Indocin

Generic Name: indomethacin (Oral route)

in-doe-METH-a-sin

Oral route(Capsule;Capsule, Extended Release;Suspension)

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased in patients with cardiovascular disease or risk factors for cardiovascular disease. Indomethacin is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs can also cause an increased risk of serious gastrointestinal adverse events especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal .

Commonly used brand name(s)

In the U.S.

• Indocin


• Indocin SR

Available Dosage Forms:

• Capsule


• Suspension


• Capsule, Extended Release

Therapeutic Class: Analgesic

Pharmacologic Class: NSAID

Chemical Class: Acetic Acid (class)

Uses For Indocin

Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) used to treat mild to moderate pain and help relieve symptoms of arthritis (e.g., osteoarthritis and rheumatoid arthritis) or gout, such as inflammation, swelling, stiffness, and joint pain. However, this medicine does not cure arthritis and will help you only as long as you continue to take it.

Indomethacin is also used to treat ankylosing spondylitis, which is a type of arthritis that affects the joints in the spine. This medicine may also be used to treat painful shoulder caused by bursitis or tendinitis.

Indomethacin may also be used to treat other conditions as determined by your doctor.

This medicine is available only with your doctor's prescription.

Before Using Indocin

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of indomethacin in children below 14 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of indomethacin in the elderly. However, elderly patients may be more sensitive to the effects of indomethacin than younger adults, and are more likely to have unwanted side effects (e.g., confusion, psychosis) and age-related kidney or stomach problems, which may require caution and an adjustment in the dose for patients receiving indomethacin.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Ketorolac


• Pentoxifylline

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Ardeparin


• Argatroban


• Beta Glucan


• Bivalirudin


• Certoparin


• Cilostazol


• Citalopram


• Clopidogrel


• Clovoxamine


• Dabigatran Etexilate


• Dalteparin


• Danaparoid


• Desirudin


• Digoxin


• Dipyridamole


• Enoxaparin


• Escitalopram


• Femoxetine


• Flesinoxan


• Fluoxetine


• Fluvoxamine


• Fondaparinux


• Ginkgo


• Heparin


• Lepirudin


• Methotrexate


• Nadroparin


• Nefazodone


• Parnaparin


• Paroxetine


• Pemetrexed


• Potassium


• Protein C


• Reviparin


• Rivaroxaban


• Sertraline


• Sibutramine


• Tacrolimus


• Ticlopidine


• Tinzaparin


• Tirofiban


• Vilazodone


• Zimeldine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol


• Acetohexamide


• Alacepril


• Alprenolol


• Amiloride


• Arotinolol


• Atenolol


• Azilsartan Medoxomil


• Azosemide


• Befunolol


• Bemetizide


• Benazepril


• Bendroflumethiazide


• Benzthiazide


• Betaxolol


• Bevantolol


• Bisoprolol


• Bopindolol


• Bucindolol


• Bumetanide


• Bupranolol


• Buthiazide


• Candesartan Cilexetil


• Canrenoate


• Captopril


• Carteolol


• Carvedilol


• Celiprolol


• Chlorothiazide


• Chlorpropamide


• Chlorthalidone


• Cilazapril


• Clopamide


• Cyclopenthiazide


• Cyclosporine


• Delapril


• Desvenlafaxine


• Dilevalol


• Dipyridamole


• Duloxetine


• Enalaprilat


• Enalapril Maleate


• Eprosartan


• Esmolol


• Ethacrynic Acid


• Fosinopril


• Furosemide


• Gentamicin


• Gliclazide


• Glimepiride


• Glipizide


• Gliquidone


• Glyburide


• Hydrochlorothiazide


• Hydroflumethiazide


• Imidapril


• Indapamide


• Irbesartan


• Labetalol


• Landiolol


• Levobetaxolol


• Levobunolol


• Lisinopril


• Lithium


• Losartan


• Mepindolol


• Methyclothiazide


• Metipranolol


• Metolazone


• Metoprolol


• Milnacipran


• Moexipril


• Nadolol


• Nebivolol


• Nipradilol


• Olmesartan Medoxomil


• Oxprenolol


• Penbutolol


• Pentopril


• Perindopril


• Pindolol


• Piretanide


• Polythiazide


• Propranolol


• Quinapril


• Ramipril


• Sotalol


• Spirapril


• Spironolactone


• Talinolol


• Tasosartan


• Telmisartan


• Temocapril


• Tertatolol


• Timolol


• Tolazamide


• Tolbutamide


• Torsemide


• Trandolapril


• Triamterene


• Trichlormethiazide


• Valsartan


• Venlafaxine


• Warfarin


• Xipamide


• Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Anemia or


• Asthma or


• Bleeding problems or


• Blood clots or


• Depression or other mental changes or


• Edema (fluid retention or body swelling) or


• Heart attack, history of or


• Heart disease (e.g., congestive heart failure) or


• Hepatitis, history of or


• Hypertension (high blood pressure) or


• Kidney disease or


• Parkinsonism or


• Seizures or epilepsy, history of or


• Stomach or intestinal ulcers or bleeding, history of or


• Stroke, history of—Use with caution. May make these conditions worse.

• Aspirin-sensitive asthma, history of or


• Aspirin sensitivity, history of—This medicine should not be used in patients with these conditions.

• Heart surgery (e.g., coronary artery bypass graft [CABG] surgery)—This medicine should not be used to relieve pain right before or after the surgery.

• Liver disease—Use with caution. Effects may be increased because of slower removal of the medicine from the body.

Proper Use of indomethacin

This section provides information on the proper use of a number of products that contain indomethacin. It may not be specific to Indocin. Please read with care.

For safe and effective use of this medicine, do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Taking too much of this medicine may increase the chance of unwanted effects.

This medicine should come with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Shake the oral suspension well before each use. Measure the medicine with a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.

When used for severe or continuing arthritis, this medicine must be taken regularly as ordered by your doctor in order for it to help you. This medicine usually begins to work within one week, but in severe cases up to two weeks or even longer may pass before you begin to feel better. Also, several weeks may pass before you feel the full effects of this medicine.

It is best to take this medicine with food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (capsules and suspension):
  
  • For acute gouty arthritis:
    
    • Adults—50 milligrams (mg) three times a day. Your doctor may decrease your dose as needed.
    
    
    • Children 15 years of age and above—Dose is based on body weight and must be determined by your doctor.
    
    
    • Children below 14 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For acute painful shoulder (bursitis or tendinitis):
    
    • Adults—75 to 150 milligrams (mg) per day, divided into three or four equal doses, and taken for one to two weeks as determined by your doctor.
    
    
    • Children 15 years of age and above—Dose is based on body weight and must be determined by your doctor.
    
    
    • Children below 14 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For moderate to severe ankylosing spondylitis, osteoarthritis, or rheumatoid arthritis:
    
    • Adults—25 milligrams (mg) two or three times a day. Your doctor may increase your dose by 25 or 50 mg per day, as needed. However, the total dose is usually not more than 200 mg per day.
    
    
    • Children 15 years of age and above—Dose is based on body weight and must be determined by your doctor.
    
    
    • Children below 14 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Indocin

It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

This medicine may raise your risk of having a heart attack or stroke. This is more likely in people who already have heart disease. People who use this medicine for a long time might also have a higher risk.

