Tivorbex

Indomethacin comes as a capsule, an extended-release (long-acting) capsule, and a suspension to take by mouth and as a suppository to be used rectally. Indomethacin capsules and liquid usually are taken two to four times a day. Indomethacin suppositories usually are used two to four times daily. Extended-release capsules are usually taken one or two times a day. Indomethacin capsules, extended-release capsules, and suspension should be taken with food, immediately after meals, or with antacids. Take indomethacin at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take indomethacin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the extended-release capsules whole; do not split, chew, or crush them.

Shake the suspension well before each use to mix the medication evenly.

Your doctor may change the dose of your medication during your treatment. In some cases, your doctor may start you on a low dose of indomethacin and gradually increase your dose, not more often than once a week. In other cases, your doctor may start you on an average dose of indomethacin and decrease your dose once your symptoms are controlled. Follow these directions carefully and ask your doctor or pharmacist if you have any questions.

To use indomethacin suppositories, follow these steps:

1. Remove the wrapper.
2. Dip the tip of the suppository in water.
3. Lie down on your left side and raise your right knee to your chest. (A left-handed person should lie on the right side and raise the left knee.)
4. Using your finger, insert the suppository about 1 inch (2.5 centimeters) into the rectum. Hold it in place for a few moments.
5. Stand up after about 15 minutes. Wash your hands thoroughly and resume your normal activities.
6. You should try to keep the suppository in place and avoid having a bowel movement for 1 hour after you insert the suppository.

Before taking indomethacin,

• tell your doctor and pharmacist if you are allergic to indomethacin, aspirin or other NSAIDs such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn), any other medications, or any of the inactive ingredients in indomethacin capsules, suspension, extended release capsules, or suppositories. Ask your pharmacist for a list of the inactive ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin, in Lotrel), captopril, enalapril (Vasotec, in Vaseretic), fosinopril, lisinopril (in Zestoretic), moexipril (Univasc, in Uniretic), perindopril (Aceon, in Prestalia), quinapril (Accupril, in Accuretic, in Quinaretic), ramipril (Altace), and trandolapril (Mavik, in Tarka); angiotensin receptor blockers such as candesartan (Atacand, in Atacand HCT), eprosartan (Teveten), irbesartan (Avapro, in Avalide), losartan (Cozaar. in Hyzaar), olmesartan (Benicar, in Azor, in Benicar HCT, in Tribenzor), telmisartan (Micardis, in Micardis HCT, in Twynsta), and valsartan (in Diovan HCT, in Exforge); beta blockers such as atenolol (Tenormin, in Tenoretic), labetalol (Trandate), metoprolol (Lopressor, Toprol XL, in Dutoprol), nadolol (Corgard, in Corzide), and propranolol (Hemangeol, Inderal, Innopran); cyclosporine (Gengraf, Neoral, Sandimmune); digoxin (Lanoxin); diuretics ('water pills') such as triamterene (Dyrenium, in Dyazide); lithium (Lithobid); methotrexate (Otrexup, Rasuvo, Trexall); phenytoin (Dilantin, Phenytek); and probenecid (Probalan, in Col-Probenecid). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had asthma, especially if you also have frequent stuffed or runny nose or nasal polyps (swelling of the lining of the nose); heart failure; seizures; Parkinson's disease; depression or mental illness; or liver or kidney disease. If you will be using indomethacin suppositories, also tell your doctor if you have or have ever had proctitis (inflammation of the rectum) or have or have recently had rectal bleeding.
• tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy; you plan to become pregnant; or you are breastfeeding. If you become pregnant while taking indomethacin, call your doctor.
• talk to your doctor about the risks and benefits of taking indomethacin if you are 65 years of age or older. Older adults should not usually take indomethacin because it is not as safe as other medications that can be used to treat the same condition.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking indomethacin.
• you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
• talk to your doctor about the safe use of alcohol during your treatment with indomethacin. Alcohol can make the side effects of indomethacin worse.

Follow all directions on your prescription label. Do not take this medicine in larger amounts or for longer than recommended. Use the lowest dose that is effective in treating your condition.

Do not crush, chew, break, or open an extended-release capsule. Swallow it whole.

