Propylthiouracil

REMEDYREPACK INC.

PROPYLTHIOURACIL TABLETS, USP

FULL PRESCRIBING INFORMATION: CONTENTS*

• SPL UNCLASSIFIED
• BOXED WARNING
• PROPYLTHIOURACIL DESCRIPTION
• CLINICAL PHARMACOLOGY
• INDICATIONS & USAGE
• PROPYLTHIOURACIL CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
• PROPYLTHIOURACIL ADVERSE REACTIONS
• OVERDOSAGE
• DOSAGE & ADMINISTRATION
• HOW SUPPLIED
• SPL MEDGUIDE
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

FULL PRESCRIBING INFORMATION

SPL UNCLASSIFIED

Rev. 08/11

Rx Only

PROPYLTHIOURACIL DESCRIPTION

Propylthiouracil (6-propyl-2-thiouracil) is one of the thiocarbamide compounds. It is a white, crystalline substance that has a bitter taste and is very slightly soluble in water.

Propylthiouracil is an antithyroid drug administered orally. The structural formula is:

Each tablet contains propylthiouracil 50 mg and the following inactive ingredients: anhydrous lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Propylthiouracil inhibits the synthesis of thyroid hormones and thus is effective in the treatment of hyperthyroidism. The drug does not inactivate existing thyroxine and triodothyronine that are stored in the thyroid or circulating in the blood, nor does it interfere with the effectiveness of thyroid hormones given by mouth or by injection. Propylthiouracil inhibits the conversation of thyroxine to triiodothyronine to peripheral tissues and may therefore be an effective treatment for thyroid storm.

Propylthiouracil is readily absorbed and is extensively metabolized. Approximately 35% of the drug is excreted in the urine, in intact and in conjugated forms, within 24 hours.

INDICATIONS & USAGE

Propylthiouracil is indicated:

• in patients with Graves' disease with hyperthyroidism or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option.
• to ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole.

PROPYLTHIOURACIL CONTRAINDICATIONS

Propylthiouracil is contraindicated in patients who have demonstrated hypersensitivity to the drug or any of the other product components.

WARNINGS

.

Liver injury resulting in liver failure, liver transplantation, or death, has been reported with propylthiouracil therapy in adult and pediatric patients. No cases of liver failure have been reported with the use of methimazole in pediatric patients. For this reason, propylthiouracil is not recommended for pediatric patients except when methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate therapies.

There are cases of liver injury, including liver faillure and death, in women treated with propylthiouracil during pregnancy. Two reports of in utero exposure with liver failure and death of a newborn have been reported. The use of an alternative antithyroid medication (e.g., methimazole) may be advisable following the first trimester of pregnancy (see PRECAUTIONS, Pregnancy).

Biochemical monitoring of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT, AST) is not expected to attenuate the risk of severe liver injury due to its rapid and unpredictable onset. Patients should be informed of the risk of liver failure. Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, right upper quadrant pain, etc.) particularly in the first six months of therapy. When these symptoms occur, propylthouracil should be discontinued immediately and liver function tests and ALT and AST levels obtained.

Agranulocytosis occurs in approximately 0.2% to 0.5% of patients and is a potentially llife-threatening side effect of propylthiouracil therapy. Agranulocytosis typically occurs within the first 3 months of therapy. Patients should be instructed to immediately report any symptoms suggestive of agranulocytosis, such as fever or sore throat. Leukopenia, thrombocytopenia, and aplastic anemia (pancytopenia) may also occur. Propylthiouracil should be discontinued if agranulocytosis, aplastic anemia (pancytopenia), ANCA-positive vasculitis, hepatitis, interstitial pneumonitis, fever, or exfoliative dermatitis is suspected, and the patient's bone marrow indices should be obtained.

Propylthiouracil can cause hypothyroidism necessitating routine monitoring of TSH and free T4 levels with adjustments in dosing to maintain a euthyroid state. Because the drug readily crosses placental membranes, propylthiouracil can cause fetal goiter and cretinism when administered to a pregnant woman (see PRECAUTIONS, Pregnancy).

PRECAUTIONS

Patients should be instructed to report any symptoms of hepatic dysfunction (anorexia, pruritus, jau7ndice, light colored stools, dark urine, right upper quadrant pain, etc.), particularly in the first six months of therapy. When these symptoms occur, measurement should be made of liver function (bilirubin, alkaline phosphatase) and hepatocellular integrity (ALT/AST levels).

Patients who receive propylthiouracil should be under close surveillance and should be counseled regarding the necessity of reporting any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. In such cases, white blood cell and differential counts should be obtained to determine whether agranulocytosis has developed. Particular care should be exercised with patients who are receiving concomitant drugs known to be associated with agranulocytosis.

Patients should be advised that if they become pregnant or intend to become pregnant white taking an antithyroid drug, they should contact their physician immediately about their therapy.

Patients should report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise. They also should report symptoms suggestive of hepatic dysfunction (anorexia, pruritis, right upper quadrant pain, etc).

Because propylthiouracil may cause hypoprothrombinemia and bleeding, monitoring of prothrombin time should be considered during therapy with the drug, especially before surgical procedures.