This medicine may cause bleeding in your stomach or intestines. These problems can happen without warning signs. This is more likely if you have had a stomach ulcer in the past, if you smoke or drink alcohol regularly, if you are over 60 years of age, are in poor health, or are using certain other medicines (such as a steroid medicine or a blood thinner).

Serious skin reactions can occur during treatment with this medicine. Check with your doctor right away if you have any of the following symptoms while taking this medicine: blistering, peeling, loosening of the skin; chills; cough; diarrhea; fever; itching; joint or muscle pain' red skin lesions; sore throat; sores, ulcers, white spots in the mouth or on the lips; or unusual tiredness or weakness.

Some possible warning signs of serious side effects that can occur during treatment with this medicine may include black, tarry stools; decreased urination; severe stomach pain; skin rash; swelling of the face, fingers, feet, or lower legs; unusual bleeding or bruising; unusual weight gain; vomiting of blood or material that looks like coffee ground; or yellow skin or eyes. Also, signs of serious heart problems could occur such as chest pain, tightness in the chest, fast or irregular heartbeat, unusual flushing or warmth of the skin, weakness, or slurring of speech. Stop taking this medicine and check with your doctor immediately if you notice any of these warning signs.

This medicine may also cause a serious type of allergic reaction called anaphylaxis. Although this is rare, it may occur more often in patients who are allergic to aspirin or to any of the nonsteroidal anti-inflammatory drugs (NSAIDs). Anaphylaxis can be life-threatening and requires immediate medical attention. The most serious signs of this reaction are very fast or irregular breathing, gasping for breath, wheezing, or fainting. Other signs may include changes in color of the skin of the face; very fast but irregular heartbeat or pulse; hive-like swellings on the skin; and puffiness or swellings of the eyelids or around the eyes. If these effects occur, get emergency help at once.

Using this medicine while you are pregnant can harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away. Do not use this medicine during the later part of a pregnancy unless your doctor tells you to.

Check with your doctor immediately if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

This medicine may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Even if taken at bedtime, it may cause some people to feel drowsy or less alert on arising. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert.

Before having any kind of surgery or medical tests, tell your doctor that you are taking this medicine. It may be necessary for you to stop treatment for a while, or to change to a different nonsteroidal anti-inflammatory drug before your procedure.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Indocin Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common

• Acid or sour stomach


• belching


• diarrhea


• heartburn


• indigestion


• nausea


• stomach discomfort, upset, or pain


• vomiting

Rare

• Abdominal or stomach cramping, burning, or tenderness


• back or leg pains


• bleeding gums


• blistering, peeling, or loosening of the skin


• bloody or black, tarry stools


• blue lips and fingernails


• blurred vision


• breast enlargement and tenderness


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• burning upper abdominal pain


• canker sores


• change in consciousness


• change in hearing


• chest pain, discomfort, or burning


• clay colored stools


• cloudy or bloody urine


• confusion


• continuing diarrhea


• cough or hoarseness


• coughing that sometimes produces a pink frothy sputum


• cracks in the skin


• dark urine


• decreased appetite


• decreased vision or any change in vision


• depression


• difficult or labored breathing


• difficulty with swallowing


• dilated neck veins


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position


• double vision


• dry mouth


• extreme fatigue


• false sense of well-being


• feeling of unreality


• feeling of warmth


• fever with or without chills


• flushed, dry skin


• fruit-like breath odor


• general body swelling


• greatly decreased frequency of urination or amount of urine


• hair loss


• headache


• heavier menstrual periods


• hives or welts


• increased hunger


• increased sweating


• increased thirst


• increased urination


• irregular breathing


• irritation and swelling of the eye


• itching skin


• jerky movements of the head, face, mouth, and neck


• joint pain


• large, flat, blue or purplish patches in the skin


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• loss of appetite


• loss of balance control


• loss of bladder control


• loss of consciousness


• loss of hearing


• loss of heat from the body


• lower back or side pain


• mask-like face


• mental confusion


• mood swings


• muscle aches, pains, or weakness


• muscle spasm or jerking of all extremities


• nervousness


• noisy, rattling breathing


• nosebleeds


• numbness or tingling in the hands, feet, or lips


• pain in the ankles or knees


• pain or discomfort in the upper stomach, or throat


• pain with swallowing


• painful or difficult urination


• painful, red lumps under the skin, mostly on the legs


• pale skin


• persistent bleeding or oozing from puncture sites, mouth, or nose


• personality changes


• pinpoint red or purple spots on the skin


• pounding in the ears


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• red skin lesions, often with a purple center


• red, irritated eyes


• red, swollen skin


• redness of the face, neck, arms and occasionally, upper chest


• scaly skin


• seeing double


• seeing, hearing, or feeling things that are not there


• seizures


• sense of detachment from self or body


• severe constipation


• severe mental changes


• severe or continuing stomach pain


• shortness of breath


• shuffling walk


• skin rash


• slow, fast, irregular, pounding, or racing heartbeat or pulse


• slowed movements


• slurred speech


• small red or purple spots on the skin


• sore throat


• sores, ulcers, or white spots on the lips or tongue or inside the mouth


• stiffness of the arms and legs


• sudden loss of consciousness


• sugar in the urine


• swelling in the legs and ankles


• swelling of the face, fingers, feet, or lower legs


• swelling of the breasts or breast soreness in both females and males


• swollen or painful glands


• tightness in the chest


• trembling and shaking of the fingers and hands


• troubled breathing at rest


• troubled breathing with exertion


• unexplained weight loss


• unpleasant breath odor


• unsteadiness or awkwardness


• unusual bleeding or bruising


• unusual tiredness or weakness


• vaginal bleeding


• vomiting of blood or material that looks like coffee grounds


• weakness in the arms, hands, legs, or feet


• weight gain


• wheezing


• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Confusion about identity, place, and time


• severe headache


• unusual drowsiness, dullness, or feeling of sluggishness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Mild headache

Less common

• Continuing ringing or buzzing or other unexplained noise in the ears


• difficulty having a bowel movement (stool)


• discouragement


• feeling sad or empty


• general feeling of discomfort or illness


• hearing loss


• irritability


• loss of interest or pleasure


• sleepiness


• trouble with concentrating

Rare

• Anxiety


• bloated full feeling


• changes in patterns and rhythms of speech


• excess air or gas in the stomach or intestines


• feeling of constant movement of self or surroundings


• involuntary muscle movements


• lightheadedness


• passing gas


• sensation of spinning


• sleeplessness


• tiredness


• trouble with speaking


• trouble sleeping


• unable to sleep

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Indocin side effects (in more detail)

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More Indocin resources

• Indocin Side Effects (in more detail)
• Indocin Use in Pregnancy & Breastfeeding
• Drug Images
• Indocin Drug Interactions
• Indocin Support Group
• 14 Reviews for Indocin - Add your own review/rating

• Indocin Concise Consumer Information (Cerner Multum)


• Indocin MedFacts Consumer Leaflet (Wolters Kluwer)


• Indocin Monograph (AHFS DI)


• Indomethacin Prescribing Information (FDA)


• Indomethacin MedFacts Consumer Leaflet (Wolters Kluwer)


• Indomethacin Professional Patient Advice (Wolters Kluwer)


• Indocin SR Sustained-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Indocin SR Prescribing Information (FDA)

Compare Indocin with other medications

• Ankylosing Spondylitis
• Back Pain
• Bartter Syndrome
• Bursitis
• Cluster Headaches
• Frozen Shoulder
• Gitelman Syndrome
• Gout, Acute
• Langerhans' Cell Histiocytosis
• Osteoarthritis
• Pain
• Patent Ductus Arteriosus
• Rheumatoid Arthritis
• Sciatica
• Tendonitis

Thioguanine

TABLOID®

brand Thioguanine

40-mg Scored Tablets

CAUTION

TABLOID brand Thioguanine is a potent drug. It should not be used unless a diagnosis of acute nonlymphocytic leukemia has been adequately established and the responsible physician is knowledgeable in assessing response to chemotherapy.