If you take indomethacin for a long period of time, your doctor may want to check you on a regular basis to make sure this medicine is not causing harmful effects.

Store at room temperature away from moisture and heat. Do not allow the liquid medicine to freeze.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include vomiting, severe headache, dizziness, confusion, numbness, tingling, or seizure (convulsions).

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Oral:

Take oral indomethacin exactly as prescribed.

This medication comes in oral suspension, capsule, and extended release capsule forms and is taken two or three times a day, with food.

Do not chew, divide, or break extended release indomethacin capsules. Swallow these capsules whole.

Topical:

Use indomethacin suppositories exactly as prescribed.

This medication comes in rectal suppository form and is used two or three times a day.

Injectable:

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of indomethacin at the same time.

Store indomethacin at room temperature (or whichever proper storage method applies).

Keep this and all medicines out of the reach of children.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include vomiting, severe headache, dizziness, confusion, numbness, tingling, or seizure (convulsions).

Avoid drinking alcohol. It may increase your risk of stomach bleeding.

Avoid taking aspirin while you are taking indomethacin.

Ask a doctor or pharmacist before using any cold, allergy, or pain medicine. Many medicines available over the counter contain aspirin or other medicines similar to indomethacin. Taking certain products together can cause you to get too much of this type of medication. Check the label to see if a medicine contains aspirin, ibuprofen, ketoprofen, or naproxen.

Get emergency medical help if you have signs of an allergic reaction: sneezing, runny or stuffy nose; wheezing or trouble breathing; hives; swelling of your face, lips, tongue, or throat.

Get emergency medical help if you have signs of a heart attack or stroke: chest pain spreading to your jaw or shoulder, sudden numbness or weakness on one side of the body, slurred speech, feeling short of breath.

Stop using indomethacin and call your doctor at once if you have:

• changes in your vision;

• shortness of breath (even with mild exertion);

• swelling or rapid weight gain;

• the first sign of any skin rash, no matter how mild;

• signs of stomach bleeding--bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;

• liver problems--nausea, upper stomach pain, itching, tired feeling, flu-like symptoms, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• kidney problems--little or no urinating, painful or difficult urination, swelling in your feet or ankles, feeling tired or short of breath;

• low red blood cells (anemia)--pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• upset stomach, nausea, vomiting;

• diarrhea, constipation;

• headache, dizziness, drowsiness;

• feeling tired or depressed; or

• ringing in your ears.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tivorbex (indomethacin) Capsules 20 mg – dark blue body and light blue cap (imprinted IP-201 on the body and 20 mg on the cap in white ink).

Tivorbex (indomethacin) Capsules 40 mg – dark blue body and blue cap (imprinted IP-202 on the body and 40 mg on the cap in white ink).

See Table 2 for clinically significant drug interactions with indomethacin.

Effects on Laboratory Tests

Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.

False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.

Tivorbex (indomethacin) capsule is a nonsteroidal anti-inflammatory drug, available as hard gelatin capsules of 20 mg and 40 mg for oral administration. The chemical name is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The molecular weight is 357.8. Its molecular formula is C19H16ClNO4, and it has the following chemical structure.

Indomethacin is a white to yellow crystalline powder. It is practically insoluble in water and sparingly soluble in alcohol. Indomethacin has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali.

The inactive ingredients in Tivorbex include: lactose monohydrate, sodium lauryl sulfate, microcrystalline cellulose, croscarmellose sodium and sodium stearyl fumarate. The capsule shells contain gelatin, titanium dioxide, and dyes FD&C blue #1, FD&C blue #2 and FD&C red #40. The imprinting on the gelatin capsules is white edible ink. The 20 mg capsules have a dark blue body imprinted with IP-201 and light blue cap imprinted with 20 mg in white ink. The 40 mg capsules have a dark blue body imprinted with IP-202 and blue cap imprinted with 40 mg in white ink.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.08 times the MRHD on a mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.06 times [mice] and 0.12 times [rats] the MRHD on a mg/m2 basis, respectively).

Mutagenesis

Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.

Impairment of Fertility

Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.02 times the MRHD on a mg/m2 basis) or a two litter reproduction study in rats (0.04 times the MRHD on a mg/m2 basis).