Sulfasalazine

Sulfasalazine is used to treat bowel inflammation, diarrhea (stool frequency), rectal bleeding, and abdominal pain in patients with ulcerative colitis, a condition in which the bowel is inflamed. Sulfasalazine delayed-release (Azulfidine EN-tabs) is also used to treat rheumatoid arthritis in adults and children whose disease has not responded well to other medications. Sulfasalazine is in a class of medications called anti-inflammatory drugs. It works by reducing inflammation (swelling) inside the body.

Sulfasalazine comes as a regular or delayed-release tablet.

The regular tablets are usually taken four times a day. The doses should be evenly-spaced throughout the day, so they're no more than eight hours apart.

The delayed-release tablets may be taken less often throughout the day. Your doctor will tell you how often to take them.

Take this medicine after a meal or with a snack. Then drink a full glass of water (8 ounces).

Swallow the tablets whole. Don't chew or crush them.

Follow your doctor's instructions carefully when taking sulfasalazine. Don't take more or less of the drug than is prescribed.

Be sure to drink plenty of fluids throughout the day while taking sulfasalazine.

Sulfasalazine Overdose

Symptoms of a sulfasalazine overdose may include:

• Severe stomach/abdominal pain
• Extreme drowsiness
• Seizures
• Persistent vomiting

If you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Sulfasalazine

If you miss a dose of sulfasalazine, take it as soon as you remember.

However, skip the missed dose if it's almost time for your next scheduled dose.

Don't take extra medicine to make up for a missed dose.

You should not use sulfasalazine if you are allergic to it, or if you have:

• a blockage in your bladder or intestines;

• porphyria (a genetic enzyme disorder that causes symptoms affecting the skin or nervous system);

• if you are allergic to sulfa drugs (such as Bactrim, SMX-TMP, SMZ-TMP, and others); or

• if you are allergic to aspirin or other salicylates (such as Nuprin Backache Caplet, Kaopectate, KneeRelief, Pamprin Cramp Formula, Pepto-Bismol, Tricosal, Trilisate, and others).

To make sure sulfasalazine is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease, or a history of kidney stones;

• a genetic enzyme deficiency called glucose-6-phosphate dehydrogenase (G6PD) deficiency;

• a blood cell disorder;

• weak immune system (caused by disease or by using certain medicine);

• heart disease;

• asthma; or

• history of chronic infections.

FDA pregnancy category B. Sulfasalazine is not expected to harm an unborn baby. However, you may need to take folic acid supplements if you take sulfasalazine during pregnancy. Follow your doctor's instructions. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Sulfasalazine can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Sulfasalazine should not be given to a child younger than 2 years old.

Other drugs may interact with sulfasalazine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Prodrug converted in vivo to sulfapyridine (a sulfonamide anti-infective) and 5-aminosalicylic acid (mesalamine; anti-inflammatory agent).116

Pharmacodynamics

The mode of action of Sulfasalazine (SSZ) or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of SSZ, SP, and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety.

Pharmacokinetics

In vivo studies have indicated that the absolute bioavailability of orally administered SSZ is less than 15% for parent drug. In the intestine, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Of the two species, SP is relatively well absorbed from the intestine and highly metabolized, while 5-ASA is much less well absorbed.

Following oral administration of 1 g of SSZ to 9 healthy males, less than 15% of a dose of SSZ is absorbed as parent drug. Detectable serum concentrations of SSZ have been found in healthy subjects within 90 minutes after the ingestion. Maximum concentrations of SSZ occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 6 hours.

In comparison, peak plasma levels of both SP and 5-ASA occur approximately 10 hours after dosing. This longer time to peak is indicative of gastrointestinal transit to the lower intestine where bacteria mediated metabolism occurs. SP apparently is well absorbed from the colon with an estimated bioavailability of 60%. In this same study, 5-ASA is much less well absorbed from the gastrointestinal tract with an estimated bioavailability of from 10 to 30%.

Following intravenous injection, the calculated volume of distribution (Vdss) for SSZ was 7.5 ± 1.6 L. SSZ is highly bound to albumin (>99.3%) while SP is only about 70% bound to albumin. Acetylsulfapyridine (AcSP), the principal metabolite of SP, is approximately 90% bound to plasma proteins.