Thioguanine Description

TABLOID brand Thioguanine was synthesized and developed by Hitchings, Elion, and associates at the Wellcome Research Laboratories. It is one of a large series of purine analogues which interfere with nucleic acid biosynthesis, and has been found active against selected human neoplastic diseases.

Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione, is an analogue of the nucleic acid constituent guanine, and is closely related structurally and functionally to PURINETHOL® (mercaptopurine). Its structural formula is:

TABLOID brand Thioguanine is available in tablets for oral administration. Each scored tablet contains 40 mg Thioguanine and the inactive ingredients acacia, lactose monohydrate, magnesium stearate, potato starch, and stearic acid.

Thioguanine - Clinical Pharmacology

Clinical studies have shown that the absorption of an oral dose of Thioguanine in humans is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%). Following oral administration of 35S-6-Thioguanine, total plasma radioactivity reached a maximum at 8 hours and declined slowly thereafter. Parent drug represented only a very small fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the period of measurements.

The oral administration of radiolabeled Thioguanine revealed only trace quantities of parent drug in the urine. However, a methylated metabolite, 2-amino-6-methylthiopurine (MTG), appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were found in the urine in small amounts. Intravenous administration of 35S-6-Thioguanine disclosed a median plasma half-disappearance time of 80 minutes (range: 25 to 240 minutes) when the compound was given in single doses of 65 to 300 mg/m2. Although initial plasma levels of Thioguanine did correlate with the dose level, there was no correlation between the plasma half-disappearance time and the dose.

Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies with intravenous 35S-6-Thioguanine have shown that the amount of Thioguanine incorporated into nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced by Thioguanine. Tissue distribution studies of 35S-6-Thioguanine in mice showed only traces of radioactivity in brain after oral administration. No measurements have been made of Thioguanine concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in animals, together with the lack of CNS penetration by the closely related compound, mercaptopurine, suggest that Thioguanine does not reach therapeutic concentrations in the CSF.

Monitoring of plasma levels of Thioguanine during therapy is of questionable value. There is technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 2 mcg/mL after a therapeutic oral dose. More significantly, Thioguanine enters rapidly into the anabolic and catabolic pathways for purines, and the active intracellular metabolites have appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of Thioguanine are evident long after the parent drug has disappeared from plasma. Because of this rapid metabolism of Thioguanine to active intracellular derivatives, hemodialysis would not be expected to appreciably reduce toxicity of the drug.

Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanylic acid (TGMP). This nucleotide reaches high intracellular concentrations at therapeutic doses. TGMP interferes at several points with the synthesis of guanine nucleotides. It inhibits de novo purine biosynthesis by pseudo-feedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase—the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. At one time TGMP was felt to be a significant inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have shown this not to be so.

Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) (as well as their 2′-deoxyribosyl analogues) by the same enzymes which metabolize guanine nucleotides. Thioguanine nucleotides are incorporated into both the RNA and the DNA by phosphodiester linkages and it has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of Thioguanine.

Thus, Thioguanine has multiple metabolic effects and at present it is not possible to designate one major site of action. Its tumor inhibitory properties may be due to one or more of its effects on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides.

The catabolism of Thioguanine and its metabolites is complex and shows significant differences between humans and the mouse. In both humans and mice, after oral administration of 35S-6-Thioguanine, urine contains virtually no detectable intact Thioguanine. While deamination and subsequent oxidation to thiouric acid occurs only to a small extent in humans, it is the main pathway in mice. The product of deamination by guanase, 6-thioxanthine is inactive, having negligible antitumor activity. This pathway of Thioguanine inactivation is not dependent on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not block the detoxification of Thioguanine even though the inactive 6-thioxanthine is normally further oxidized by xanthine oxidase to thiouric acid before it is eliminated. In humans, methylation of Thioguanine is much more extensive than in the mouse. The product of methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than Thioguanine and its formation is likewise unaffected by the presence of allopurinol. Appreciable amounts of inorganic sulfate are also found in both murine and human urine, presumably arising from further metabolism of the methylated derivatives.

In some animal tumors, resistance to the effect of Thioguanine correlates with the loss of HGPRTase activity and the resulting inability to convert Thioguanine to thioguanylic acid. However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance between Thioguanine and its close analogue, PURINETHOL (mercaptopurine).

Indications and Usage for Thioguanine

a) Acute Nonlymphocytic Leukemias

TABLOID brand Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity (see WARNINGS and ADVERSE REACTIONS).

The response to this agent depends upon the age of the patient (younger patients faring better than older) and whether Thioguanine is used in previously treated or previously untreated patients. Reliance upon Thioguanine alone is seldom justified for initial remission induction of acute nonlymphocytic leukemias because combination chemotherapy including Thioguanine results in more frequent remission induction and longer duration of remission than Thioguanine alone.

b) Other Neoplasms

TABLOID brand Thioguanine is not effective in chronic lymphocytic leukemia, Hodgkin’s lymphoma, multiple myeloma, or solid tumors. Although Thioguanine is one of several agents with activity in the treatment of the chronic phase of chronic myelogenous leukemia, more objective responses are observed with MYLERAN® (busulfan), and therefore busulfan is usually regarded as the preferred drug.

Contraindications

Thioguanine should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine.

Warnings

SINCE DRUGS USED IN CANCER CHEMOTHERAPY ARE POTENTIALLY HAZARDOUS, IT IS RECOMMENDED THAT ONLY PHYSICIANS EXPERIENCED WITH THE RISKS OF Thioguanine AND KNOWLEDGEABLE IN THE NATURAL HISTORY OF ACUTE NONLYMPHOCYTIC LEUKEMIAS ADMINISTER THIS DRUG.

Thioguanine IS NOT RECOMMENDED FOR MAINTENANCE THERAPY OR SIMILAR LONG-TERM CONTINUOUS TREATMENTS DUE TO THE HIGH RISK OF LIVER TOXICITY ASSOCIATED WITH VASCULAR ENDOTHELIAL DAMAGE (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS). This liver toxicity has been observed in a high proportion of children receiving Thioguanine as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use of Thioguanine. This liver toxicity is particularly prevalent in males. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and oesophageal varices). Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.

Thioguanine therapy should be discontinued in patients with evidence of liver toxicity as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal.

Patients must be carefully monitored (see PRECAUTIONS, Laboratory Tests). Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported in association with liver toxicity but do not always occur.

The most consistent, dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of these findings may also reflect progression of the underlying disease. Since Thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of Thioguanine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. Prescribers should be aware that some laboratories offer testing for TPMT deficiency. Since bone marrow suppression may be associated with factors other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. Bone marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.

It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on Thioguanine therapy. In cases where the cause of fluctuations in the formed elements in the peripheral blood is obscure, bone marrow examination may be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of Thioguanine must be based not only on the absolute hematologic values, but also upon the rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently in order to evaluate the effect of the therapy. The dosage of Thioguanine may need to be reduced when this agent is combined with other drugs whose primary toxicity is myelosuppression.

Myelosuppression is often unavoidable during the induction phase of adult acute nonlymphocytic leukemias if remission induction is to be successful. Whether or not this demands modification or cessation of dosage depends both upon the response of the underlying disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) which may be available. Life-threatening infections and bleeding have been observed as consequences of Thioguanine-induced granulocytopenia and thrombocytopenia.

The effect of Thioguanine on the immunocompetence of patients is unknown.

Pregnancy

Pregnancy Category D. Drugs such as Thioguanine are potential mutagens and teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of the limbs. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Precautions

General

Although the primary toxicity of Thioguanine is myelosuppression, other toxicities have occasionally been observed, particularly when Thioguanine is used in combination with other cancer chemotherapeutic agents.

A few cases of jaundice have been reported in patients with leukemia receiving Thioguanine. Among these were 2 adult male patients and 4 pediatric patients with acute myelogenous leukemia and an adult male with acute lymphocytic leukemia who developed hepatic veno-occlusive disease while receiving chemotherapy for their leukemia. Six patients had received cytarabine prior to treatment with Thioguanine, and some were receiving other chemotherapy in addition to Thioguanine when they became symptomatic. While hepatic veno-occlusive disease has not been reported in patients treated with Thioguanine alone, it is recommended that Thioguanine be withheld if there is evidence of toxic hepatitis or biliary stasis, and that appropriate clinical and laboratory investigations be initiated to establish the etiology of the hepatic dysfunction. Deterioration in liver function studies during Thioguanine therapy should prompt discontinuation of treatment and a search for an explanation of the hepatotoxicity.

Administration of live vaccines to immunocompromised patients should be avoided.

Information for Patients

Patients should be informed that the major toxicities of Thioguanine are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant.

Laboratory Tests

Prescribers should be aware that some laboratories offer testing for TPMT deficiency (see WARNINGS).

It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It may be advisable to perform liver function tests more frequently in patients with known pre-existing liver disease or in patients who are receiving Thioguanine and other hepatotoxic drugs. Patients should be instructed to discontinue Thioguanine immediately if clinical jaundice is detected (see WARNINGS).

Drug Interactions

There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine.

As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Thioguanine therapy (see WARNINGS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

In view of its action on cellular DNA, Thioguanine is potentially mutagenic and carcinogenic, and consideration should be given to the theoretical risk of carcinogenesis when Thioguanine is administered (see WARNINGS).

Pregnancy

Teratogenic Effects

Pregnancy Category D. See WARNINGS section.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for Thioguanine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See DOSAGE AND ADMINISTRATION section.

Geriatric Use

Clinical studies of Thioguanine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general,dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

 The most frequent adverse reaction to Thioguanine is myelosuppression. The induction of complete remission of acute myelogenous leukemia usually requires combination chemotherapy in dosages which produce marrow hypoplasia. Since consolidation and maintenance of remission are also effected by multiple-drug regimens whose component agents cause myelosuppression, pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to prevent life-threatening cytopenias whenever these adverse reactions are observed.

Hyperuricemia frequently occurs in patients receiving Thioguanine as a consequence of rapid cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as ZYLOPRIM® (allopurinol). Unlike PURINETHOL (mercaptopurine) and IMURAN® (azathioprine), Thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation.

Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal necrosis and perforation have been reported in patients who received multiple-drug chemotherapy including Thioguanine.

Hepatic Effects

Liver toxicity associated with vascular endothelial damage has been reported when Thioguanine is used in maintenance or similar long-term continuous therapy which is not recommended (see WARNINGS and DOSAGE AND ADMINISTRATION). This usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or signs and symptoms of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Elevation of liver transaminases, alkaline phosphatase, and gamma glutamyl transferase and jaundice may also occur. Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.

Liver toxicity during short-term cyclical therapy presents as veno-occlusive disease. Reversal of signs and symptoms of this liver toxicity has been reported upon withdrawal of short-term or long-term continuous therapy.

Centrilobular hepatic necrosis has been reported in a few cases; however, the reports are confounded by the use of high doses of Thioguanine, other chemotherapeutic agents, and oral contraceptives and chronic alcohol abuse.

Overdosage

Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, hypotension, and diaphoresis; or delayed, such as myelosuppression and azotemia. It is not known whether Thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of Thioguanine into active metabolites with long persistence. The oral LD50 of Thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively. Symptoms of overdosage may occur after a single dose of as little as 2.0 to 3.0 mg/kg Thioguanine. As much as 35 mg/kg has been given in a single oral dose with reversible myelosuppression observed. There is no known pharmacologic antagonist of Thioguanine. The drug should be discontinued immediately if unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if sepsis is documented. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis.

Thioguanine Dosage and Administration

 TABLOID brand Thioguanine is administered orally. The dosage which will be tolerated and effective varies according to the stage and type of neoplastic process being treated. Because the usual therapies for adult and pediatric acute nonlymphocytic leukemias involve the use of Thioguanine with other agents in combination, physicians responsible for administering these therapies should be experienced in the use of cancer chemotherapy and in the chosen protocol.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of Thioguanine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients (see WARNINGS). Prescribers should be aware that some laboratories offer testing for TPMT deficiency.

Ninety-six (59%) of 163 pediatric patients with previously untreated acute nonlymphocytic leukemia obtained complete remission with a multiple-drug protocol including Thioguanine, prednisone, cytarabine, cyclophosphamide, and vincristine. Remission was maintained with daily Thioguanine, 4-day pulses of cytarabine and cyclophosphamide, and a single dose of vincristine every 28 days. The median duration of remission was 11.5 months.

Fifty-three percent of previously untreated adults with acute nonlymphocytic leukemias attained remission following use of the combination of Thioguanine and cytarabine according to a protocol developed at The Memorial Sloan-Kettering Cancer Center. A median duration of remission of 8.8 months was achieved with the multiple-drug maintenance regimen which included Thioguanine.

On those occasions when single-agent chemotherapy with Thioguanine may be appropriate, the usual initial dosage for pediatric patients and adults is approximately 2 mg/kg of body weight per day. If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day. The total daily dose may be given at one time.

The dosage of Thioguanine used does not depend on whether or not the patient is receiving ZYLOPRIM (allopurinol); this is in contradistinction to the dosage reduction which is mandatory when PURINETHOL (mercaptopurine) or IMURAN (azathioprine) is given simultaneously with allopurinol.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8

There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How is Thioguanine Supplied

 Greenish-yellow, scored, round tablets containing 40 mg Thioguanine, imprinted with “WELLCOME” and “U3B” on each tablet; in bottles of 25 (NDC 0173-0880-25).

Store at 15° to 25°C (59° to 77°F) in a dry place.

REFERENCES

1. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.


2. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health and Human Services, 1992, US Dept of Health and Human Services, Public Health Service publication NIH 92-2621.


3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591.


4. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.


5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.


6. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263.


7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.


8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

TABLOID and MYLERAN are registered trademarks of GlaxoSmithKline. The following are registered trademarks of their respective owners: PURINETHOL/Teva Pharmaceutical Works; ZYLOPRIM and IMURAN/Promethius Laboratories Inc.

Manufactured by

DSM Pharmaceuticals, Inc.

Greenville, NC 27834

for GlaxoSmithKline

Research Triangle Park, NC 27709

©2009, GlaxoSmithKline. All rights reserved.

