thiotepa

THIOTEPA

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use

Overview and uses

Thiotepa is ethylenimine derivative, an alkylating agent used for the treatment of cancer.

Indication (uses)

  • Class 3 beta thalassemia
    • To reduce the risk of graft rejection. Thiotepa is used in conjunction with high dose Busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic progenitor (stem) cell transplantation (HSCT) in pediatric patients with class 3 beta thalassemia.
  • Adenocarcinoma of the breast or ovary
  • Malignant effusions
    • Indicated for controlling Intracavitary effusions secondary to diffuse or localized neoplastic diseases of various serosal cavities.
  • Superficial papillary carcinoma of the urinary bladder.

Pharmacological classification

Alkylating agent used for the treatment of cancer.

Brand names

Tepadina, Thioplex

Dosage form

  • Available in injections as single dose vials for reconstitution containing lyophilized white powder of Thiotepa in strength of 15 mg and 100 mg.

Mechanism of action

Alkylating agents produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. These intermediates may react with carboxyl, hydroxyl, amino, sulfhydryl and phosphate groups of biomacromolecules. Alkylation results in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of nucleic acids with proteins can also take place.

Dosage

  • Class 3 beta thalassemia
    • Two doses of 5 mg/kg are administered at an interval of 12 hours on day – 6 before allogeneic HSCT in conjunction with high dose busulfan and cyclophosphamide.
  • Adenocarcinoma of the breast or ovary
    • 3 mg/kg to 0.4 mg/kg at an interval of 1 – 4 weeks.
    • Maintenance dose should be given on the basis of pretreatment blood counts and subsequent blood counts.
    • Maintenance dose should not be administered more frequently than weekly.
  • Malignant effusion
    • 6 mg/kg to 0.8 mg/kg administered Intracavitary at an interval of 1 – 4 weeks.
    • Maintenance dose should be given on the basis of pretreatment blood counts and subsequent blood counts.
    • Maintenance dose should not be administered more frequently than weekly.
  • Superficial papillary carcinoma of the urinary bladder
    • 60 mg in 30 – 60 ml of sodium chloride injection administered into the bladder by catheter. This solution should be retained for 2 hours by the patient.
    • If the patient finds it impossible to retain this solution of 60 ml for 2 hours, the dose may be given in a volume of 30 ml.

Pediatric patients

  • Safety and effectiveness of Thiotepa in the treatment of Superficial papillary carcinoma of the urinary bladder, Malignant effusion and Adenocarcinoma of the breast or ovary is not yet established.

Hepatic dose adjustment

  • Thiotepa is extensively metabolized in liver.
  • Monitor patients with moderate to severe hepatic impairment (bilirubin levels greater than 3 times the normal upper limit and any AST) for the signs and symptoms of toxicity.

Renal dose adjustments

  • In patients with moderate renal impairment, (Creatinine clearance 30 ml/min to 59 ml/min) decreased renal excretion may lead to increased plasma levels of Thiotepa and TEPA, which may lead to increased toxicity.
  • In patients with moderate to severe renal impairment (Creatinine clearance less than 30 ml/min), close monitoring for the signs and symptoms of toxicity should be done for an extended period of time following the treatment with Thiotepa.

Geriatric dose adjustments

  • Data not available.
  • In general, caution should be exercised while administering Thiotepa in elderly patients since an increase in age is related to reduced hepatic, renal and/or cardiac functions as well as presence of concomitant disease or treatment of concomitant disease.

Overdosage

  • No specific antidote is known.
  • Patient should be closely monitored for hematological status.
  • General supportive measures should be given.
  • Myeloablation and pancytopenia are the most important adverse reactions associated with the Overdosage of Thiotepa.

