Mesalamine

 Risk Factor: BM
 Class: GASTROINTESTINAL AGENTS / Anti-inflammatory Bowel Disease Agents

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Mesalamine (5-aminosalicylic acid, 5-ASA) is administered by either rectal suspension or suppository for the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. It also results from metabolism in the large intestine of the oral preparation sulfasalazine, which is split to mesalamine and sulfapyridine (see also Sulfasalazine), and from olsalazine, an oral formulation of a salicylate compound that is metabolized in the colon to two molecules of mesalamine. The history, pharmacology, and pharmacokinetics of mesalamine and olsalazine were extensively reviewed in a 1992 Reference (1).

Reproduction studies in rats and rabbits at oral doses of 480 mg/kg/day observed no fetal toxicity or teratogenicity (2).

Sulfasalazine and one of the metabolites, sulfapyridine, readily cross the placenta and could displace bilirubin from albumin if the concentrations were great enough. Mesalamine, however, is bound to different sites on albumin than bilirubin and, thus, has no bilirubin-displacing ability (3). Moreover, only small amounts of mesalamine are absorbed from the cecum and colon into the systemic circulation, and most of this is rapidly excreted in the urine (4).

A 1987 Reference reported the concentrations of mesalamine and its metabolite, acetyl-5-aminosalicylic acid, in amniotic fluid at 16 weeks' gestation and in maternal and cord plasma at term in women treated prophylactically with sulfasalazine 3 g/day (5). The drug and metabolite levels and the number of patients were as follows: amniotic fluid (N=4), 0.020.08 g/mL and 0.070.77 g/mL, respectively; maternal plasma (N=5), 0.080.29 g/mL and 0.311.27 g/mL, respectively; and cord plasma (N=5), <0.020.10 g/mL and 0.291.80 g/mL, respectively. No effects on the fetus or newborn from the maternal drug therapy were mentioned. At delivery in a woman taking 1 g of mesalamine 3 times daily, the concentrations of the drug and its metabolite, 3.3 hours after the last dose, in the mother's serum were 1.2 and 2.8 g/mL, respectively, and in the umbilical cord serum, 0.4 and 5.7 g/mL, respectively (6). The cord:maternal serum ratios were 0.33 and 2.0, respectively.

A review of drug therapy for ulcerative colitis recommended that women taking mesalamine to maintain remission of the disease should continue the drug when trying to conceive or when pregnant (7). A study published in 1993 described the course of 19 pregnancies in 17 women (ulcerative colitis N=10; Crohn's disease N=7) who received mesalamine (mean dose 1.7 g/day; range 0.82.4 g/day) throughout gestation (8). Full-term deliveries occurred in 18 and one patient, with a history of four previous miscarriages, suffered a spontaneous abortion. No congenital malformations were observed.

Only one report has described possible in utero mesalamine-induced toxicity that may have occurred during 2nd trimester exposure to the drug (9). The 24-year-old mother was treated, between the 13th and 24th week of gestation, for Crohn's disease with 4 g/day of mesalamine for 5 weeks, then tapered to 2 g/day for 6 weeks, then stopped. A fetal ultrasound at 17 weeks' gestation was normal, but a second examination at 21 weeks' showed bilateral renal hyperechogenicity (9). The term male infant had a serum creatinine at birth of 115 mol/L (normal 1835 mol/L). Renal hyperechogenicity was confirmed at various times up to 6 months of age. At this age, the serum creatinine was 62 mol/L with a creatinine clearance of 52 mL/min (normal 8090 mL/min). A renal biopsy at 6 months of age showed focal tubulointerstitial lesions with interstitial fibrosis and tubular atrophy in the absence of cell infiltration (9). Because no other cause of the renal lesions could be found and there was some resemblance to lesions induced by another prostaglandin synthesis inhibitor, indomethacin, the authors attributed the defect to mesalamine (9). A letter published in response to this study, however, questioned the association between the drug and observed renal defect because of the lack of toxicity in an unpublished series of 60 exposed pregnancies and the lack of evidence that mesalamine causes renal prostaglandin synthesis inhibition in utero (10).

A 1997 report described the successful outcomes of 19 pregnancies followed prospectively in 16 women with proven distal colitis (11). The women received either 4-g mesalamine enemas three times weekly or a 500-mg mesalamine suppository every night throughout gestation. No fetal abnormalities were observed during pregnancy and all of the full-term offspring were normal at birth and at a median follow-up of 2 years (range 2 months-5 years) (11).