June 2009 TBL:1PI

Principal Display Panel

NDC 0173-0880-25

TABLOID® brand

Thioguanine

Each scored tablet contains 40 mg

Rx only 25 Tablets

WARNING: This drug is only to be taken under close medical supervision. Do not take in larger doses or more frequently or for a longer time than specifically directed by the physician. Periodic blood counts are necessary to determine proper dose and to avoid ill effects.

Store at 15o to 25oC (59o to 77oF) in a dry place. Dispense in tight container as defined in the USP. Read side panel warning carefully before using. See package insert for Dosage and Administration.

Manufactured by DSM Pharmaceuticals, Inc.

Greenville, NC 27834

for GlaxoSmithKline

RTP, NC 27709

Made in Italy.

10000000062812 Rev. 10/08

TABLOID  Thioguanine  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0173-0880 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Thioguanine (Thioguanine) Thioguanine 40 mg

Inactive Ingredients Ingredient Name Strength ACACIA   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   STARCH, POTATO   STEARIC ACID

Product Characteristics Color GREEN (GREENISH-YELLOW) Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code WELLCOME;U3B Contains

Packaging # NDC Package Description Multilevel Packaging 1 0173-0880-25 25 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA012429	12/18/1984

Labeler - GlaxoSmithKline LLC (167380711)

Revised: 03/2010GlaxoSmithKline LLC

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Compare Thioguanine with other medications

• Acute Nonlymphocytic Leukemia

Mastalone

Mastalone may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Mastalone

Neomycin

Neomycin sulfate (a derivative of Neomycin) is reported as an ingredient of Mastalone in the following countries:

• New Zealand

Oleandomycin

Oleandomycin phosphate (a derivative of Oleandomycin) is reported as an ingredient of Mastalone in the following countries:

• New Zealand

Oxytetracycline

Oxytetracycline hydrochloride (a derivative of Oxytetracycline) is reported as an ingredient of Mastalone in the following countries:

• New Zealand

Prednisolone

Prednisolone is reported as an ingredient of Mastalone in the following countries:

• New Zealand

International Drug Name Search

Simvasin Spirig

Simvasin Spirig may be available in the countries listed below.

Ingredient matches for Simvasin Spirig

Simvastatin

Simvastatin is reported as an ingredient of Simvasin Spirig in the following countries:

• Switzerland

International Drug Name Search

Infliximab

Class: Disease-modifying Antirheumatic Agents
CAS Number: 170277-31-3
Brands: Remicade

Special Alerts:

CORRECTION NOTICE:

The Editors of AHFS Drug Information (AHFS DI) and AHFS DI Essentials wish to inform you of an error in the Infliximab (Systemic) monograph. The error appears under the subhead IV Administration: Rate of Administration, in Dosage and Administration: Administration. In Table 1: Rate Titration Schedule, the entry in column 1, line 4 should read: 80 mL/hour.

The originally stated infusion rate of 80 mL/minute is incorrect. The correct infusion rate is 80 mL/hour.

MEDWATCH ALERT:

[Posted 09/07/2011] ISSUE: FDA notified healthcare professionals that the Boxed Warning for the entire class of Tumor Necrosis Factor-alpha (TNFα) blockers has been updated to include the risk of infection from two bacterial pathogens, Legionella and Listeria. In addition, the Boxed Warning and Warnings and Precautions sections of the labels for all of the TNFα blockers have been revised so that they contain consistent information about the risk for serious infections and the associated disease-causing pathogens.

Patients treated with TNFα blockers are at increased risk for developing serious infections involving multiple organ systems and sites that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens.

BACKGROUND: The class of TNFα blockers are used to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and/or juvenile idiopathic arthritis.

RECOMMENDATION: The risks and the benefits of TNFα blockers should be considered prior to initiating therapy in patients with chronic or recurrent infection and patients with underlying conditions that may predispose them to infection. See the Drug Safety Communication for a listing of recommendations for healthcare professionals and patients, as well as a data summary. For more information visit the FDA website at: and .

[Posted 04/14/2011] ISSUE: FDA continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL, primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factors (TNF) blockers, as well as with azathioprine, and/or mercaptopurine. TNF blockers include infliximab (Remicade), etancercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi).

BACKGROUND: HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn’s disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.

Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine, there have been cases reported in patients receiving azathioprine or mercaptopurine alone.

• 
  

  Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.

  
  


• 
  

  Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.

  
  


• 
  

  Know that people with rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or meracaptopurine.

  
  

Read the Drug Safety Communications for other specific recommendations for Healthcare Professionals and Patients and the Data Summary for additional information. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for infliximab to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Serious Infections


• 
  

  Serious, sometimes fatal infections including tuberculosis (frequently disseminated or extrapulmonary), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported.¹ (See Infectious Complications under Cautions.)

  
  


• 
  

  Carefully consider risks and benefits prior to initiating infliximab therapy in patients with chronic or recurring infections.¹

  
  


• 
  

  Evaluate patients for latent tuberculosis infection prior to and periodically during infliximab therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating infliximab therapy.¹

  
  


• 
  

  Closely monitor patients for infection, including active tuberculosis in those with a negative tuberculin skin test, during and after treatment.¹ Discontinue infliximab if serious infection or sepsis occurs.¹ Consider empiric antifungal therapy if serious systemic illness occurs in a patient at risk for invasive fungal infections.¹

  
  

• Malignancy


• 
  

  Lymphoma and other malignancies (some fatal) reported in children and adolescents receiving TNF blocking agents.¹ (See Malignancies and Lymphoproliferative Disorders under Cautions.)

  
  


• 
  

  Aggressive, fatal hepatosplenic T-cell lymphoma reported in patients with Crohn's disease or ulcerative colitis receiving TNF blocking agents, including infliximab.¹ Most of the patients were adolescent or young adult males; all received concomitant therapy with azathioprine or mercaptopurine at or prior to diagnosis.¹

  
  

Introduction

Biologic response modifier and disease-modifying antirheumatic drug (DMARD); chimeric human-murine monoclonal antibody that blocks the biologic activity of tumor necrosis factor (TNF, TNF-α).^{1 7 20 24}

Uses for Infliximab

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Crohn’s Disease

Used to reduce signs and symptoms of Crohn’s disease and to induce and maintain clinical remission in adults and pediatric patients with moderate to severe active disease who have had an inadequate response to conventional therapies (e.g., corticosteroids, mesalamine or sulfasalazine, azathioprine or mercaptopurine).^{1 5 6 38 51 72 89 136 142}

Used to reduce the number of draining enterocutaneous and rectovaginal fistulas and to maintain fistula closure in adults with fistulizing Crohn’s disease (designated an orphan drug by FDA for this use).^{1 64 94 140 141 142 143} Consider use when fistulas have not responded to appropriate anti-infective regimens (e.g., ciprofloxacin and/or metronidazole) and/or immunosuppressive therapy (e.g., azathioprine or mercaptopurine).^{47 65 66 70}

Rheumatoid Arthritis in Adults

Used in conjunction with methotrexate to manage the signs and symptoms of rheumatoid arthritis, to improve physical function, and to inhibit progression of structural damage associated with the disease in adults with moderate to severe active rheumatoid arthritis.^{1 14 15 17 18 41}

Ankylosing Spondylitis

Management of the signs and symptoms of active ankylosing spondylitis.^{1 72 108 109 117 137 138}