Thyroid function tests should be monitored periodically during therapy. Once clinical evidence of hyperthyroidism has resolved, the finding of an elevated serum TSH indicates that a lower maintenance dose of propylthiouracil should be employed.

Due to the potential inhibition of vitamin K activity by propylthiouracil, the activity of oral anticoagulants (e.g., warfarin) may be increased; additional monitoring of PT/INR should be considered, especially before surgical procedures.

Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A reduced dose of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid.

Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be needed.

Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.

Laboratory animals treated with propylthiouracil for > 1 year have demonstrated thyroid hyperplasia and carcinoma formation¹. Such animal findings are seen with continuous suppression of thyroid function by sufficient doses of a variety of antithyroid agents, as well as in dietary iodine deficiency, subtotal thyroidectomy, and implantation of autonomous thyrotropic hormone - secreting pituitary tumors. Pituitary adenomas have also been described.

Pregnancy Category D. SEE WARNINGS.

Propylthiouracil is transferred to breasdt milk to a small extent and therefore likely results in clinically insignificant doses to the suckling infant. One one study, nine lactating women were administered 400 mg of propylthiouracil by mouth. The mean amount of propylthiouracil excreted during 4 hours after drug administration was 0.025% of the administered dose.

Post-marketing reports of severe liver injury including hepatic failure requiring liver transplantation or resulting in death have been reported in the pediatric population. No such reports have been observed with methimazole. As such, propylthiouracil is not recommended for use in the pediatric population except in rare instances in which methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate.

When used in children, parents and patients should be informed of the risk of liver failure. If patients taking propylthiouracil develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, propylthiouracil should be discontinued immediately by the patient, a physician should be contacted, and a white blood cell count, liver function tests, and transaminase levels obtained.

PROPYLTHIOURACIL ADVERSE REACTIONS

Major adverse reactions (much less common than the minor adverse reactions) include liver injury resulting in hepatitis, liver failure, a need for liver transplantation or death. Inhibition of myelopoiesis (agranulocytosis, granulopenia, and thrombocytopenia), aplastic anemia, drug fever, a lupus-like syndrome (including splenomegaly and vasculitis), hepatitis, periartentis, and hypoprothrombinemia and bleeding have been reported. Nephritis, glomerulonephritis, interstitial pneumonitis, exfoliative dermatitis, and erythema nodosum have been reported. Reports of a vasculitis syndrome associated with the presence of anti-neutrophilic cytoplasmic antibodies (ANCA) have also been received. Manifestations of ANCA-positive vasculitis may include rapidly progressive glomerulonephritis (crescentic and pauci-immune necrotizing glomerulonephritis), sometimes leading to acute renal failure; pulmonary infiltrates or alveolar hemorrhage; skin ulcers; and leucocytoclastic vasculitis. Minor adverse reactions include skin rash, urticaria, nausea, vomiting, epigastric distress, arthralgia, paresthesias, loss of taste, taste perversion, abnormal Ioss of hair, myalgia, headache, pruritus, drowsiness, neuritis, edema, vertigo, skin pigmentation, jaundice, sialadenopathy, and lymphadenopathy.

It should be noted that about 10% of patients with untreated hyperthyroidism have leukopenia (white blood cell count of less than 4,000/mm³), often with relative granulopenia.

To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Nausea, vomiting, epigastric distress, headache, fever, arthralgia, pruritus, edema, and pancytopenia. Agranulocytosis is the most serious effect. Rarely, exfoliative dermatitis, hepatitis, neuropathies, or CNS stimulation or depression may occur.

No information is available on the following: LD₅₀: concentration of propylthiouracil in biologic fluids associated with toxicity and/or death; the amount of drug in a single dose usually associated with symptoms of overdosage; or the amount of propylthiouracil in a single dose likely to be life-threatening.

To obtain up-to-date information about the treatment of overdose, a good resource is the certified Regional Poison Control Center. In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's medical status.

DOSAGE & ADMINISTRATION

Propylthiouracil is administered orally. The total daily dosage is usually given in 3 equal doses at approximately 8-hour intervals.

The initial dose is 300 mg daily. In patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg daily; an occasional patient will require 600 to 900 mg daily initially. The usual maintenance dose is 100 to 150 mg daily. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Propylthiouracil is generally not recommended for use in the pediatric patient population except in rare instances in which other alternative therapies are not appropriate options. Studies evaluating appropriate dosing regimen have not been conducted in the pediatric population although general practice would suggest initiation of therapy in patients 6 years or older at a dosage of 50 mg daily with careful upward titration based on clinical response and evaluation of TSH and free T4 levels. Although cases of severe liver injury have been reported with doses as low as 50 mg/day, most cases were associated with doses of 300 mg/day and higher.

Clinical studies of propylthiouracil 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, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED

Propylthiouracil Tablets, USP, 50 mg: White, Round, Scored Tablet, Debossed “West-ward 480”.

•   Bottles of 100 tablets.
•   Bottles of 1000 tablets.
•   Unit Dose Boxes of 100 tablets.

Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Reference:

• International Agency for Research on Cancer, IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 1974; 7:67-76.

Manufactured By:
West-ward Pharmaceutical Corp.
Eatontown, NJ 07724
Revised August 2011

SPL MEDGUIDE

PROPYLTHIOURACIL TABLETS, USP (Pro-pil-thi-o-ur-a-sil)

Read this Medication Guide before you start taking Propylthiouracil and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about Propylthiouracil?
Propythiouracil can cause serious side effects, including:
Severe liver problems. In some cases, these liver problems can lead to liver failure, the need for liver transplant, or death.

Stop taking Propylthiouracil and call your doctor right away if you have:

• fever
• loss of appetite
• nausea
• vomiting
• tiredness
• itchiness
• pain or tenderness in your right upper stomach area (abdomen)
• dark (tea colored) urine
• pale or light colored bowel movements (stools)
• yellowing of your skin or whites of your eyes

What is Propylthiouracil?
Propylthiouracil is a prescription medicine used to treat people who have Graves' disease with hyperthyroidism or toxic multinodular goiter. Propylthiouracil is used when:

• certain other antithyroid medicines do not work well.
• thyroid surgery or radioactive iodine therapy is not a treatment option.
• to decrease symptoms of hyperthyroidism in preparation for a thyroidectomy (removal of the thyroid gland) or radioactive iodine therapy.

Propylthiouracil is not recommended for use in children.

Propylthiouracil may be used when an antithyroid drug is needed during or just before the first trimester of pregnancy.

Who should not take Propylthiouracil?
Do not take Propylthiouracil if you are allergic to Propylthiouracil or any of its ingredients. See the end of this Medication Guide for a complete list of ingredients in Propylthiouracil.

What should I tell my doctor before taking Propylthiouracil?
Before you take Propylthiouracil, tell your doctor if you:

• plan to have surgery.
• have any other medical conditions.
• are pregnant or plan to become pregnant.
  • Propylthiouracil may cause liver problems, liver failure and death in pregnant women.
  • Propylthiouracil may harm your unborn baby.
• are breast-feeding or plan to breast-feed. Propylthiouracil can pass into your breast milk. Talk to you doctor about the best way to feed your baby if you take Propylthiouracil.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Propylthiouracil may affect the way other medicines work.

Especially, tell your doctor if you take:

• a blood thinner medicine warfarin sodium (Coumadin, Jantoven)
• medicine for heart problems
• medicine for high blood pressure
• Digoxin (Lanoxicaps, Lanoxin)
• Theophylline (Elixophyllin, Theolair, Theochron, Theo-24, Uniphyl)

Ask your doctor if you are not sure if your medicine is one of these.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take Propylthiouracil?

• Take Propylthiouracil exactly as your doctor tells you to take it.
• Your doctor may change your dose if needed.
• Propylthiouracil is usually taken 3 times a day (every 8 hours).
• If you take too much Propylthiouracil, call your Regional Poison Control Center or go to the nearest hospital emergency room right away.
• If you take too much Propylthiouracil you may have the following symptoms:
  • nausea
  • vomiting
  • upper stomach pain or tenderness
  • headache
  • fever
  • joint pain
  • swelling of your body, arms, and legs
• If you miss a dose of Propylthiouracil, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not double your dose.

What are the possible side effects of Propylthiouracil?
Propylthiouracil may cause serious side effects, including:

• liver problems. See "What is the most important information I should know about Propylthiouracil?"
• low white blood cell counts. This usually happens within the first 3 months of treatment and can be life-threatening. You may have a higher chance of getting an infection when your white blood cell count is low.

Tell your doctor right away if you have:

• a fever
• chills
• sore throat
• hypothyroidism. Your doctor should do blood tests regularly during treatment to check your thyroid.
• increased bleeding especially with surgical procedures and particularly if you are taking blood thinners.

The most common side effects of Propylthiouracil include:

• skin rash or hives
• nausea
• vomiting
• upper stomach pain or tenderness
• joint pain
• itching or tingling
• loss or change in taste
• loss of hair
• muscle pain
• headache
• sleepiness
• nerve pain
• swelling (edema)
• dizziness
• enlarged salivary glands or enlarged lymph nodes

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Propylthiouracil. For more information, ask your doctor or pharmacist.

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

How should I store Propylthiouracil?
Store at 20-25ºC (68-77ºF) [See USP Controlled Room Temperature].
Keep Propylthiouracil and all medicines out of the reach of children.

General information about the sale and effective use of Propylthiouracil:
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use Propylthiouracil for a condition for which it was not prescribed.
Do not give Propylthiouracil to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Propylthiouracil. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Propylthiouracil that is written for health professionals.

West-ward Pharmaceutical Corp.
www.west-ward.com
1-877-233-2001

What are the ingredients in Propylthiouracil?
Active ingredient: propylthiouracil
Inactive ingredients: anhydrous lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate.

West-ward Pharmaceutical Corp.
Eatontown, NJ 07724 USA

This Medication Guide has been approved by the U.S. Food and Drug Administration.
04/2010

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION