Adalimumab

Name: Adalimumab

What is adalimumab, and how does it work (mechanism of action)?

Adalimumab is an injectable protein(antibody) that blocks the inflammatory effects of tumor necrosis factor alpha (TNF alpha) in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn 's disease of the intestine. Inflammation is the body's reaction to injury and is a necessary process for the repair of injury. TNF is a protein that the body produces when there is inflammation. TNF promotes inflammation and the signs of inflammation, which, in the case of arthritis, include fever as well as pain, tenderness, and swelling of joints. In the case of Crohn's disease, the signs of inflammation include fever, abdominal pain, and diarrhea. The unchecked inflammation of rheumatoid arthritis eventually leads to destruction of the joints. The inflammation in Crohn's disease can lead to strictures (narrowing) of the intestine or intestinal perforation. Adalimumab is a synthetic (man-made) antibody that binds to TNF in the body and thereby blocks the effects of TNF. As a result, inflammation and its consequences in the joints and intestine are reduced. In arthritis, the progressive destruction of the joints is slowed or prevented. Adalimumab is a disease modifying anti-rheumatic drugs (DMARD) because it slows or prevents destruction of joints. Adalimumab was approved by the FDA in December 2002.

What is adalimumab?

Adalimumab reduces the effects of a substance in the body that can cause inflammation.

Adalimumab is used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and a chronic skin condition called hidradenitis suppurativa. It is also used to treat Crohn's disease or ulcerative colitis, after other drugs have been tried without successful treatment of symptoms.

Adalimumab may also be used for purposes not listed in this medication guide.

What is the most important information I should know about adalimumab?

Some people using adalimumab have developed a rare fast-growing type of lymphoma (cancer), which can be fatal. Adalimumab can also lower blood cells that help your body fight infections and help your blood to clot. Serious and sometimes fatal infections may occur.

Call your doctor at once if you have symptoms such as fever, night sweats, weight loss, feeling full after eating only a small amount, pain in your upper stomach, easy bruising or bleeding, dark urine, or jaundice (yellowing of the skin or eyes).

What should I discuss with my healthcare provider before using adalimumab?

You should not use this medicine if you are allergic to adalimumab, or if you have an active infection.

Some people using adalimumab have developed a rare fast-growing type of lymphoma (cancer). This condition affects the liver, spleen, and bone marrow, and it can be fatal. This has occurred mainly in teenagers and young adults using adalimumab or similar medicines to treat Crohn's disease or ulcerative colitis. However, people with autoimmune disorders may have a higher risk of lymphoma.

To make sure adalimumab is safe for you, tell your doctor if you have ever had:

  • chronic infections;

  • cancer;

  • hepatitis B;

  • congestive heart failure;

  • any numbness or tingling, or a nerve-muscle disorder such as multiple sclerosis or Guillain-Barre syndrome;

  • an allergy to latex rubber; or

  • if you have recently received or are scheduled to receive any vaccine.

Make sure you are current on all vaccines before you start treatment with adalimumab.

Tell your doctor if you have ever had tuberculosis, if anyone in your household has tuberculosis, or if you have recently traveled to an area where tuberculosis is common.

Some infections are more likely to occur in certain areas of the world. Tell your doctor where you live and where you have recently traveled or plan to travel to during treatment.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

If you have a baby after receiving adalimumab during pregnancy, tell the baby's doctor before your baby is given any vaccines.

It is not known whether adalimumab passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Adalimumab should not be given to a child younger than 2 years old (or 6 years old if treating Crohn's disease). Children using adalimumab should be current on all childhood immunizations before starting treatment.

Using adalimumab may increase your risk of certain types of cancer, such as lymphoma (cancer of the lymph nodes), or melanoma (a tumor that usually affects the skin). You may also develop an autoimmune disorder such as a lupus-like syndrome. Talk with your doctor about your specific risk.

What should I avoid while using adalimumab?

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using adalimumab. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Adalimumab dosing information

Usual Adult Dose for Ankylosing Spondylitis:

40 mg subcutaneously every other week

Comments:
-In the treatment of rheumatoid arthritis, some patients not taking concomitant methotrexate may derive additional benefit from increasing the dosing frequency to 40 mg every week.
-Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics, or other disease modifying agents may be given concomitantly.

Uses:
-To reduce signs and symptoms in adult patients with active ankylosing spondylitis (AS)
-Alone or in combination with non-biologic DMARDs to inhibit the progression of structural damage and improve physical function in adult patients with active psoriatic arthritis
-Alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs) to reduce signs and symptoms, inducing major clinical response, inhibit the progression of structural damage, and improve physical function in adult patients with moderately to severely active rheumatoid arthritis (RA)

Usual Adult Dose for Rheumatoid Arthritis:

40 mg subcutaneously every other week

Comments:
-In the treatment of rheumatoid arthritis, some patients not taking concomitant methotrexate may derive additional benefit from increasing the dosing frequency to 40 mg every week.
-Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics, or other disease modifying agents may be given concomitantly.

Uses:
-To reduce signs and symptoms in adult patients with active ankylosing spondylitis (AS)
-Alone or in combination with non-biologic DMARDs to inhibit the progression of structural damage and improve physical function in adult patients with active psoriatic arthritis
-Alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs) to reduce signs and symptoms, inducing major clinical response, inhibit the progression of structural damage, and improve physical function in adult patients with moderately to severely active rheumatoid arthritis (RA)

Usual Adult Dose for Psoriatic Arthritis:

40 mg subcutaneously every other week

Comments:
-In the treatment of rheumatoid arthritis, some patients not taking concomitant methotrexate may derive additional benefit from increasing the dosing frequency to 40 mg every week.
-Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics, or other disease modifying agents may be given concomitantly.

Uses:
-To reduce signs and symptoms in adult patients with active ankylosing spondylitis (AS)
-Alone or in combination with non-biologic DMARDs to inhibit the progression of structural damage and improve physical function in adult patients with active psoriatic arthritis
-Alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs) to reduce signs and symptoms, inducing major clinical response, inhibit the progression of structural damage, and improve physical function in adult patients with moderately to severely active rheumatoid arthritis (RA)

Usual Adult Dose for Crohn's Disease -- Acute:

-Initial dose: 160 mg subcutaneously on Day 1 (given in one day or split over 2 consecutive days), followed by 80 mg subcutaneously 2 weeks later (Day 15)
-Maintenance dose (beginning 2 weeks later [Day 29]): 40 mg subcutaneously every other week

Comments:
-Aminosalicylates and/or corticosteroids may be continued during treatment.
-Azathioprine, 6-mercaptopurine (6-MP), or methotrexate (MTX) may be continued during treatment if necessary.
-Treatment beyond one year in Crohn's Disease has not been established.
-Treatment in ulcerative colitis should only be continued in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.

Uses:
-To reduce signs and induce and maintain remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy; to reduce signs and induce remission in these patients if they have also lost response to or are intolerant to infliximab
-To induce and maintain remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine (6-MP) (the effectiveness of this drug in patients who have lost response to or were intolerant to TNF blockers has not been established)

Usual Adult Dose for Crohn's Disease -- Maintenance:

-Initial dose: 160 mg subcutaneously on Day 1 (given in one day or split over 2 consecutive days), followed by 80 mg subcutaneously 2 weeks later (Day 15)
-Maintenance dose (beginning 2 weeks later [Day 29]): 40 mg subcutaneously every other week

Comments:
-Aminosalicylates and/or corticosteroids may be continued during treatment.
-Azathioprine, 6-mercaptopurine (6-MP), or methotrexate (MTX) may be continued during treatment if necessary.
-Treatment beyond one year in Crohn's Disease has not been established.
-Treatment in ulcerative colitis should only be continued in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.