Psoriatic Arthritis

Used to manage the signs and symptoms of active arthritis in adults with psoriatic arthritis.^{1 72 105 106 107 108 131}

Ulcerative Colitis

Used to manage the signs and symptoms, to achieve clinical remission and mucosal healing, and to eliminate corticosteroid use in adults with moderate to severe active ulcerative colitis who have had an inadequate response to conventional therapies.^{1 47 72 112 113 114 147}

Juvenile Arthritis

Has been used with some success in a limited number of adults and pediatric patients with juvenile arthritis†.^{72 103 104}

Behcet’s Syndrome

Has been used in a limited number of patients with Behcet’s syndrome†.^{93 102 115 116 93}

Infliximab Dosage and Administration

General

Premedication and Patient Monitoring

• 
  

  Consider administration of premedication prior to each dose to minimize risk of infusion-related reactions.^{47 72}

  
  


• 
  

  Patients receiving initial infusion and patients without a history of acute infusion reactions: Oral diphenhydramine hydrochloride (25–50 mg) and acetaminophen (650 mg) can be given before the infusion.^{47 72}

  
  


• 
  

  Patients with a history of acute infusion reactions: Oral or IV prednisone (40 mg) or hydrocortisone (100 mg), oral or IV diphenhydramine hydrochloride (25–50 mg), and acetaminophen (650 mg) can be given before the infusion.^{72 142}

  
  


• 
  

  Monitor patients closely during and after each IV infusion.⁷² Measure vital signs (pulse and BP) immediately prior to infusion, during the infusion (every 30 minutes in patients without a history of acute infusion reactions and every 15 minutes in those with a history of reactions), and for 30 minutes after completion of the infusion.⁷²

  
  


• 
  

  If DBP drops 15–20 mm Hg or symptoms of hypersensitivity (e.g., urticaria, shortness of breath) occur, stop the infusion immediately, evaluate manifestations, and initiate appropriate therapy.⁷²

  
  


• 
  

  If the reaction is not severe and is mitigated with a regimen of oral diphenhydramine hydrochloride (25–50 mg), oral acetaminophen (650 mg), and oral or IV prednisone (40 mg), the infusion may be resumed with caution following the rate titration schedule using an initial rate of 10 mL/hour.⁷² (See Rate Titration Schedule Table under Dosage and Administration.)

  
  


• 
  

  The infusion should be discontinued and not completed if the reaction does not resolve with the regimen described above or is more severe and/or requires treatment with epinephrine.⁷²

  
  

Concomitant Therapy for Crohn’s Disease

• 
  

  Corticosteroids, mesalamine, sulfasalazine, azathioprine, mercaptopurine, methotrexate, and anti-infective agents may be continued.¹

  
  

Concomitant Therapy for Rheumatoid Arthritis

• 
  

  Intended for use concomitantly with methotrexate; only limited data available regarding the efficacy of infliximab without concomitant methotrexate.^{1 17 18 20 21 23 1}

  
  


• 
  

  Corticosteroids and NSAIAs may be continued.¹

  
  

Concomitant Therapy for Psoriatic Arthritis

• 
  

  Corticosteroids, NSAIAs, and methotrexate may be continued.¹

  
  

Concomitant Therapy for Ulcerative Colitis

• 
  

  Corticosteroids, azathioprine, mercaptopurine, and 5-aminosalicylates may be continued.^{1 147}

  
  

REMS Program

• 
  

  FDA has approved a Risk Evaluation and Mitigation Strategy (REMS) for infliximab.¹⁵⁶

  
  


• 
  

  The program consists of a medication guide that must be provided to patients (see Advice to Patients) and a communication plan consisting of letters and an education guide targeting selected groups of clinicians.¹⁵⁶

  
  


• 
  

  The goals are to inform patients about the serious risks associated with the drug and to inform clinicians about invasive fungal infections associated with use of TNF blocking agents (see Warnings/Precautions under Cautions).¹⁵⁶

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.¹

Administer with an in-line, sterile, nonpyrogenic, low-protein-binding filter with a pore diameter of ≤1.2 mcm.¹

Consult manufacturer’s labeling for additional information on reconstitution, dilution, and administration of infliximab.¹

Reconstitution

Reconstitute vial containing 100 mg of infliximab powder with 10 mL of sterile water for injection to provide a solution containing 10 mg/mL.¹ Reconstitute the number of vials needed to provide the indicated dosage of infliximab.¹

Direct diluent toward the side of the vial with a sterile syringe and a ≤21-gauge needle; swirl vial gently to ensure dissolution; do not shake or agitate vigorously (to avoid foaming).¹

Allow reconstituted solution to stand for 5 minutes before dilution.¹

Dilution

Remove the volume of diluent equal to the total required volume of reconstituted infliximab solution from a 250-mL bag or bottle of 0.9% sodium chloride injection.¹ Slowly add reconstituted infliximab to the bag to a total volume of 250 mL; mix gently.¹ Concentration of the solution for infusion should be 0.4–4 mg/mL.¹

Rate of Administration

Infuse over a period of at least 2 hours.¹

IV infusions may be given at a rate of 2 mL/minute or, alternatively, a rate titration schedule may be used in an attempt to prevent or ameliorate acute infusion reactions.⁷²

A rate titration schedule can be used in patients receiving an initial infliximab dose, those without a history of acute infusion reactions, and those with a history of such reactions.⁷²

Table 1. Rate Titration Schedule

Rate	Time
10 mL/hour	first 15 minutes72
20 mL/hour	next 15 minutes72
40 mL/hour	next 15 minutes72
80 mL/hour	next 15 minutes72
150 mL/hour	next 30 minutes72
250 mL/hour	next 30 minutes72

Dosage

Pediatric Patients

Crohn’s Disease

Management of Moderate or Severe Active Crohn’s Disease

IV

Children ≥6 years of age: 5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).^{1 47 86 87}

Adults

Crohn’s Disease

Management of Moderate or Severe Active Crohn’s Disease or Fistulizing Crohn’s Disease

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).¹

Consider dose of 10 mg/kg for patients who respond initially but subsequently lose response.¹

Patients who do not respond by week 14 are unlikely to respond with continued administration; consider discontinuing the drug.¹

Rheumatoid Arthritis

Moderate to Severe Active Rheumatoid Arthritis

IV

3 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).¹

Increase dosage up to 10 mg/kg and/or administer as often as once every 4 weeks for patients who have an incomplete response to 3 mg/kg; consider that risk of serious infection is increased with higher dosages.^{1 72}

Ankylosing Spondylitis

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 6 weeks (maintenance regimen).¹

Psoriatic Arthritis

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).¹

Ulcerative Colitis

Moderate to Severe Active Ulcerative Colitis

IV

5 mg/kg at 0, 2, and 6 weeks (induction regimen), then every 8 weeks (maintenance regimen).¹

Cautions for Infliximab

Contraindications

• 
  

  Doses >5 mg/kg in patients with moderate or severe heart failure.¹ (See Cardiovascular Effects under Cautions.)