A 1998 prospective study reported the pregnancy outcomes of 165 women exposed to mesalamine (146 during the 1st trimester) who had contacted a teratogen information service (TIS) (12). The study patients were compared to 165 matched controls who had called the TIS concerning nonteratogenic exposures. There were no significant differences between the two groups in spontaneous abortions (6.7% vs. 8.5%), ectopic pregnancies (0.6% vs. 0%), or elective abortions (none were associated with malformed fetuses) (4.2% vs. 1.8%). There was one major defect (an extra right thumb) in the study group compared to five major anomalies in controls (n.s.). Eight subjects had minor malformations compared to five controls (n.s.). However, compared to controls, more preterm deliveries occurred in subjects (13.0% vs. 4.7%, p=0.02) and the mean birth weight was lower (3253 g vs. 3461 g, p=0.0005). Mean maternal weight gain was also lower (13.1 kg vs. 15.6 kg, p=0.0002) (12).

In contrast to sulfasalazine, mesalamine apparently has no adverse effect on spermatogenesis. Treatment of males with sulfasalazine may adversely affect spermatogenesis (13,14,15,16 and 17), but either stopping therapy or changing to mesalamine allows recovery of sperm production, usually within 3 months (14,15,16 and 17).

In summary, the maternal benefits of therapy with mesalamine appear to outweigh the potential risks to the fetus. No teratogenic effects due to mesalamine have been described and, although toxicity in the fetus has been reported in one case, a causal relationship between the drug and that outcome is controversial.

Breast Feeding Summary

Small amounts of mesalamine are excreted into human milk. A 1990 report described the excretion of mesalamine and its metabolite, acetyl-5-aminosalicylic acid, into breast milk (18). The woman was receiving 500 mg 3 times daily for ulcerative colitis. In a single plasma and milk sample obtained 5.25 hours after a dose, milk and plasma levels of mesalamine were 0.11 and 0.41 g/mL, respectively, a milk:plasma ratio of 0.27. Milk and plasma levels of acetyl-5-aminosalicylic acid were 12.4 and 2.44 g/mL, respectively, a ratio of 5.1. In another study, women treated prophylactically with 3 g/day of sulfasalazine had milk levels of mesalamine and acetyl-5-aminosalicylic acid of 0.02 and 1.133.44 g/mL, respectively (5). No adverse effects on the nursing infants were mentioned.

Low concentrations of mesalamine and its metabolite were also found in a woman taking 1 g 3 times daily (6). Maternal serum levels of the drug and metabolite, determined at 7 and 11 days postpartum, were 0.6 and 1.1 g/mL (day 7) and 1.1 and 1.8 g/mL (day 11), respectively. Milk concentrations of the drug and metabolite at these times were 0.1 and 18.1 g/mL (day 7) and 0.1 and 12.3 g/mL (day 11), respectively, representing milk:plasma ratios for mesalamine of 0.17 and 0.09 (day 7 and 11), respectively, and for the metabolite of 16.5 and 6.8 (day 7 and 11), respectively. The estimated daily intake by the infant of mesalamine and metabolite was 0.065 mg (0.015 mg/kg) and 10 mg (2.3 mg/kg), respectively, considered to be negligible amounts (6).

A study published in 1993 described the excretion of olsalazine, a prodrug that is partially (2.4%) absorbed into the systemic circulation before conversion of the remainder by colonic bacteria into two molecules of mesalamine (see also Olsalazine), in the breast milk of a woman 4 months postpartum (19). Following a 500-mg oral dose, olsalazine, olsalazine sulfate, and mesalamine were undetectable in breast milk up to 48 hours (detection limits 0.5 mol/L, 0.2 mol/L, and 1.0 mol/L, respectively). Acetyl-5-aminosalicylic concentrations at 10, 14, and 24 hours, were 0.8, 0.86, and 1.24 mol/L, respectively, but undetectable (detection limit 1.0 mol/L) during the first 6 hours and after 24 hours. The quantities detected were considered clinically insignificant (19).