Uses:
-To reduce signs and induce and maintain remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy; to reduce signs and induce remission in these patients if they have also lost response to or are intolerant to infliximab
-To induce and maintain remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine (6-MP) (the effectiveness of this drug in patients who have lost response to or were intolerant to TNF blockers has not been established)

Usual Adult Dose for Ulcerative Colitis:

-Initial dose: 160 mg subcutaneously on Day 1 (given in one day or split over 2 consecutive days), followed by 80 mg subcutaneously 2 weeks later (Day 15)
-Maintenance dose (beginning 2 weeks later [Day 29]): 40 mg subcutaneously every other week

Comments:
-Aminosalicylates and/or corticosteroids may be continued during treatment.
-Azathioprine, 6-mercaptopurine (6-MP), or methotrexate (MTX) may be continued during treatment if necessary.
-Treatment beyond one year in Crohn's Disease has not been established.
-Treatment in ulcerative colitis should only be continued in patients who have shown evidence of clinical remission by eight weeks (Day 57) of therapy.

Uses:
-To reduce signs and induce and maintain remission in adult patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy; to reduce signs and induce remission in these patients if they have also lost response to or are intolerant to infliximab
-To induce and maintain remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine (6-MP) (the effectiveness of this drug in patients who have lost response to or were intolerant to TNF blockers has not been established)

Usual Adult Dose for Uveitis:

-Initial dose: 80 mg subcutaneously
-Maintenance dose: 40 mg subcutaneously every other week, starting one week after the initial dose

Comments:
-Treatment beyond one year for moderate to severe chronic plaque psoriasis has not been studied.

Uses:
-For the treatment of adult patients with moderate to severe chronic plaque psoriasis (Ps) who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate
-For the treatment of noninfectious intermediate, posterior, and panuveitis in adult patients

Usual Adult Dose for Plaque Psoriasis:

-Initial dose: 80 mg subcutaneously
-Maintenance dose: 40 mg subcutaneously every other week, starting one week after the initial dose

Comments:
-Treatment beyond one year for moderate to severe chronic plaque psoriasis has not been studied.

Uses:
-For the treatment of adult patients with moderate to severe chronic plaque psoriasis (Ps) who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate
-For the treatment of noninfectious intermediate, posterior, and panuveitis in adult patients

Usual Adult Dose for Hidradenitis Suppurativa:

-Initial dose: 160 mg subcutaneously (given in one day or split over 2 consecutive days), followed by 80 mg subcutaneously 2 weeks later (Day 15)
-Maintenance dose: 40 mg subcutaneously each week beginning on Day 29

Comments:
-Antibiotics may be continued during treatment if necessary.
-The patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment.

Use: For the treatment of active moderate to severe hidradenitis suppurativa (HS) (acne inversa) in adult patients with an inadequate response to conventional systemic HS therapy

Usual Pediatric Dose for Juvenile Idiopathic Arthritis:

2 years and older:
-For 10 kg (22 pounds) to less than 15 kg (33 pounds):10 mg subcutaneously every other week
-For 15 kg (33 pounds) to less than 30 kg (66 pounds): 20 mg subcutaneously every other week
-For 30 kg (66 pounds) or greater: 40 mg subcutaneously every other week

Comments:
-Safety and efficacy has not been established in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.
-Methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics may be continued during treatment.

Uses: To reduce symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in pediatric patients 2 years of age and older, used alone or in combination with methotrexate

Usual Pediatric Dose for Crohn's Disease -- Acute:

6 years and older:
-For 17 kg (37 pounds) to less than 40 kg (88 pounds):
Initial dose: 80 mg subcutaneously (Day 1), then 40 mg subcutaneously 2 weeks later (Day 15)
Maintenance dose: 20 mg subcutaneously every other week
-For 40 kg (88 pounds) or greater:
Initial dose: 160 mg subcutaneously (Day 1) given in one day or split over 2 consecutive days, then 80 mg subcutaneously 2 weeks later (Day 15)
Maintenance dose: 40 mg subcutaneously every other week

Uses: To reduce symptoms and induce and maintain clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn's disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate

Usual Pediatric Dose for Crohn's Disease -- Maintenance:

