SULINDAC

Drugs in Pregnancy and Lactation.

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Name: SULINDAC
Class: Nonsteroidal Anti-inflammatory
Risk Factor:    B*

Fetal Risk Summary

Sulindac is a nonsteroidal anti-inflammatory prodrug (NSAID) that is converted in vivo to the biologically active sulfide metabolite. It is used for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, and acute painful shoulder. Sulindac is in the same NSAID subclass (acetic acids) as diclofenac, indomethacin, and tolmetin.

When administered to pregnant rats, similar to other nonsteroidal antiinflammatory agents, sulindac reduces fetal weight and pup survival (at doses 2.5 times or higher than the usual maximum human daily dose), prolongs the duration of gestation, and may cause dystocia (1,2).

Consistent with the molecular weight (about 356), sulindac and its active metabolite cross the human placenta to the fetus. Nine women at a mean gestational age of 31.8 weeks (24.3–36.4 weeks) were given a single 200-mg oral dose of the drug a mean 5.5 hours (4.4–6.7 hours) before cordocentesis (3,4). Maternal serum was obtained a mean 5.8 hours (3.5–7.3 hours) after the dose. The mean concentrations of sulindac in the mothers and fetuses were 0.59 and 0.98 ΅g/mL, respectively, and of the sulfide metabolite 1.42 and 0.68 ΅g/mL, respectively. The corresponding sulfide:sulindac ratios in the mother and fetal compartments were 2.32 and 0.53, respectively. The reduced amounts of metabolite in the fetus, compared with those in the mother, were thought to be caused by decreased placental transfer of the metabolite and slower metabolism of sulindac in the fetus (4). Because of these findings, the investigators theorized that, as a tocolytic, sulindac would be expected to cause less fetal toxicity than indomethacin.

Using a human term placental perfusion model, a 1999 study demonstrated that the sulfide metabolite reaches the fetus in higher concentrations than does sulindac or indomethacin (5). The fetal:maternal ratios after 2-hour perfusions were 0.34 (sulindac), 0.54 (sulfide metabolite), and 0.45 (indomethacin). Neither sulindac nor indomethacin were metabolized by the placenta.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 69 newborns had been exposed to sulindac during the 1st trimester (F. Rosa, personal communication, FDA, 1995). Three (4.3%) major birth defects were observed (three expected), including one cardiovascular defect (one expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb-reduction defects, and hypospadias) for which specific data were available. For exposure during any trimester (102 newborns), two malformations of the eyeball (excludes oculomotor and ptosis) were observed (none expected), but no brain defects were recorded.

A combined 2001 population-based observational cohort study and a case-control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (6). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with spontaneous abortions (SABs) (see Ibuprofen for details).

An abstract and a full report, both published in 1992, described the use of sulindac in the treatment of preterm labor in comparison with indomethacin (7,8). The gestational ages at treatment for the groups were 29 and 30 weeks, respectively. The sulindac group (N=18) received 200 mg orally every 12 hours for 48 hours, whereas those receiving indomethacin (N=18) were given 100 mg orally once followed by 25 mg orally every 4 hours for 48 hours. Both groups received IV magnesium sulfate and some in both groups received subcutaneous terbutaline. The response to tocolysis was statistically similar for sulindac and indomethacin. However, the sulindac-treated women had significantly greater hourly fetal urine output, the deepest amniotic fluid pocket, and the largest amniotic fluid index. Patent ductus arteriosus was observed in 11% vs. 22%, respectively, and intraventricular hemorrhage in the newborn occurred in 11% of both groups. These differences were not significant. No cases of primary pulmonary hypertension in the newborns were observed (7,8).

A comparison between sulindac (200 mg orally every 12 hours times 4 days) and indomethacin (100 mg rectally on the 1st day, then 50 mg orally every 8 hours times 3 days) on fetal cardiac function was published in 1995 (9). Each group was composed of 10 patients with threatened premature labor between 28 and 32 weeks' gestation. Significant reductions in the mean pulsatility index of the fetal ductus arteriosus began 4 hours after the first indomethacin dose. The reduction increased with time and resolved 24 hours after the last dose. Other secondary changes in fetal cardiac function resulting from ductal constriction were also noted. In the sulindac group, a significant decrease in the mean pulsatility index, without secondary changes, was observed only at 24 hours (9).

A study comparing the fetal cardiovascular effects of sulindac (200 mg orally every 12 hours) and terbutaline (5 mg orally every 4 hours) for 68 hours at an approximate mean gestational age of 32 weeks was published in abstract form in 1996 (10) and in a full report in 1999 (11). Significant ductal constriction was noted only in the sulindac group. In contrast to the study cited above, therapy was stopped because of severe constriction in 2 (one at 12 hours and the other at 24 hours) of the 10 patients. The constriction of the fetal ductus arteriosus occurred within 5 hours of receiving sulindac and resolved within 48 hours of discontinuing the drug (10,11).

A 1994 abstract reported that the tocolytic effect of a 7-day course of sulindac, 200 mg orally every 12 hours, following arrest of labor with IV magnesium sulfate was no different than placebo and observation (12). The difference in prolongation of pregnancy between the sulindac (N=13) and placebo (N=15) groups, 33±25 days vs. 26±17 days, respectively, was not significant. No differences between the groups on days 0,7, and 14 were found for hourly fetal urine production, amniotic fluid index, or ductus arteriosus velocity (12).

Two 1995 References from the same group of investigators, using a similar study design, concluded that sulindac did not reduce the rate of premature birth but did lengthen the interval to retocolysis in those patients who required retocolysis (13,14). No difference was found between sulindac and placebo in prolongation of pregnancy, delivery at >35 weeks' gestation, recurrent preterm labor, birth weight, or time spent in the neonatal intensive care unit. No adverse effects were observed in the exposed fetuses (13,14).

As demonstrated with other NSAIDs (see also Indomethacin), sulindac reduces amniotic fluid volume by decreasing fetal urine output in a dose-related manner (15). Sulindac, 200 mg twice daily, was given to the mothers of three sets of monoamniotic twins, diagnosed as having cord entanglement, beginning at 24, 27, and 29 weeks, respectively, and continued until elective cesarean section at 32 weeks' gestation. One of the twins had a preexisting heart defect (transposition of the great vessels and a ventricular septal defect). The dose was reduced in one patient to 200 mg/day to maintain an adequate amniotic fluid index. No significant changes in the umbilical artery or the ductus arteriosus Doppler waveforms were observed. All of the newborns had appropriate weights for gestation, had normal renal function during the first week of life, and none required ventilation (15).

A 2000 abstract described a retrospective case-cohort study that compared the neonatal effects of sulindac with indomethacin (16). The infants (born between 1994 and 1999) had been exposed to antenatal sulindac (N=25) or indomethacin (N=66) and weighed <1500 g. Those exposed to both drugs or with congenital abnormalities were excluded. There were no significant differences between the indomethacin and sulindac groups in intraventricular hemorrhage (IVH) (32% vs. 36%), grade III-IV IVH (14% vs. 12%), necrotizing enterocolitis (8% vs. 8%), serum creatinine >1.4 mg/dL (19% vs. 15%), patent ductus arteriosus (17% vs. 28%), and mortality (12% vs. 12%), respectively. However, there was a significant increase in the risk for bronchopulmonary dysplasia after exposure to indomethacin (adjusted odds ratio 4.9, 95% confidence interval 1.01–23.44) (16).

Theoretically, sulindac, a prostaglandin synthesis inhibitor, could cause constriction of the ductus arteriosus in utero, as well as inhibition of labor, prolongation of pregnancy, and suppression of fetal renal function (17,18). Persistent pulmonary hypertension of the newborn should also be considered. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including sulindac, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (19,20). Moreover, as noted above, NSAIDs have been associated with SABs.

[*Risk Factor D if used in the 3rd trimester or near delivery].

Breast Feeding Summary

No reports describing the use of sulindac during breast feeding or analyzing the amount of drug in milk have been located. The mean adult serum half-life of the biologically active sulfide metabolite is 16.4 hours (1). One reviewer concluded that because of the prolonged half-life, other agents in this class (diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, and tolmetin) were safer alternatives if a nonsteroidal antiinflammatory agent was required during nursing (21).

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References

  1. Product information. Clinoril. Merck, 2001.
  2. Lione A, Scialli AR. The developmental toxicity of indomethacin and sulindac. Reprod Toxicol 1995;9:7–20.
  3. Kramer W, Saade G, Belfort M, Ou C-N, Rognerud C, Knudsen L, Moise K Jr. Placental transfer of sulindac and its active metabolite in humans (abstract). Am J Obstet Gynecol 1994;170:389.
  4. Kramer WB, Saade G, Ou C-N, Rognerud C, Dorman K, Mayes M, Moise KJ Jr. Placental transfer of sulindac and its active sulfide metabolite in humans. Am J Obstet Gynecol 1995;172:886–90.
  5. Lampela ES, Nuutinen LH, Ala-Kkokko TL, Parikka RM, Laitinen RS, Jouppila PI, Vahakangas KH. Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model. Am J Obstet Gynecol 1999;180:174–80.
  6. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. Br Med J 2001;322:266–70.
  7. Carlan SJ, O'Brien WF, O'Leary TD, Mastrogiannis DS. A randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor (abstract). Am J Obstet Gynecol 1992;166:361.
  8. Carlan SJ, O'Brien WF, O'Leary TD, Mastrogiannis D. Randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor. Obstet Gynecol 1992;79:223–8.
  9. Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. Am J Obstet Gynecol 1995;173:20–5.
  10. Kramer W, Saade G, Belfort M, Dorman K, Mayes M, Moise K Jr. Randomized double-blind study comparing sulindac to terbutaline: fetal cardiovascular effects (abstract). Am J Obstet Gynecol 1996;174:326.
  11. Kramer WB, Saade GR, Belfort M, Dorman K, Mayes M, Moise KJ Jr. A randomized double-blind study comparing the fetal effects of sulindac to terbutaline during the management of preterm labor. Am J Obstet Gynecol 1999;180:396–401.
  12. Carlan S, Jones M, Schorr S, McNeill T, Rawji H, Clark K. Oral sulindac to prevent recurrence of preterm labor (abstract). Am J Obstet Gynecol 1994;170:381.
  13. Jones M, Carlan S, Schorr S, McNeill T, Rawji R, Clark K, Fuentes A. Oral sulindac to prevent recurrence of preterm labor (abstract). Am J Obstet Gynecol 1995;172:416.
  14. Carlan SJ, O'Brien WF, Jones MH, O'Leary TD, Roth L. Outpatient oral sulindac to prevent recurrence of preterm labor. Obstet Gynecol 1995;85:769–74.
  15. Peek MJ, McCarthy A, Kyle P, Sepulveda W, Fisk NM. Medical amnioreduction with sulindac to reduce cord complications in monoamniotic twins. Am J Obstet Gynecol 1997;176:334–6.
  16. Sciscione A, Leef K, Vakili B, Paul D. Neonatal effects after antenatal treatment with indomethacin vs. sulindac (abstract). Am J Obstet Gynecol 2000;182:S66.
  17. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.
  18. Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
  19. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In Witorsch RJ, editor. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93.
  20. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.
  21. Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.

Index

Q&A about Sulindac

Jess
Can you take Diclofenac or Sulindac with Lisinopril?
My fiancee has kidney failure and is on dialysis. He's on several blood pressure medications, including Lisinopril. He has inflammation that he's been taking Advil for, but is concerned about the potassium. However, he feels he needs to take something stronger.

Can he take Sulindac (Clinoril) or Diclofenac (Voltaren) with Lisinopril?

Will this have the same potassium problem?

And if you can't take them together, why not?
k
Clinoril - NSAID

Renal Insufficiency

Sulindac pharmacokinetics have been investigated in patients with renal insufficiency. The disposition of sulindac was studied in end-stage renal disease patients requiring hemodialysis. Plasma concentrations of sulindac and it sulfone metabolite were comparable to those of normal healthy volunteers whereas concentrations of the active sulfide metabolite were significantly reduced. Plasma protein binding was reduced and the AUC of the unbound sulfide metabolite was about half that in healthy subjects.

Sulindac and its metabolites are not significantly removed from the blood in patients undergoing hemodialysis.

Since Clinoril is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored.

A lower daily dosage should be anticipated to avoid excessive drug accumulation.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of Clinoril in patients with advanced renal disease. Therefore, treatment with Clinoril is not recommended in these patients with advanced renal disease. If Clinoril therapy must be initiated, close monitoring of the patient's renal function is advisable.

Voltaren - NSAID

Caution should be used when initiating treatment with Voltaren in patients with considerable dehydration.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Any patient that is currently on dialysis should discuss any medications that are considering to incorporate in their daily regime with their doctor.
Jenna_Fr...
Sulindac Given To Treat Migraine Headaches?
I was recently diagnosed with Muscle Tension related Migraine headaches. My P.A. prescribed me Cyclobenzaprine and Sulindac. He explained to me that the Cyclobenzaprine was a muscle relaxer to be taken at night and that Sulindac, an NSAID, should be taken morning and night. Since taking the medication, I have been headache free!

However, I have noticed that each time I take a Sulindac, my hands get a little itchy. It took me a few doses to realize that the itchy hands were occuring after taking the medicine and not from jewelry irritation, etc.

I have a follow-up with my P.A. this week to discuss the treatment. I will definitely bring up the itchiness...

So I guess that my question is... the Sulindac pills are a bright yellow color. Or perhaps goldenrod would be a better color to describe it. What are they dyed with? I have a sensitivity to sulfur... could that be the culprit?

P.S. I love being headache free, but taking medication daily is a bummer.
sweetien...
Here is some information about Sulindac and its side effects that may be helpful:

"Sulindac, like other NSAIDs, can cause serious skin side effects...Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible."

Since you are experiencing itchiness in your hands, I would definitely bring it up to your P.A. and see what they recommend. I did not find any information that listed sulfur in the ingredients.

Best wishes and take care!
Robin T
What medicine with help Osteorarthritis in both of my knees??
Anyone know what medicine with help with pain in both knees from Osteorarthritis? First I was on Sulindac 200mg 2x's a day. Then the Dr. told me to take 3 ibruprofen with each meal. But that didn't work either. Now I am on naproxen 500 mg one every 12 hours. But that only seems to help for about 2 hours at the most, then I'm in pain again. I need something that will actually work, can anyone help? Thanks!
Neil L
I would like to suggest that you go to a Rheumatologist. They specialize in arthritis and it's treatment. Hope that you're pain free soon.