Thiotepa for Injection USP is an ethylenimine-type compound. It is supplied as a non-pyrogenic, sterile Iyophilized powder for intravenous, intracavitary or intravesical administration, containing 15 mg of thiotepa. Thiotepa is a synthetic product with antitumor activity. The chemical name for thiotepa is Tris (1-aziridinyl) phosphine sulfide. Thiotepa has the following structural formula:

Thiotepa has the molecular formula C₆H₁₂N₃PS, and a molecular weight of 189.22. When reconstituted with Sterile Water for Injection, the resulting solution has a pH of approximately 5.5 to 7.5. Thiotepa is stable in alkaline medium and unstable in acid medium.

Last updated on RxList: 11/20/2008

Thiotepa has been tried with varying results in the palliation of a wide variety of neoplastic diseases. However, the most consistent results have been seen in the following tumors:

1. Adenocarcinoma of the breast.
2. Adenocarcinoma of the ovary.
3. For controlling intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities.
4. For the treatment of superficial papillary carcinoma of the urinary bladder.

While now largely superseded by other treatments, thiotepa has been effective against other lymphomas, such as lymphosarcoma and Hodgkin's disease.

Since absorption from the gastrointestinal tract is variable, thiotepa should not be administered orally.

Dosage must be carefully individualized. A slow response to thiotepa does not necessarily indicate a lack of effect. Therefore, increasing the frequency of dosing may only increase toxicity. After maximum benefit is obtained by initial therapy, it is necessary to continue the patient on maintenance therapy (1 to 4 week intervals). In order to continue optimal effect, maintenance doses should not be administered more frequently than weekly in order to preserve correlation between dose and blood counts.

Preparation and Administration Precautions: Thiotepa is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised in handling and preparation of thiotepa. Skin reactions associated with accidental exposure to thiotepa may occur. The use of gloves is recommended. If thiotepa solution contacts the skin, immediately wash the skin thoroughly with soap and water. If thiotepa contacts mucous membranes, the membranes should be flushed thoroughly with water.

Preparation of Solution: Thiotepa for injection should be reconstituted with 1.5 mL of Sterile Water for Injection resulting in a drug concentration of approximately 10 mg/mL. The actual withdrawable quantities and concentration achieved are illustrated in the following table:

The reconstituted solution is hypotonic and should be further diluted with Sodium Chloride Injection (0. 9% sodium chloride) before use.

When reconstituted with Sterile Water for Injection, solutions of thiotepa should be stored in a refrigerator and used within 8 hours. Reconstituted solutions further diluted with Sodium Chloride Injection should be used immediately.

In order to eliminate haze, filter solutions through a 0.22 micron filter* prior to adminstration. Filtering does not alter solution potency. Reconstituted solutions should be clear. Solutions that remain opaque or precipitate after filtration should not be used.

*Polysulfone membrane (Gelman's Sterile Aerodisc®, Single Use) or triton-free mixed ester of cellulose/PVC (Millipore's MILLEX®-GS Filter Unit).

Initial and Maintenance Doses: Initially the higher dose in the given range is commonly administered. The maintenance dose should be adjusted weekly on the basis of pretreatment control blood counts and subsequent blood counts.

Intravenous Administration: Thiotepa may be given by rapid intravenous administration in doses of 0.3 to 0.4 mg/kg. Doses should be given at 1 to 4 week intervals.

Intracavitary Administration: The dosage recommended is 0.6 to 0.8 mg/kg. Administration is usually effected through the same tubing which is used to remove the fluid from the cavity involved.

Intravesical Administration: Patients with papillary carcinoma of the bladder are dehydrated for 8 to 12 hours prior to treatment. Then 60 mg of thiotepa in 30 to 60 mL of Sodium Chloride Injection is instilled into the bladder by catheter. For maximum effect, the solution should be retained for 2 hours. If the patient finds it impossible to retain 60 mL for 2 hours, the dose may be given in a volume of 30 mL. If desired, the patient may be positioned every 15 minutes for maximum area contact. The usual course of treatment is once a week for 4 weeks. The course may be repeated if necessary, but second and third courses must be given with caution since bone-marrow depression may be increased. Deaths have occurred after intravesical administration, caused by bone-marrow depression from systemically absorbed drug.

Handling and Disposal: Follow safe cytotoxic agent handling procedures. Several guidelines on this subject have been published.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of nonpyrogenic, sterile lyophilized powder, supplied as follows:

NDC 55390-030-10. Unit carton contains 1 x 15 mg single dose vial thiotepa.

Store in a refrigerator between 2° to 8°C (36° to 46°F). PROTECT FROM LIGHT AT ALL TIMES.

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146. Manufactured for: Bedford Laboratories, Bedford, OH 44146. April 2001. FDA Rev date: 4/2/200

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.

