Thiotepa

Common side effects of thiotepa include:

• increased risk to infection
• whole-body inflammation sepsis)
• decreased counts of white blood cells, platelets and red blood cells (anaemia)
• the transplanted cells attack your body (graft versus host disease)
• dizziness, headache, blurred vision
• uncontrolled shaking of the body (convulsion)
• sensation of tingling, pricking or numbness
• partial loss of movement
• cardiac arrest
• nausea, vomiting, diarrhea
• inflammation of the mucosa of the mouth (mucositis)
• irritated stomach, gullet, intestine
• inflammation of the colon
• anorexia, decreased appetite
• high blood sugar
• skin rash, itching, shedding
• skin colour disorder
• redness of the skin
• hair loss
• back and abdominal pain
• muscle and joint pain
• inflammation of lung tissue
• enlarged liver
• altered organ function
• blocking of a liver vein (VOD)
• yellowing of the skin and eyes (jaundice)
• hearing impairment
• high blood pressure
• increased liver, renal and digestive enzymes
• abnormal blood electrolytes
• weight gain
• fever, general weakness, chills
• bleeding
• nasal bleeding
• general swelling due to fluid retention (oedema)
• pain or inflammation at the injection site
• eye infection (conjunctivitis)
• decreased sperm cell count
• vaginal bleeding
• absence of menstrual periods (amenorrhea)
• memory loss
• delaying in weight and height increase
• bladder disfunction
• underproduction of testosterone
• insufficient production of thyroid hormone
• deficient activity of the pituitary gland
• anxiety, confusion
• abnormal bulging outward of one of the arteries in the brain (intracranial aneurysm)
• allergic reactions
• blockage of a blood vessel (embolism)
• heart problems
• oxygen deficiency
• fluid accumulation in the lungs (pulmonary edema)
• pulmonary bleeding
• respiratory arrest
• blood in the urine (haematuria) and moderate renal insufficiency
• inflammation of the urinary bladder
• discomfort in urination and decrease in urine output (disuria and oliguria)
• increase in the amount of nitrogen components in the blood stream (BUN increase)
• cataract
• inability of the liver
• cerebral haemorrhage
• cough
• constipation and upset stomach
• obstruction of the bowel
• perforation of stomach
• changes in muscle tone
• gross lack of coordination of muscle movements
• bruises due to a low platelet count
• menopausal symptoms
• cancer (second primary malignancies)
• abnormal brain function

This is not a complete list of thiotepa side effects. Ask your doctor or pharmacist for more information.

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

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

The most serious side effects of thiotepa therapy may include:

• decrease in circulating blood cell counts (intended effect of the medicine to prepare you for your transplant infusion)
• infection
• liver disorders including blocking of a liver vein
• the graft attacks your body (graft versus host disease)
• respiratory complications

Your doctor will monitor your blood counts and liver enzymes regularly to detect and manage these events.

Thiotepa may interfere with the normal menstrual cycle (period) in women, may stop sperm production in men, and may cause infertility (difficulty becoming pregnant).

Before taking thiotepa, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to thiotepa or to any of its ingredients
• liver, kidney, or bone-marrow damage. However, if the need outweighs the risks, thiotepa may be used in low dosage, and accompanied by monitoring tests.

Before taking thiopeta, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to thiotepa, any other medications, or any of the ingredients in thiotepa injection
• are taking other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products
• have or have ever had kidney or liver disease. Your doctor may not want you not to receive thiotepa.
• have previously received or will be receiving radiation (x-ray) therapy or other chemotherapy and if you have or have ever had any medical conditions
• If you are pregnant or planning to become pregnant.
• are breastfeeding. You should not breastfeed while you are receiving thiotepa.

Take thiopeta exactly as prescribed.

This medication is available in an injectable form to be given directly into a vein (IV), into a body cavity, or into the urinary bladder by a healthcare professional.

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

Bladder Cancer

Used intravesically for the treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder cancer.103 104 105 106 111 b

Less effective than live intravesical Bacillus Calmette-Guerin (BCG) in reducing the frequency of tumor recurrence in patients with superficial bladder cancer.107

Breast Cancer

Used in the treatment of adenocarcinoma of the breast;100 b however, other agents are preferred.111

Ovarian Cancer

Used in the treatment of adenocarcinoma of the ovary;100 b however, other agents are preferred.111

Malignant Effusions

Used by intracavitary injection to control pleural, pericardial, or peritoneal effusions secondary to metastatic tumors.100 b

Lymphomas

Has been used for treatment of lymphomas (e.g., lymphosarcoma, Hodgkin's disease); however, other treatments are preferred.b

Meningeal Neoplasms

Has been investigated as an intrathecal† agent in the treatment of malignant meningeal neoplasms (e.g., leukemia), but additional studies are required to determine safety and efficacy.a

Pterygium

Has been used as an ophthalmic instillation† to prevent the recurrence of pterygium† following surgical excision; however, postoperative β-irradiation generally is preferred as preventive therapy because it results in a low incidence of recurrence and is relatively easy to administer.a

Many clinicians recommend use be limited to management of pterygium† that recurs following postoperative β-irradiation.a

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Feeling very tired or weak.
• For women, no period.
• Mouth irritation or mouth sores.
• Trouble passing urine.
• Change in eyesight, eye pain, or very bad eye irritation.
• Very bad brain problems have happened with this medicine. Sometimes, these have been deadly with high doses of thiotepa. Call your doctor right away if you feel very sleepy or confused, or if there is a change in how you act, hallucinations (seeing or hearing things that are not there), memory problems, seizures, trouble moving around, or very bad headache.