As mentioned above, SSZ is metabolized by intestinal bacteria to SP and 5-ASA. Approximately 15% of a dose of SSZ is absorbed as parent and is metabolized to some extent in the liver to the same two species. The observed plasma half-life for intravenous Sulfasalazine is 7.6 ± 3.4 hours. The primary route of metabolism of SP is via acetylation to form AcSP. The rate of metabolism of SP to AcSP is dependent upon acetylator phenotype. In fast acetylators, the mean plasma half-life of SP is 10.4 hours while in slow acetylators, it is 14.8 hours. SP can also be metabolized to 5-hydroxy-sulfapyridine (SPOH) and N-acetyl-5-hydroxy-sulfapyridine. 5-ASA is primarily metabolized in both the liver and intestine to N-acetyl-5-aminosalicylic acid via a non-acetylation phenotype dependent route. Due to low plasma levels produced by 5-ASA after oral administration, reliable estimates of plasma half-life are not possible.

Absorbed SP and 5-ASA and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-ASA and acetyl-5-ASA with the feces. The calculated clearance of SSZ following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total clearance.

Special Populations

Elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for SSZ, SP, and their metabolites. The clinical impact of this is unknown.

Small studies have been reported in the literature in children down to the age of 4 years with ulcerative colitis and inflammatory bowel disease. In these populations, relative to adults, the pharmacokinetics of SSZ and SP correlated poorly with either age or dose.

The metabolism of SP to AcSP is mediated by polymorphic enzymes such that two distinct populations of slow and fast metabolizers exist. Approximately 60% of the Caucasian population can be classified as belonging to the slow acetylator phenotype. These subjects will display a prolonged plasma half-life for SP (14.8 hours vs. 10.4 hours) and an accumulation of higher plasma levels of SP than fast acetylators. The clinical implication of this is unclear; however, in a small pharmacokinetic trial where acetylator status was determined, subjects who were slow acetylators of SP showed a higher incidence of adverse events.

Gender appears not to have an effect on either the rate or the pattern of metabolites of SSZ, SP, or 5-ASA.

The most common adverse reactions associated with Sulfasalazine are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. These occur in about one-third of the patients. Less frequent adverse reactions are skin rash, pruritus, urticaria, fever, Heinz body anemia, hemolytic anemia, and cyanosis, which may occur at a frequency of one in every thirty patients or less. Experience suggests that with a daily dosage of 4 g or more, or total serum sulfapyridine levels above 50 μg/mL, the incidence of adverse reactions tends to increase.

Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the sulfonamides require that each of these reactions be considered when Sulfasalazine tablets are administered. Less common or rare adverse reactions include:

Blood dyscrasias: aplastic anemia, agranulocytosis, leukopenia, megaloblastic (macrocytic) anemia, purpura, thrombocytopenia, hypoprothrombinemia, methemoglobinemia, congenital neutropenia, and myelodysplastic syndrome.

Hypersensitivity reactions: erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell's syndrome) with corneal damage, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis, sometimes leading to liver transplantation, parapsoriasis varioliformis acuta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection, and alopecia.

Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, abdominal pains, and neutropenic enterocolitis.

Central nervous system reactions: transverse myelitis, convulsions, meningitis, transient lesions of the posterior spinal column, cauda equina syndrome, Guillian-Barre syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, ataxia, hallucinations, tinnitus, and drowsiness.

Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-uremic syndrome.

Other reactions: urine discoloration and skin discoloration.

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Goiter production, diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in this species.

Postmarketing Reports

The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine:

Blood dyscrasias: pseudomononucleosis

Cardiac disorders: myocarditis

Hepatobiliary disorders: reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatitis cholestatic, cholestasis and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported.