  
  


• 
  

  Known hypersensitivity to infliximab, murine proteins, or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Infectious Complications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Serious, sometimes fatal infections (including bacterial, mycobacterial, invasive fungal, viral, and other opportunistic infections) reported with infliximab or other TNF blocking agents,¹ particularly in patients receiving concomitant therapy with other immunosuppressive agents (e.g., methotrexate, corticosteroids).^{1 72 118 155} The most common opportunistic infections include tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis.¹ Infections frequently are disseminated.¹

Do not initiate infliximab in patients with active infections, including clinically important localized infections.¹ Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic or recurring infections, patients with underlying conditions that may predispose them to infections, and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses such as histoplasmosis, coccidioidomycosis, and blastomycosis are endemic.¹

Closely monitor patients during and after infliximab therapy for signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock).^{1 155}

If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.^{1 155} Discontinue infliximab if serious infection or sepsis develops.^{1 155}

Evaluate all patients for active or latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.¹ When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to infliximab therapy.^{1 14 18 42 59 72 111 118} Also consider antimycobacterial therapy prior to infliximab therapy for individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and for individuals with a negative tuberculin skin test who have risk factors for tuberculosis.¹ Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.¹

Monitor all patients, including those with negative tuberculin skin tests, for active tuberculosis.¹ Strongly consider tuberculosis in patients who develop new infections while receiving infliximab, especially if they previously have traveled to countries where tuberculosis is highly prevalent or have been in close contact with an individual with active tuberculosis.¹

Invasive fungal infections often not recognized in patients receiving TNF blocking agents; this has led to delays in appropriate treatment.¹⁵⁵

Consider empiric antifungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.^{1 155} Whenever feasible, consult specialist in fungal infections when making decisions regarding initiation and duration of antifungal therapy.^{1 155}

When deciding whether to reinitiate TNF blocking agent therapy following resolution of an invasive fungal infection, reevaluate risks and benefits, particularly in patients who reside in regions where mycoses are endemic.¹⁵⁵ Whenever feasible, consult specialist in fungal infections.¹⁵⁵

Increased incidence of serious infection observed with concomitant use of etanercept (another TNF blocking agent) and anakinra (a human interleukin-1 receptor antagonist).¹ Similar toxicities expected with concomitant use of anakinra and other agents that block TNF, including infliximab.¹ (See Specific Drugs under Interactions.)

Increased incidence of infection and serious infection reported with concomitant use of a TNF blocking agent and abatacept.¹⁵² (See Specific Drugs under Interactions.)

Hepatitis B Virus (HBV) Reactivation

Increased risk of reactivation of HBV infection in patients who are chronic carriers of the virus (i.e., hepatitis B surface antigen-positive [HBsAg-positive]).¹ Use of multiple immunosuppressive agents may contribute to HBV reactivation.¹

Screen at-risk patients prior to initiation of therapy.¹ Evaluate and monitor HBV carriers before, during, and for up to several months after therapy.¹ Safety and efficacy of antiviral therapy for prevention of HBV reactivation not established.¹ Discontinue infliximab and initiate appropriate treatment (e.g., antiviral therapy) if HBV reactivation occurs.¹ Not known whether infliximab can be readministered once control of a reactivated HBV infection is achieved; caution advised in this situation.¹

Hepatic Effects

Severe hepatic reactions (e.g., acute liver failure, jaundice, hepatitis, cholestasis, autoimmune hepatitis) reported; some cases were fatal or needed liver transplantation.^{1 144} Hepatic reactions occurred between 2 weeks and >1 year following initiation of therapy; elevations of hepatic transaminase enzymes not observed prior to discovery of liver injury in many cases.^{1 144}

Evaluate patients with signs of liver dysfunction.^{1 144} If jaundice and/or marked hepatic aminotransferase elevations (≥5 times the ULN) develop, discontinue infliximab and investigate hepatic abnormality.¹

Malignancies and Lymphoproliferative Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Lymphoma and other malignancies (some fatal) reported during postmarketing surveillance in children and adolescents receiving TNF blocking agents, particularly in those receiving other immunosuppressive agents (e.g., azathioprine, methotrexate) concomitantly.^{1 154} Malignancies included lymphomas (about 50% of the cases) (e.g., Hodgkin’s disease, non-Hodgkin’s lymphoma) and various other malignancies (e.g., leukemia, melanoma, solid organ cancers), including rare malignancies usually associated with immunosuppression and malignancies not usually observed in children and adolescents (e.g., leiomyosarcoma, hepatic malignancies, renal cell carcinoma).^{1 154} Median time to occurrence was 30 months (range: 1–84 months) after the initial TNF blocking agent dose.¹ FDA has concluded that there is an increased risk of malignancy with TNF blocking agents in children and adolescents; however, the strength of the association is not fully characterized.¹⁵⁴

Aggressive, fatal cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, reported in patients with Crohn's disease or ulcerative colitis receiving TNF blocking agents, including infliximab.¹ Most of the patients were adolescent or young adult males; all received concomitant therapy with azathioprine or mercaptopurine at or prior to diagnosis.¹ Unclear whether occurrence is related to infliximab or combination of infliximab and other immunosuppressive agents.¹

In controlled studies, lymphoma was reported more frequently in patients receiving infliximab or other TNF blocking agents than in control patients.¹ Patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis, especially those with highly active disease and/or chronic exposure to immunosuppressive therapies, may be at increased risk of lymphoma.^{1 28 30 38 42}

Acute and chronic leukemias (some fatal) reported during postmarketing surveillance of TNF blocking agents in adults and pediatric patients, particularly in those receiving other immunosuppressive agents concomitantly.^{1 154} Leukemia (most commonly acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia) generally occurred during first 2 years of therapy.¹⁵⁴ FDA has concluded that there is a possible association between TNF blocking agents and development of leukemia; interpretation of findings is complicated because patients with rheumatoid arthritis may be at increased risk for leukemia independent of any treatment with TNF blocking agents.^{1 154}

Malignancies (mainly lung cancer or head and neck malignancies) reported in more infliximab-treated than placebo-treated patients with moderate to severe COPD†; all had been heavy smokers.^{1 157} Exercise caution when considering infliximab therapy in patients with moderate to severe COPD.¹

In infliximab-treated psoriasis patients, nonmelanoma skin cancer reported more commonly in those who had received prior phototherapy; monitor psoriasis patients, especially those who have received prolonged prior phototherapy, for nonmelanoma skin cancer.¹

Other malignancies (basal cell carcinoma, breast cancer, melanoma, colorectal cancer, rectal adenocarcinoma, squamous cell carcinoma) reported in patients receiving infliximab.^{1 14 17 141}

In controlled clinical studies of infliximab, the rate of malignancies other than lymphoma and nonmelanoma skin cancer was increased in infliximab-treated patients compared with control patients, but the rate was similar to the expected rate in the general population.¹

Role of TNF blocking agents in development of malignancies not fully determined.^{1 22 28 30 31 32 33 38 42 43 62 154 157}

Some immune related diseases (e.g., Crohn’s disease) have been shown to increase risk of cancer independent of treatment with TNF blocking agents, while for others (e.g., juvenile idiopathic arthritis) it is unknown whether there is an increased risk of cancer.¹⁵⁴

Consider possibility of and monitor for occurrence of malignancies during and following treatment with TNF blocking agents.¹⁵⁴ Exercise caution when considering use of infliximab in patients with malignancy or a history of malignancy or when considering whether to continue therapy in patients who develop a malignancy; effect on development and course of malignancies not fully evaluated.^{1 22 28 30 31 32 33 34 35 38 43 44 59 62 64}

Cardiovascular Effects

Associated with adverse outcomes in patients with heart failure (increased mortality and hospitalization due to worsening heart failure).^{1 139}

Use in patients with heart failure only after consideration of other treatment options.¹ If used in patients with moderate or severe heart failure, do not exceed doses of 5 mg/kg and monitor cardiac status closely.¹ (See Contraindications under Cautions.)