2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985; 253(11):1590-1592.

3. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

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

5. Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. Ca - A Cancer Journal for Clinicians. Sept/Oct 1983; 258-263.

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

7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES). AM J Health-Syst Pharm. 1996:53:1669-1685.

Last updated on RxList: 11/20/2008

In addition to its effect on the blood-forming elements (see WARNINGS and PRECAUTIONS sections), thiotepa may cause other adverse reactions.

General: Fatigue, weakness. Febrile reaction and discharge from a subcutaneous lesion may occur as the result of breakdown of tumor tissue.

Hypersensitivity Reactions: Allergic reactions - rash, urticaria, laryngeal edema, asthma, anaphylactic shock, wheezing.

Local Reactions: Contact dermatitis, pain at the injection site.

Gastrointestinal: Nausea, vomiting, abdominal pain, anorexia.

Renal: Dysuria, urinary retention. There have been rare reports of chemical cystitis or hemorrhagic cystitis following intravesical, but not parenteral administration of thiotepa.

Respiratory: Prolonged apnea has been reported when succinylcholine was administered prior to surgery, following combined use of thiotepa and other anticancer agents. It was theorized that this was caused by decrease of pseudocholinesterase activity caused by the anticancer drugs.

Neurologic: Dizziness, headache, blurred vision.

Skin: Dermatitis, alopecia. Skin depigmentation has been reported following topical use.

Special Senses: Conjunctivitis.

Reproductive: Amenorrhea, interference with spermatogenesis.

It is not advisable to combine, simultaneously or sequentially, cancer chemotherapeutic agents or a cancer chemotherapeutic agent and a therapeutic modality having the same mechanism of action. Therefore, thiotepa combined with other alkylating agents such as nitrogen mustard or cyclophosphamide or thiotepa combined with irradiation would serve to intensify toxicity rather than to enhance therapeutic response. If these agents must follow each other, it is important that recovery from the first agent, as indicated by white blood cell count, be complete before therapy with the second agent is instituted.

Other drugs which are known to produce bone-marrow depression should be avoided.

Last updated on RxList: 11/20/2008

Death has occurred after intravesical administration, caused by bone-marrow depression from systematically absorbed drug.

Death from septicemia and hemorrhage has occurred as a direct result of hematopoietic depression by thiotepa.

Thiotepa is highly toxic to the hematopoietic system. A rapidly falling white blood cell or platelet count indicates the necessity for discontinuing or reducing the dosage of thiotepa. Weekly blood and platelet counts are recommended during therapy and for at least 3 weeks after therapy has been discontinued.

Thiotepa can cause fetal harm when administered to a pregnant woman. Thiotepa given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m²), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m²), based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21 mg/m²), approximately equal to the maximum recommended human therapeutic dose, based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m²), approximately two times the maximum recommended human therapeutic dose based on body-surface area.

Effective contraception should be used during thiotepa therapy if either the patient or partner is of childbearing potential. There are no adequate and well-controlled studies in pregnant women. If thiotepa is used during pregnancy, or if pregnancy occurs during thiotepa therapy, the patient and partner should be apprised of the potential hazard to the fetus.

Thiotepa is a polyfunctional alkylating agent, capable of cross-linking the DNA within a cell and changing its nature. The replication of the cell is, therefore, altered, and thiotepa may be described as mutagenic. An in vitro study has shown that it causes chromosomal aberrations of the chromatid type and that the frequency of induced aberrations increases with the age of the subject.

Like many alkylating agents, thiotepa has been reported to be carcinogenic when administered to laboratory animals. Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. In patients treated with thiotepa, cases of myelodysplastic syndromes and acute non-lymphocytic leukemia have been reported.

General

The serious complication of excessive thiotepa therapy, or sensitivity to the effects of thiotepa, is bone-marrow depression. If proper precautions are not observed thiotepa may cause leukopenia, thrombocytopenia, and anemia.

Laboratory Tests

The most reliable guide to thiotepa toxicity is the white blood cell count. If this falls to 3000 or less, the dose should be discontinued. Another good index of thiotepa toxicity is the platelet count; if this falls to 150,000, therapy should be discontinued. Red blood cell count is a less accurate indicator of thiotepa toxicity. If the drug is used in patients with hepatic or renal damage (see CONTRAINDICATIONS section), regular assessment of hepatic and renal function tests are indicated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Also see WARNINGS section.

Carcinogenesis

In mice, repeated IP administration of thiotepa (1.15 or 2.3 mg/kg three times per week for 52 or 43 weeks, respectively) produced a significant increase in the combined incidence of squamous-cell carcinomas of the skin, preputial gland, and ear canal, and combined incidence of lymphoma and lymphocytic leukemia. In other studies in mice, repeated IP administration of thiotepa (4 or 8 mg/kg three times per week for 4 weeks followed by a 20-week observation period or 1.8 mg/kg three times per week for 4 weeks followed by a 35-week observation period) resulted in an increased incidence of lung tumors. In rats, repeated IP administration of thiotepa (0.7 or 1.4 mg/kg three times per week for 52 or 34 weeks, respectively) produced significant increases in the incidence of squamous-cell carcinomas of the skin or ear canal, combined hematopoietic neoplasms, and uterine adenocarcinomas. Thiotepa given intravenously (IV) to rats (1 mg/kg once per week for 52 weeks) produced an increased incidence of malignant tumors (abdominal cavity sarcoma, lymphosarcoma myelosis, seminoma, fibrosarcoma, salivary gland hemangioendothelioma, mammary sarcoma, pheochromocytoma) and benign tumors.

The lowest reported carcinogenic dose in mice (1.15 mg/kg, 3.68 mg/m²) is approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area. The lowest reported carcinogenic dose in rats (0.7 mg/kg, 4.9 mg/m²) is approximately 6-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Mutagenesis

Thiotepa was mutagenic in in vitro assays in Salmonella typhimurium, E coli, Chinese hamster lung and human lymphocytes. Chromosomal aberrations and sister chromatid exchanges were observed in vitro with thiotepa in bean root tips, human lymphocytes, Chinese hamster lung, and monkey lymphocytes. Mutations were observed with oral thiotepa in mouse at doses > 2.5 mg/kg (8 mg/m²). The mouse micronucleus test was positive with IP administration of > 1 mg/kg (3.2 mg/m²). Other positive in vivo chromosomal aberration or mutation assays included Drosophila melanogaster, Chinese hamster marrow, murine marrow, monkey lymphocyte, and murine germ cell.

Impairment of Fertility

Thiotepa impaired fertility in male mice at PO or IP doses ≥ 0.7 mg/kg (2.24 mg/m²), approximately 12-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa (0.5 mg) inhibited implantation in female rats when instilled into the uterine cavity. Thiotepa interfered with spermatogenesis in mice at IP doses ≥ 0.5 mg/kg (1.6 mg/m²), approximately 17-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa interfered with spermatogenesis in hamsters at an IP dose of 1 mg/kg (4.1 mg/m²), approximately 7-fold less than the maximum recommended human therapeutic dose based on body-surface area.

Pregnancy: Teratagenic Effects - Category D

See WARNINGS section.

Thiotepa can cause fetal harm when administered to a pregnant woman. Thiotepa given by the IP route was teratogenic in mice at doses ≥ 1 mg/kg (3.2 mg/m²), approximately 8-fold less than the maximum recommended human therapeutic dose based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥ 3 mg/kg (21 mg/m²), approximately equal to the maximum recommended human therapeutic dose based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m²), approximately 2 times the maximum recommended human therapeutic dose based on body-surface area. Patients of childbearing potential should be advised to avoid pregnancy. There are no adequate and well-controlled studies in pregnant women. If thiotepa is used during pregnancy, or if pregnancy occurs during thiotepa therapy, the patient and partner should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether thiotepa is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for thiotepa in animal studies, 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

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of thiotepa did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects, and 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 decreasing hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Last updated on RxList: 11/20/2008

Hematopoietic toxicity can occur following overdose, manifested by a decrease in the white cell count and/or platelets. Red blood cell count is a less accurate indicator of thiotepa toxicity. Bleeding manifestations may develop. The patient may become more vulnerable to infection, and less able to combat such infection.

Dosages within and minimally above the recommended therapeutic doses have been associated with potentially life-threatening hematopoi-etic toxicity. Thiotepa has a toxic effect on the hematopoietic system that is dose related.

Thiotepa is dialyzable.

There is no known antidote for overdosage with thiotepa. Transfusions of whole blood or platelets have proven beneficial to the patient in combating hematopoietic toxicity.

Thiotepa is contraindicated in patients with a known hypersensitivity (allergy) to this preparation.

Therapy is probably contraindicated in cases of existing hepatic, renal, or bone-marrow damage. However, if the need outweighs the risk in such patients, thiotepa may be used in low dosage, and accompanied by hepatic, renal and hemopoietic function tests.

Last updated on RxList: 11/20/2008

Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylenimine radicals which, like irradiation, disrupt the bonds of DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the N-7 position, which severs the linkage between the purine base and the sugar and liberates alkylated guanines.

The pharmacokinetics of thiotepa and TEPA in thirteen female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals are presented in the following table:

TEPA, which possesses cytotoxic activity, appears to be the major metabolite of thiotepa found in human serum and urine. Urinary excretion of ¹⁴C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. Thiotepa and TEPA in urine each accounts for less than 2% of the administered dose.

The pharmacokinetics of thiotepa in renal and hepatic dysfunction patients have not been evaluated. Possible pharmacokinetic interactions of thiotepa with any concomitantly administered medications have not been formally investigated.

Last updated on RxList: 11/20/2008

The patient should notify the physician in the case of any sign of bleeding (epistaxis, easy bruising, change in color of urine, black stool) or infection (fever, chills) or for possible pregnancy to patient or partner.

Effective contraception should be used during thiotepa therapy if either the patient or the partner is of childbearing potential.

Last updated on RxList: 11/20/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

THIOTEPA - INJECTION

(thigh-oh-TEP-uh)

COMMON BRAND NAME(S): Thioplex

USES: Thiotepa is used to treat cancer. It works by slowing or stopping the growth of cancer cells. Thiotepa is often given into the bladder to treat bladder cancer.

HOW TO USE: Follow all instructions for proper mixing and dilution with the correct IV/irrigation fluids. Before using, check this medication visually for particles. If particles are present, do not use the liquid.

This medication is given by injection into a vein by a health care professional, usually once a week or as directed by your doctor. Sometimes, thiotepa is injected directly into the tumor. Tell your doctor or nurse immediately if you experience pain, burning, or redness at the injection site.

For treatment of bladder cancer, thiotepa is usually given into the bladder through a tube (catheter). Your doctor may direct you to limit fluids for 8 to 12 hours before the medication is given. The solution is usually left in place for 2 hours and then drained out through the bladder tube. Your doctor may direct you to change positions every 15 minutes while the solution is in your bladder to make sure the solution treats all parts of your bladder.

The dosage and how often the medication is given is based on your medical condition and response to treatment. Your doctor will do blood tests (complete blood count) to find the right dose for you. Your next dose may need to be rescheduled if your white blood cell count or platelets are too low.

Learn how to handle, use, and discard chemotherapy and medical supplies safely. Consult your pharmacist. Wear gloves and wash your hands carefully after handling this drug. Avoid getting this medication in your eyes or on your skin. If the medication gets in your eye, wash the affected eye(s) well with water and contact your doctor. If the medication gets on your skin, wash the area well with soap and water.

SIDE EFFECTS: Pain/redness at the injection site, dizziness, headache, blurred vision, fever, nausea, vomiting, stomach/abdominal pain, or loss of appetite may occur. Changes in diet such as eating several small meals or limiting activity may help lessen some of these effects. In some cases, drug treatment may be necessary to prevent or relieve nausea and vomiting. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Temporary hair loss is another common side effect. Normal hair growth should return after treatment has ended.

Many people using this medication have serious side effects. However, remember that your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Painful sores on the lips, mouth, and throat may occur. To decrease the risk, limit hot foods and drinks, brush your teeth carefully, avoid using mouthwash that contains alcohol, and rinse your mouth frequently with cool water.

This medication can lower the body's ability to fight an infection. Tell your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

This medication may also cause very serious bleeding. Tell your doctor immediately if any signs of serious bleeding occur, including: easy bruising/bleeding, bloody/black/tarry stools, coughing up blood, nosebleeds that are frequent or hard to stop, dizziness/fainting, fast/irregular heartbeat, pale/gray/bluish skin, unusual tiredness/weakness, vomit that is bloody or looks like coffee grounds.

Tell your doctor immediately if any of these rare but very serious side effects occur: severe stomach/abdominal pain, lower back/side pain, painful/difficult urination, pink/dark urine.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using thiotepa, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially: bone marrow problems (e.g., low white blood cell count/platelets from previous chemotherapy/radiation treatment), kidney disease, liver disease.

Wash your hands well to prevent the spread of infections. Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug must not be used during pregnancy. It may harm the unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. Males and females must use 2 reliable forms of birth control (e.g., condoms and birth control pills) during treatment with this drug. Talk with your doctor about effective forms of birth control.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: live virus vaccines (e.g., oral polio vaccine, flu vaccine inhaled through the nose), nalidixic acid.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting thiotepa.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially: aspirin and other NSAIDs (e.g., ibuprofen), drugs that may harm the immune system (e.g., chemotherapy, corticosteroids such as prednisone).

Check all prescription and nonprescription medicine labels carefully since many contain pain relievers/fever reducers (NSAIDs such as ibuprofen, naproxen, or aspirin) that may increase your risk of bleeding. Low-dose aspirin should be continued if prescribed by your doctor for heart attack or stroke prevention (usually at dosages of 81-325 milligrams a day). Consult your doctor or pharmacist for more details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood counts, kidney tests, liver tests) should be performed while you are being treated with the medication and for several weeks after your last dose to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. Keep all medical/lab appointments. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store in the refrigerator between 36-46 degrees F (2-8 degrees C) and protect from light. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.