab group (n=3853) compared with 1 lymphoma in the control group (n=2183). In combined controlled and uncontrolled open-label portions of the clinical trials with a median duration of about 2 years, including 6539 patients and more than 16,000 patient-years of adalimumab therapy, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. Patients with rheumatoid arthritis, especially those with highly active disease, are at an increased risk for developing lymphoma (Prod Info HUMIRA(R) subcutaneous injection, 2009).
C) NON-CUTANEOUS CANCERS PLUS MELANOMA 1) Results from meta analyses and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of non-cutaneous cancers plus melanoma associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for non-cutaneous cancers plus melanoma using the unadjusted meta-analytic method was 1.31 (95% confidence interval, 0.69 to 2.48). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).
D) NON-MELANOMA SKIN CANCER 1) More cases of malignancies have occurred in patients receiving adalimumab than in controls; however the number and type are similar to what would be expected in the general population. In controlled trials of patients treated with adalimumab for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and plaque psoriasis, non-melanoma skin cancers occurred at a rate of 0.9 per 100 patient-years (95% confidence interval (CI), 0.57 to 1.35 ) among 3853 adalimumab-treated patients compared to a rate of 0.3 per 100 patient-years (95% CI, 0.08 to 0.8) among 2183 control patients (Prod Info HUMIRA(R) subcutaneous injection, 2009).
2) Results from meta analyses and exposure adjusted pooled analyses involving 8808 patients with rheumatoid arthritis found no increase in the odds of non-melanoma skin cancers associated with recommended doses of adalimumab, etanercept, or infliximab. Results of 18 randomized controlled trials with over 7846 years of follow-up were included in the analyses. The odds ratio for non-melanoma skin cancer using the unadjusted meta-analytic method was 1.27 (95% confidence interval, 0.67 to 2.42). In the studies that reported incidence of malignancies, 34 of 4099 patients who were randomized to recommended doses over 3805 patient-years developed malignancies (0.8%). Of these malignancies, 12 occurred after crossover while 10 were unable to be allocated to the controlled or uncontrolled portion of the trial. Of the 2672 control patients, 15 (0.6%) developed a malignancy over 2124 patient-years. Overall, there was no increased risk for lymphomas, non-melanoma skin cancers, or the composite endpoint of non-cutaneous cancer and melanoma at recommended doses (Leombruno et al, 2008).
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Genotoxicity |
A) There was no evidence of clastogenicity or mutagenicity in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively (Prod Info HUMIRA(R) subcutaneous injection, 2009).
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