Diarrhea in a nursing infant, apparently as a result of the rectal administration of mesalamine to the mother, has been reported (20). The mother had relapsing ulcerative proctitis. Six weeks after childbirth, treatment was begun with 500-mg mesalamine suppositories twice daily. Her exclusively breast-fed infant developed watery diarrhea 12 hours after the mother's first dose. After 2 days of therapy, the mother stopped the suppositories and the infant's diarrhea stopped 10 hours later. Therapy was reinstituted on four occasions with diarrhea developing each time in the infant 812 hours after the mother's first dose and stopping 812 hours after therapy was halted. Because of the severity of the mother's disease, breast feeding was discontinued and no further episodes of diarrhea were observed in the infant (20).

Because of the adverse effect described above, a possible allergic reaction, nursing infants of women being treated with mesalamine or olsalazine should be closely observed for changes in stool consistency. The American Academy of Pediatrics classifies mesalamine (i.e., 5-aminosalicylic acid) as a drug that has produced adverse effects in a nursing infant and should be used with caution during breast feeding (21).

References

1. Segars LW, Gales BJ. Mesalamine and olsalazine: 5-aminosalicylic acid agents for the treatment of inflammatory bowel disease. Clin Pharm 1992;11:51428.
2. Product information. Asacol. Procter & Gamble Pharmaceuticals, 2000.
3. Jarnerot G, Andersen S, Esbjorner E, Sandstrom B, Brodersen R. Albumin reserve for binding of bilirubin in maternal and cord serum under treatment with sulphasalazine. Scand J Gastroenterol 1981;16:104955.
4. Berlin CM Jr, Yaffe SJ. Disposition of salicylazosulfapyridine (Azulfidine) and metabolites in human breast milk. Dev Pharmacol Ther 1980;1:319.
5. Christensen LA, Rasmussen SN, Hansen SH, Bondesen S, Hvidberg EF. Salazosulfapyridine and metabolites in fetal and maternal body fluids with special Reference to 5-aminosalicylic acid. Acta Obstet Gynecol Scand 1987;66:433435.
6. Klotz U, Harings-Kaim A. Negligible excretion of 5-aminosalicylic acid in breast milk. Lancet 1993;342:6189.
7. Kamm MA, Senapati A. Drug management of ulcerative colitis. Br Med J 1992;305:358.
8. Habal FM, Hui G, Greenberg GR. Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course. Gastroenterology 1993;105:105760.
9. Colombel J-F, Brabant G, Gubler M-C, Locquet A, Comes M-C, Dehennault M, Delcroix M. Renal insufficiency in infant: side-effect of prenatal exposure to mesalazine? Lancet 1994;344:6201.
10. Marteau P, Devaux CB. Mesalazine during pregnancy. Lancet 1994;344:17089.
11. Bell CM, Habal FM. Safety of topical 5-aminosalicylic acid in pregnancy. Am J Gastroenterol 1997;92:22012.
12. Diav-Citrin O, Park Y-H, Veerasuntharam G, Polachek H, Bologa M, Pastuszak A, Koren G. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998;114:238.
13. Freeman JG, Reece VAC, Venables CW. Sulphasalazine and spermatogenesis. Digestion 1982;23:6871.
14. Toovey S, Hudson E, Hendry WF, Levi AJ. Sulphasalazine and male infertility: reversibility and possible mechanism. Gut 1981;22:44551.
15. O'Morain C, Smethurst P, Dore CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984;25:107884.
16. Chatzinoff M, Guarino JM, Corson SL, Batzer FR, Friedman LS. Sulfasalazine-induced abnormal sperm penetration assay reversed on changing to 5-aminosalicylic acid enemas. Dig Dis Sci 1988;33:10810.
17. Delaere KP, Strijbos WE, Meuleman EJ. Sulphasalazine-induced reversible male infertility. Acta Urol Belg 1989;57:2933.
18. Jenss H, Weber P, Hartmann F. 5-Aminosalicylic acid and its metabolite in breast milk during lactation. Am J Gastroenterol 1990;85:331.
19. Miller LG, Hopkinson JM, Motil KJ, Corboy JE, Andersson S. Disposition of olsalazine and metabolites in breast milk. J Clin Pharmacol 1993;33:7036.
20. Nelis GF. Diarrhoea due to 5-aminosalicylic acid in breast milk. Lancet 1989;1:383.
21. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.
    
    

Questions and Answers

the drug mesalamine can be taken for life long or not if taken what is the risk?,

check out this site...way to much infor for me...

http://www.medicinenet.com/mesalamine/ar...

What is the difference between Pentasa and Lialda? They are both medications for Crohn's disease.?, I am a little confused because they both have the generic name of mesalamine. Is the only difference the strength and amount of times you need to take it?

hi, i am a female crohn's pt. for 28 yrs. dxed at the age of 12. Here is the most accurate information for you:

Lialda, for active, mild to moderate ulcerative colitis, is the only FDA-approved once-daily oral prescription drug of its kind.www.lialda.com - 1.2 g

Pentasa (mesalamine) is used to treat ulcerative colitis, proctitis, and proctosigmoiditis. usually comes in 500 mg capsules yes, the dosage is different in both

The newer treatments to treat Crohn's are Entocort, Remicade, Humira, 6MP, and Imuran. Pentasa is a thing of the past for crohn's pts. b/c many GIs have realized that it doesn't really get their pts. into remission. The same goes for Asacol. Pts. are taking more than 10 pills a day and aren't happy so their GIs are switching to other treatments with 3 pills or less.

If you go to the Crohn's & Colitis Foundation of America's site, they have more information on the newer meds, women's issues, diet, surgery, as well as locating a local support chapter, a hotline & live chat run by healthcare experts well versed in CD, plus there is an open forum where pts. and their family and friends can post questions to others in the same situation.

I've been around many yrs. and have seen some great changes when it comes to treating CD. The newer meds are definitely the way to go. Ask your GI if you are a candidate for them.

my heart goes out to you. i wish you a life long remission.

For treatment of severe Crohn's Disease, what are the benefits/side-effects of cortisone vs mesalamine enemas?, At various times, my daughter has been on either cortisone or mesalamine daily enemas, to treat her severe Crohn's Disease. Right now, it is the cortisone variety. What experiences have any of you Crohn's patients had with benefits and/or side-effects of either of these treatments? Can cortisone enemas cause side-effects similar to those of oral prednisone (weight-gain, "moon face"...)? Thank you!

Hi Elisabeth, if your daughter is in a big flare, why isn't the GI trying Remicade, Humira, or Entocort to get things under control? Is she on any pain meds to be made comfortable? Make sure she is on something as she has that right to be.

When I was younger, I found that the enemas really didn't help so I was on oral steroids until they stopped working at 80 mg and needed surgery to improve my quality of life.

Check out the Crohn's & Colitis Foundation for more information. They have live chats, a hotline, an open forum, plus they have meetings for kids under age 18 as well as their parents.

I know it's hard to watch your child suffer, educate yourself, ask the GI questions or even attend a CCFA meeting to talk to those who are in the same boat as yourself. Best of luck to you.

In regards to your question 4 days ago:

If I were you:I'd attend one of the CCFA support meetings & ask the members about their experience w/these meds, and then I'd ask the GI or pharmacist. But that's just me.

Can anyone tell me how Dr. Thomas Hale rates the safety of taking Pentasa while breastfeeding?, I do not have a copy of his book "Medications and Mothers Milk". If more info is needed: Pentasa is also known as Mesalamine and is a 5-aminosalicylate drug.

I don't have a copy of his book, either, but I did a little research online. Guess what? He has a forum! I put a few links at the bottom to some information about Pentasa (usually referred to as mesalamine) and its safety when breastfeeding. From what I've read, it appears to be relatively safe (only about 1% of the medication is transferred through the breastmilk). If you still aren't comfortable, check with your local chapter of La Leche League. They usually have a copy of his book!

Crohn's Disease sufferers: How do you control the diarrhea?, I'm taking Prednisone and Mesalamine, but every 20-30 min. I'm up and running to the bathroom...all day, all night, 24/7! I'm getting no sleep and no rest.

hi archang, I have had Crohn's disease since the age of 12. I can totally relate to what you are going through. how long have you been on these meds? If you've been on them for a while, it's time to call your GI and think of another game plan so you can be pain free & get some rest.

Are you a candidate for Entocort, Remicade, Humira, 6MP, or Imuran? Most GIs now are staying away from prednisone due to the lifelong side effects such as brittle bones, glaucoma, &osteoporosis.

If you go to the Crohn's & Colitis Foundation of America site you can find alot of information plus you can chat online with a healthcare professional who is extremely knowledgable about CD. There is also a help line you can call: 1-888-MY.GUT.PAIN( 1-888-694-8872) M-F 9 am - 5pm.

Yes, this disease is a pain in the butt, (no pun intended). Definitely check out the CCFA site for the latest treatments, diet, support chapters in your town, etc. to educate yourself then share that information with your GI if he is not up to date on the newer methods.

I wish you a speedy remission from one crohnie to another.