Discontinue therapy if new or worsening symptoms of heart failure occur.¹

Use in patients with heart failure (NYHA class III or IV) associated with increased mortality in patients who received infliximab 10 mg/kg and an increase in adverse cardiovascular effects (dyspnea, hypotension, angina, dizziness) in patients who received 5 or 10 mg/kg.¹ Worsening heart failure (with and without identifiable precipitating factors) and new-onset heart failure (including in patients with no known pre-existing cardiovascular disease and/or who were < 50 years of age) reported.¹ Not evaluated in patients with mild (NYHA class I or II) heart failure.¹

Hematologic Effects

Possible leukopenia, neutropenia, thrombocytopenia, and pancytopenia, sometimes with fatal outcome.¹ Use with caution in patients with a history of substantial hematologic abnormalities.¹ Consider discontinuance of the drug in patients with confirmed hematologic abnormalities.¹

Nervous System Effects

Optic neuritis, seizures, new onset or exacerbation of clinical manifestations and/or radiographic evidence of CNS demyelinating disorders, including multiple sclerosis, CNS manifestations of systemic vasculitis, and peripheral demyelinating disorders, including Guillain-Barré syndrome, reported rarely in patients receiving infliximab or other TNF blocking agents.¹

Exercise caution when considering infliximab in patients with preexisting or recent-onset CNS demyelinating disorders.¹ Consider discontinuance of the drug in patients who develop clinically important CNS adverse reactions.¹

Sensitivity Reactions

Discontinue immediately for severe hypersensitivity reaction; initiate appropriate therapy.¹ Drugs for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids, and/or epinephrine) should be immediately available.^{1 72}

Acute Infusion Reactions

Acute infusion reactions consistent with hypersensitivity reactions reported within 1–2 hours after IV infusion.^{1 10 14 18 21 36 38 41 64 72 92 128}

Signs/symptoms include urticaria, dyspnea, hypotension, fever, chills, headache, pruritus, chest pain, and/or hypertension.^{1 5 10 14 15 18 21 36 38 41 64 72 92 128 136} Anaphylactoid reactions (with laryngeal/pharyngeal edema and severe bronchospasm), anaphylaxis, seizures, and/or erythematous rash reported.^{1 36 128}

Mild acute infusion reactions often controlled by slowing or discontinuing the infusion or appropriate treatment (antihistamines).^{1 5 10 14 18 23 28 38 42 47 72 92}

Monitor patients; consider premedication; initiate infusion slowly; adjust rate or discontinue based on patient tolerance.^{47 72 47 72} (See Premedication and Patient Monitoring and also see Rate Titration Schedule Table under Dosage and Administration.)

Patients with antibodies to infliximab appear to be 2–3 times more likely to have an infusion reaction than patients who do not have antibodies to the drug.¹

Incidence of acute infusion reactions may be lower in patients receiving concomitant therapy with immunosuppressive agents (e.g., azathioprine, mercaptopurine, methotrexate) than in those not receiving such therapy.^{1 47}

Delayed Infusion Reactions

Delayed infusion reactions occur 3–12 days after an infusion and appear to be more common in patients retreated after a period of 2–4 years.^{1 10 5 40 42}

Signs/symptoms include fever, rash, pruritus, urticaria, headache, sore throat, myalgia, polyarthralgia, hand and facial edema, and/or dysphagia.^{1 10 38 40 42 136}

Delayed infusion reactions generally resolve within 1–3 days following treatment with corticosteroids, antihistamines, acetaminophen, and/or epinephrine.^{1 5 40}

Caution when retreatment follows an extended period of time (e.g., after ≥1 year).^{1 10 40 42}

Risk of delayed infusion reactions not increased in patients who have had an acute infusion reaction.^{1 40}

These reactions reported most frequently in patients who have developed infliximab-specific antibodies (human antichimeric antibodies [HACA]); reactions are associated with loss of detectable infliximab serum concentrations and possible loss of efficacy.¹ (See Immunologic Reactions and Antibody Formation under Cautions.)

Administration of an immunosuppressive agent (e.g., azathioprine, mercaptopurine, methotrexate) for ≥3 months prior to infliximab associated with a lower rate of development of HACA and a lower rate of infusion reactions.^{1 18 47 72}

Delayed hypersensitivity reactions to infliximab should be reported to the manufacturer by phone at 800-457-6399.⁴⁰

General Precautions

Immunologic Reactions and Antibody Formation

Possible formation of autoimmune antibodies.^{1 14 17 18 19 20 23 28 34 35 38 41 44 64 90 136} Lupus-like syndrome reported.¹ If manifestations suggestive of lupus-like syndrome develop, discontinue infliximab.¹

Antibodies to infliximab may develop.^{1 22 42 28 38 64 70 84 85} Antibody-positive patients more likely to experience an infusion reaction.^{1 10 23 70 85} (See Sensitivity Reactions under Cautions.)

Immunization

Avoid live vaccines (e.g., measles virus vaccine live, mumps virus vaccine live, rubella virus vaccine live, smallpox vaccine, typhoid vaccine live oral, varicella virus vaccine live, yellow fever vaccine).¹ (See Vaccines under Interactions.)

GI Effects

Safety and efficacy data in Crohn’s disease patients with intestinal strictures is limited.^{4 5 38 72 88} Development or worsening of intestinal strictures and/or intestinal obstruction reported rarely in these patients.^{4 47 70}

Use with caution in Crohn’s disease patients with intestinal strictures.^{47 70 72}

Psoriasis

New-onset psoriasis, including pustular and palmoplantar psoriasis, reported with TNF blocking agents, including infliximab.^{1 154} Onset observed weeks to years following initiation of drug.¹⁵⁴ Some patients required hospitalization.¹⁵⁴ Most patients experienced improvement following discontinuance of the TNF blocking agent.¹⁵⁴ FDA has concluded that there is a possible association between use of TNF blocking agents and development of psoriasis.¹⁵⁴

Exacerbation of existing psoriasis also reported.¹

Consider possibility of and monitor for manifestations (e.g., new rash) of new or worsening psoriasis, particularly pustular and palmoplantar psoriasis.¹⁵⁴

Specific Populations

Pregnancy

Category B.¹

Some clinicians suggest that pregnancy be ruled out (negative pregnancy test) before initiating therapy and that an effective contraceptive be used.¹¹⁰

Lactation

Not known whether infliximab is distributed into milk.¹ Due to potential risk in nursing infant, discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy established in children ≥6 years of age with Crohn’s disease; studied in this age group only in conjunction with conventional immunosuppressive agents.¹ Safety and efficacy of long-term (>1 year) therapy not established.¹

Safety and efficacy not established in children with ulcerative colitis or plaque psoriasis.¹

Has been evaluated in children 4–17 years of age with juvenile arthritis† who had not responded adequately to methotrexate.^{1 153} Further study needed to evaluate safety and efficacy.^{1 72 104 153}

Bring all vaccinations up to date prior to initiation of therapy in children with Crohn’s disease.¹

Adverse effects reported more frequently in children than in adults with Crohn’s disease include anemia, blood in stool, leukopenia, flushing, viral infection, neutropenia, bone fracture, infection, bacterial infection, and respiratory tract allergy.¹

Malignancies, some fatal, reported in children and adolescents who received TNF blocking agents.¹