Thiotepa for Injection, USP 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.

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 hematopoietic 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.

• 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 Cytotosic 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.

Manufactured by

THYMOORGAN PHARMAZIE GmbH,

Schiffgraben 23, 38690 Goslar, Germany

Distributed by

West-Ward Pharmaceuticals

Eatontown, NJ 07724 USA

Revised February 2015

 127.207.002/00

Vial Label

Known hypersensitivity (allergy) to thiotepa or any component of the formulation; concomitant use with live or attenuated vaccines (Tepadina)

Central nervous system toxicity, severe or life-threatening: Discontinue thiotepa and provide supportive care.

Hypersensitivity reactions (eg, anaphylaxis or other clinically significant reaction): Discontinue thiotepa and manage as appropriate; monitor until signs/symptoms resolve.

Myelosuppression: Thiotepa may cause severe marrow suppression, and high doses may cause marrow ablation with resulting infection or bleeding. Monitor hematologic laboratory parameters. Hematopoietic progenitor (stem) cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression after high doses of thiotepa.

Carcinogenicity: Thiotepa should be considered potentially carcinogenic in humans.

Concerns related to adverse effects:

• Bone marrow suppression: Myelosuppression (leukopenia, thrombocytopenia, and anemia) may commonly occur, particularly when used as part of the preparative regimen for hematopoietic stem cell transplantation (HSCT) or in patients with compromised bone marrow function. Do not initiate the HSCT conditioning regimen if a stem cell donor is not available. Monitor blood counts closely. Monitor for infection or bleeding; death due to septicemia and hemorrhage has occurred. Myelosuppression (including fatal cases) has also been reported with intravesicular administration (due to systemic absorption).

• CNS effects: Fatal encephalopathy has been reported in patients receiving high-dose thiotepa. Headache, apathy, psychomotor retardation, disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence, seizures, coma, inappropriate behavior, and forgetfulness have also been reported (may be dose dependent). If severe or life-threatening central nervous system toxicity occurs, discontinue treatment and manage as necessary. CNS toxicity, including seizures and intracranial hemorrhage was reported in pediatric patients who receive the recommended dose in combination with busulfan and cyclophosphamide as a stem cell conditioning regimen for beta thalassemia; do not exceed the recommended dose.

• Dermatologic toxicity: In patients receiving high-dose thiotepa, the parent drug and/or its active metabolites may be partially excreted through the skin. Thiotepa may cause skin discoloration, pruritus, blistering, desquamation, and peeling (may be more severe in skin folds, groin, axillae, and neck areas, and under dressings). Change occlusive dressing and clean covered skin at least twice daily during and for 48 hours after thiotepa administration (when used as a component of the HSCT preparative regimen). Patients should shower/bathe in water twice daily through 48 hours after receiving thiotepa. Change bed sheets daily. Accidental thiotepa exposure is also associated with skin reactions; wash skin thoroughly with soap and water and flush mucous membranes if skin and/or mucous membrane contact occurs.

• GI toxicity: In children, thiotepa is associated with a high emetic potential at doses ≥300 mg/m2 (Dupuis 2011) and is associated with a moderate emetic potential (depending on dose/indication) in adults (Roila 2016); antiemetics are recommended to prevent nausea and vomiting. Thiotepa is also associated with mucositis.

• Hepatic sinusoidal obstruction syndrome: Hepatic sinusoidal obstruction syndrome (SOS, also called veno-occlusive disease [VOD]) may occur in patients receiving thiotepa in combination with busulfan and cyclophosphamide as a preparative regimen prior to HSCT. Monitor serum transaminases, bilirubin and for signs/symptoms of hepatic SOS through day +28 of stem cell transplant; provide supportive care if SOS develops.

• Hypersensitivity: Clinically significant hypersensitivity reactions (including anaphylaxis) have occurred. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, discontinue thiotepa treatment and initiate appropriate supportive management. Monitor until resolution of symptoms.

• Secondary malignancies: Thiotepa is potentially carcinogenic; myelodysplastic syndrome and acute myeloid leukemia (AML) have been reported. There is an increased risk of secondary malignancies with thiotepa use.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; thiotepa is extensively hepatically metabolized; moderate (bilirubin >1.5 to 3 times ULN and any AST) or severe (bilirubin >3 times ULN and any AST) impairment may result in increased plasma concentrations and increased toxicity. Monitor closely.

• Renal impairment: Use with caution in patients with renal impairment; decreased renal excretion may result in increased thiotepa and TEPA plasma concentrations and increased toxicity. Monitor closely.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Vaccines: Do not administer live or attenuated viral or bacterial vaccines until the immunosuppressive effects of thiotepa have resolved.

Other warnings/precautions:

• Intrathecal safety: When used for intrathecal administration (off-label route), should not be prepared during the preparation of any other agents. After preparation, keep intrathecal medications in an isolated location or container clearly marked with a label identifying as "intrathecal" use only. Delivery of intrathecal medications to the patient should only be with other medications also intended for administration into the central nervous system (Jacobson 2009).

Adverse events were observed in animal reproduction studies. Based on the mechanism of action, thiotepa may cause fetal harm if used in pregnant women. Verify pregnancy status in women of reproductive potential prior to therapy initiation. Effective contraception should be used during treatment and for at least 6 months after the final dose. Males with female partners of reproductive potential should use effective contraception during therapy and for at least 1 year after the final dose. Both male and female fertility may be affected by thiotepa administration.