6 years and older:
-For 17 kg (37 pounds) to less than 40 kg (88 pounds):
Initial dose: 80 mg subcutaneously (Day 1), then 40 mg subcutaneously 2 weeks later (Day 15)
Maintenance dose: 20 mg subcutaneously every other week
-For 40 kg (88 pounds) or greater:
Initial dose: 160 mg subcutaneously (Day 1) given in one day or split over 2 consecutive days, then 80 mg subcutaneously 2 weeks later (Day 15)
Maintenance dose: 40 mg subcutaneously every other week

Uses: To reduce symptoms and induce and maintain clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn's disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate

Pharmacology

Adalimumab is a recombinant monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-alpha), thereby interfering with binding to TNFα receptor sites and subsequent cytokine-driven inflammatory processes. Elevated TNF levels in the synovial fluid are involved in the pathologic pain and joint destruction in immune-mediated arthritis. Adalimumab decreases signs and symptoms of psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. It inhibits progression of structural damage of rheumatoid and psoriatic arthritis. Reduces signs and symptoms and maintains clinical remission in Crohn disease and ulcerative colitis; reduces epidermal thickness and inflammatory cell infiltration in plaque psoriasis.

Distribution

Vd: 4.7 to 6 L; Synovial fluid concentrations: 31% to 96% of serum

Time to Peak

Serum: SubQ: 131 ± 56 hours

Half-Life Elimination

Terminal: ~2 weeks (range: 10 to 20 days)

Use Labeled Indications

Ankylosing spondylitis: Treatment (to reduce signs/symptoms) of active ankylosing spondylitis in adults

Crohn disease: Treatment (to reduce signs/symptoms and to induce and maintain clinical remission) of active Crohn disease (moderate to severe) in adults and pediatric patients ≥6 years (Humira only) with an inadequate response to conventional therapy or who have lost response to or are intolerant to infliximab.

Hidradenitis suppurativa (Humira only): Treatment of moderate to severe hidradenitis suppurativa

Juvenile idiopathic arthritis: Treatment (to reduce signs/symptoms) of active polyarticular juvenile idiopathic arthritis (moderate to severe) in pediatric patients ≥2 years (Humira) or ≥4 years (Amjevita); may be used alone or in combination with methotrexate

Plaque psoriasis: Treatment of chronic plaque psoriasis (moderate to severe) in adults who are candidates for systemic therapy or phototherapy, and when other systemic therapies are less appropriate (with close monitoring and regular follow-up)

Psoriatic arthritis: Treatment (to reduce signs/symptoms, inhibit progression of structural damage, and improve physical function) of active psoriatic arthritis in adults; may be used alone or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs)

Rheumatoid arthritis: Treatment (to reduce signs/symptoms, induce major clinical response, inhibit progression of structural damage, and improve physical function) of active rheumatoid arthritis (moderate to severe) in adults; may be used alone or in combination with methotrexate or other nonbiologic DMARDs

Ulcerative colitis: Treatment (to induce and sustain clinical remission) of active ulcerative colitis (moderate to severe) in adults who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine. (Note: Efficacy in patients that are intolerant to or no longer responsive to other TNF blockers has not been established.)

Uveitis (Humira only): Treatment of non-infectious intermediate, posterior, and panuveitis in adults

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Known hypersensitivity to adalimumab or any component of the formulation; severe infection (eg, sepsis, tuberculosis, opportunistic infection); moderate-to-severe heart failure (NYHA class III/IV)

Dosing Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Renal Dose Adjustments

Data not available

Adalimumab Levels and Effects while Breastfeeding

Summary of Use during Lactation

Limited information indicates that maternal adalimumab injections produce low levels in milk and do not adversely affect the nursing infant. Because adalimumab is a large protein molecule with a molecular weight of about 148,000, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Most experts feel that the drug is probably safe during nursing.[1][2][3][4][5][6][7] However, until more data become available, adalimumab should be used with caution while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. One woman received a single 40 mg of adalimumab subcutaneously at 4 weeks postpartum. Milk samples were obtained every 2 days for 8 days. A peak milk adalimumab level of 31 mcg/L was detected on day 6 after injection. Milk levels on days 5 and 8 were about 10 mcg/L.[8]

Two women received adalimumab 40 mg subcutaneously for treatment of inflammatory bowel disease at unstated intervals. The first woman received the drug during pregnancy and postpartum. At 21 weeks postpartum and 7 days after the previous dose, her breastmilk adalimumab was 4.83 mcg/L while her serum level was 6.7 mg/L. In the second woman, the milk adalimumab concentration at 8 weeks postpartum and 9 days after the last dose was 4.88 mcg/L with a simultaneous serum concentration of 5.5 mg/L.[9]

Six women who received adalimumab (dose unspecified) as part of a large registry study submitted breastmilk samples. Adalimumab was not detected in any samples between 12 and 24 hours after infusion.[10]

Infant Levels. A woman received adalimumab 40 mg subcutaneously at unstated intervals while breastfeeding (extent not stated). At 8 weeks postpartum and 9 days after the prior dose, the infant had an undetectable (<0.65 mcg/L) adalimumab serum concentration.[9]

A pregnant woman received adalimumab 40 mg every 2 weeks for Crohn's disease until week 16 of pregnancy. Her infant was exclusively breastfed until 4 months of age and the drug was reinstituted on day 24 postpartum. At 3 months of age, adalimumab was undetectable in the infant's serum.[11]

Effects in Breastfed Infants

One woman with Crohn's disease received adalimumab 40 mg subcutaneously every week during pregnancy and breastfeeding (extent not stated). Her infant demonstrated normal growth and development at 6 months of age.[12] The authors reported a brief follow-up stating that the woman also breastfed her second infant during adalimumab therapy with no adverse consequences.[13]

Another woman with Crohn's disease received adalimumab 40 mg subcutaneously every 2 weeks during pregnancy and breastfeeding (extent not stated). Her infant demonstrated normal growth and development at 6 months of age.[14]

Two women nursed their infants (extent not stated) while receiving adalimumab 40 mg subcutaneously at unstated intervals for inflammatory bowel disease. They breastfed for at least 21 weeks and 8 weeks, respectively, but the total duration was not stated. At 14.5 and 15 months of age, respectively, neither infant had any signs of adverse drug reactions, allergic reactions or severe infections leading to hospitalization. Developmental milestones were reached on time by both infants.[9]

A pregnant woman received adalimumab 40 mg every 2 weeks for Crohn's disease until week 16 of pregnancy. Her infant was exclusively breastfed until 4 months of age and the drug was reinstituted on day 24 postpartum. At 7 months of age, the infant was healthy with normal growth and development. The infant had no infections requiring antibiotics or hospitalization.[11]

A prospective cohort study followed pregnant women with inflammatory bowel disease throughout pregnancy and for 12 months postpartum. Women were assigned to one of the following groups: unexposed (no thiopurines or anti-TNF agents); group A (azathioprine or mercaptopurine); group B (infliximab, adalimumab or certolizumab) and group AB (both a thiopurine and an anti-TNF agent). Of 1052 women enrolled in the study, 72% breastfed their infants, although the extent and duration were not stated in the abstract. A total of 102 women were exposed to an anti-TNF agent and 59 were exposed to a thiopurine plus an anti-TNF agent. The use of an anti-TNF alone was not associated with any complication in the infants and their growth and development were normal throughout the 12 months. Infants exposed to both a thiopurine and an anti-TNF agent had a 50% increase in the number of infections between 9 and 12 months of age. The relationship of this increase with breastfeeding could not be determined from the available data.[15]

A case-control study compared infant outcomes between infants exposed to adalimumab or etanercept during pregnancy (n = 25) to those not exposed (n = 25). Three infants were exposed to one of the drugs during pregnancy and breastfeeding and 2 were exposed during breastfeeding only. No relevant infectious diseases nor post-vaccine complications were noted in the 5 infants exposed during lactation.[16]

A case-control study of women with chronic arthritic conditions found 2 women who received adalimumab during pregnancy and lactation (extent not stated). No differences were observed in the 2 infants' growth parameters, developmental milestones, vaccinations and diseases in the first year of life compared to those not exposed to the drugs with lactation.[17]

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

(Inflammatory Bowel Disease) Certolizumab, Infliximab, (Rheumatoid Arthritis) Certolizumab, Etanercept, Infliximab

References

1. Gisbert JP, Chaparro M. Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory bowel disease. Am J Gastroenterol. 2013;108:1426-38. PMID: 23752881

2. Nielsen OH, Maxwell C, Hendel J. IBD medications during pregnancy and lactation. Nat Rev Gastroenterol Hepatol. 2014;11:116-27. PMID: 23897285

3. Nguyen GC, Seow CH, Maxwell C et al. The Toronto Consensus Statements for the Management of IBD in Pregnancy. Gastroenterology. 2016;150:734-57. PMID: 26688268

4. van der Woude CJ, Ardizzone S, Bengtson MB et al. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. J Crohns Colitis. 2015;9:107-24. PMID: 25602023

5. Flint J, Panchal S, Hurrell A et al. BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016;55:1693-7. PMID: 26750124

6. Gotestam Skorpen C, Hoeltzenbein M, Tincani A et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795-810. PMID: 26888948

7. Mahadevan U, McConnell RA, Chambers C. Drug safety and risk of adverse outcomes for pregnant patients with inflammatory bowel diseases. Gastroenterology. 2017;152:451-62.e2. PMID: 27769809

8. Ben-Horin S, Yavzori M, Katz L et al. Adalimumab level in breast milk of a nursing mother. Clin Gastroenterol Hepatol. 2010;8:475-6. PMID: 20005982

9. Fritzsche J, Pilch A, Mury D et al. Infliximab and adalimumab use during breastfeeding. J Clin Gastroenterol. 2012;46:718-9. PMID: 22858514

10. Matro R, Martin CF, Wolf DC et al. Detection of biologic agents in breast milk and implication for infection, growth and development in infants born to women with inflammatory bowel disease: Results from the PIANO registry. Gastroenterology. 2015;148:S141. Abstract.

11. Julsgaard M , Brown S, Gibson P, Bell S. Adalimumab levels in an infant. J Crohns Colitis. 2013;7:597-8. PMID: 23102835

12. Vesga L, Terdiman JP, Mahadevan U. Adalimumab use in pregnancy. Gut. 2005;54:890. PMID: 15888806

13. Mahadevan U. Pregnancy, fertility and therapies for IBD. Gastroenterol Hepatol. 2006;2:234-6.

14. Mishkin DS, Van Deinse W, Becker JM, Farraye FA. Successful use of adalimumab (Humira) for Crohn's disease in pregnancy. Inflamm Bowel Dis. 2006;12:827-8. PMID: 16917239

15. Mahadevan U, Martin CF, Sandler RS et al. PIANO: A 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy. Gastroenterology. 2012;142 (Suppl 1):S149. Abstract 865. DOI: doi:10.1016/S0016-5085(12)60561-7

16. Reggia R, Andreoli L, Bazzani C et al. Longterm follow-up of children born to mothers with chronic arthritides and exposed to anti-TNF alfa agents during pregancy and breastfeeding: A case-control study. Arthritis Rheumatol. 2015;67 (Suppl. 10):Abstract 2524. http://acrabstracts.org/abstract/longterm-follow-up-of-children-born-to-mothers-with-chronic-arthritides-and-exposed-to-anti-tnf-alfa-agents-during-pregancy-and-breastfeeding-a-case-control-study/

17. Dall'ara F, Reggia R, Bazzani C et al. Safety of anti-TNF alfa agents during pregancy and breastfeeding: longterm follow up of exposed children in a case-series of mothers with chronic arthritides. Ann Rheum Dis. 2016;75 (Suppl 2):493. Abstract. DOI: doi:10.1136/annrheumdis-2016-eular.4123

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