Immune system disorders: anaphylaxis

Metabolism and nutrition system disorders: folate deficiency

Renal and urinary disorders: nephrolithiasis

Respiratory, thoracic and mediastinal disorders: oropharyngeal pain

Skin and subcutaneous tissue disorders: angioedema, purpura

Vascular disorders: pallor

• Salicylazosulfapyridine

• 5-Aminosalicylic Acid Derivative

JIA: Minimum trial of 3 months is necessary; Ulcerative colitis: >3 to 4 weeks

Time to Peak

Sulfasalazine: 3 to 12 hours (mean: 6 hours); Serum sulfapyridine (active metabolite): Within 6 to 24 hours

Half-Life Elimination

Sulfasalazine: 5.7 to 10 hours (prolonged in elderly); Sulfapyridine: 14.8 hours (slow acetylators) and 10.4 hours (fast acetylators)

Protein Binding

Sulfasalazine: >99% to albumin; Sulfapyridine: ~70% to albumin; Acetylsulfapyridine (AcSP): ~90% to plasma proteins

Acetylator status: SP metabolism is mediated by polymorphic enzymes such that 2 distinct populations of slow and fast metabolizer exist. Slow acetylator phenotype (~60% of White patients) display a prolonged plasma half-life and an accumulation of higher plasma levels of SP than fast acetylators. The clinical implications of this are unclear; however, slow acetylators may experience a higher incidence of adverse reactions.

Refer to adult dosing.

Manufacturer's labeling: CBC with differential and liver function tests (prior to therapy, then every other week for first 3 months of therapy, followed by every month for the second 3 months, then once every 3 months thereafter or as clinically indicated); periodic urinalysis and renal/liver function tests; stool frequency; signs of infection, dermatologic toxicity, or hypersensitivity reactions.

Alternate recommendations: Complete blood count, serum creatinine, and LFTs: Baseline and every 2 to 4 weeks for 3 months after initiation or following dose increases, then every 8 to 12 weeks during 3 to 6 months of treatment, followed by every 12 weeks beyond 6 months of treatment; monitor more frequently if clinically indicated (Singh [ACR 2016]).

It is very important that your doctor check your or your child's progress at regular visits. This will allow your doctor to check if the medicine is working properly. Blood and urine tests will be needed to check for unwanted effects.

Check with your doctor right away if you or your child have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

Check with your doctor right away if you or your child have a fever and sore throat, pale skin, unusual bruising or bleeding, or unusual tiredness or weakness. These may be symptoms of a blood problem.

Sulfasalazine may decrease the amount of sperm men make and affect their ability to have children. If you plan to have children, talk with your doctor before using sulfasalazine.

Sulfasalazine may increase your risk of developing infections. Avoid being near people who are sick or have infections while you are using sulfasalazine. Wash your hands often. Tell your doctor if you have any kind of infection before you start using sulfasalazine. Also tell your doctor if you have ever had an infection that would not go away or an infection that kept coming back.

Call your doctor right away if you start to have a cough that won't go away, weight loss, night sweats, fever, chills, or flu-like symptoms, such as a runny or stuffy nose, headache, blurred vision, or feeling generally ill. These may be signs that you have an infection.

Serious skin reactions can occur with sulfasalazine. Check with your doctor right away if you or your child have blistering, peeling, or loosening of the skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are using sulfasalazine.

Sulfasalazine may cause blood problems. These problems may result in a greater chance of certain infections, slow healing, and bleeding of the gums. Therefore, you should be careful when using regular toothbrushes, dental floss, and toothpicks. Dental work should be delayed until your blood counts have returned to normal. Check with your medical doctor or dentist if you have any questions about proper oral hygiene (mouth care) during treatment.

Sulfasalazine may cause your skin to be more sensitive to sunlight than it is normally. Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or a severe sunburn. When you begin taking sulfasalazine:

• Stay out of direct sunlight, especially between the hours of 10:00 a.m. and 3:00 p.m., if possible.
• Wear protective clothing, including a hat. Also, wear sunglasses.
• Apply a sun block product that has a skin protection factor (SPF) of at least 15. Some patients may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your health care professional.
• Apply a sun block lipstick that has an SPF of at least 15 to protect your lips.
• Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

Your skin or urine may turn an orange or yellow color while you or your child are using sulfasalazine. This is normal and nothing to worry about.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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