Side effects or adverse effects

  • Local side effects
    • Thrombophlebitis and thrombosis at the site of injection.
  • Hypersensitivity reactions
    • Anaphylaxis has been reported with Mechlorethamine use.
    • Pain in chest or abdomen, skin rash, difficulty in breathing, rapid breathing, shortness of breath, dizziness, fainting, low blood pressure are some of the symptoms.
    • Consult your doctor as soon as possible.
  • Other systemic side effects
    • Jaundice
    • Vertigo
    • Tinnitus
    • Diminished hearing
    • Occurrence/precipitation of hemolytic anemia
  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anti-cancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and haemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
      • Pigmentation of the skin and changes in the nail colour.
      • Skin discolouration
      • Pruritis
      • Blistering
      • Desquamation
      • Peeling particularly in groin, axillae, skin folds, underdressings and in neck area.
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to reduction in number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Pulmonary toxicity
        • Pneumonitis
        • Pulmonary fibrosis
        • Pulmonary veno-occlusive disease
      • Impairment of wound healing
        • Thiotepa may interfere with normal wound healing.
      • Hyponatremia
        • Hyponatremia associated with increased total body water, acute water intoxication and a syndrome resembling SIADH.
      • Secondary malignancies
        • Urinary tract cancer
        • Myelodysplasia
        • Acute leukemias
        • Lymphomas
        • Thyroid cancer
        • Sarcomas
      • Cardiac side effects
        • Congestive heart failure
        • Myocarditis
        • Myopericarditis
        • Pericardial effusion including cardiac tamponade
        • Supraventricular arrhythmias
        • Ventricular arrythmias
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.
        • Hepato veno occlusive disease
        • Renal side effects
          • Renal failure, Gout and Urate stones may develop in urinary tract.
          • Hemorrhagic cystitis, pyelitis, ureteritis and hematuria.
          • Macrohematuria, renal dysfunction, renal structural damage.
        • CNS side effects
          • Headache
          • Apathy
          • Psychomotor retardation
          • Disorientation
          • Confusion
          • Amnesia
          • Hallucination
          • Drowsiness
          • Somnolence
          • Seizures
          • Coma
          • Inappropriate behavior
          • Forgetfulness

Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Contra-indicated in patients with known hypersensitivity to Thiotepa.
  • Contra-indicated in patients with myelosuppression.
  • Contra-indicated in patients with Neurotoxicity.
  • Caution should be exercised in giving Thiotepa to patients with pre-existing infections.

Pregnancy & breast feeding warnings

Pregnancy

  • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Nursing:

  • It is not known whether Thiotepa is excreted in human breast milk or not.
  • Because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Thiotepa is a substrate for both CYP3A4 and CYP2B6.
  • CYP3A inducers/inducers like phenytoin, carnamazepine, fosphenytoin, clarithromycin, ritonavir, phenobarbital, rifampin, St. John’s wart may affect the metabolism of Thiotepa to its active metabolite TEPA. Close monitoring of patients is highly recommended in patients taking Thiotepa with CYP3A inducers for toxicities. Dose adjustments should be considered in such patients.
  • CYP3A4 inhibitors/inducers like ketoconazole, fluconazole, itraconazole, sorafenib, aprepitant, fosaprepitant, grapefruit and grapefruit juice may affect the metabolism of Thiotepa to its active metabolite TEPA, affecting the efficacy of Thiotepa.
  • CYP2B6 substrates like cyclophosphamide should be avoided concomitantly with Thiotepa. Thiotepa may increase the exposure of these drugs.
  • Concomitant use of Thiotepa with following drugs/medicines should be strictly avoided.
    • ACE inhibitors can cause leukopenia.
    • Adalimumab as it increases the risk of infections.
    • Busulfan – blood levels or side effects of Busulfan may be increased by Thiotepa.
    • Cisplatin – blood levels or side effects of Cisplatin may be increased by Thiotepa.
    • Lomustine – blood levels or side effects of Lomustine may be increased by Thiotepa.
    • Cyclophosphamide – blood levels or side effects of Cyclophosphamide may be increased by Thiotepa.
    • Mechlorethamine – blood levels or side effects of Mechlorethamine may be increased by Thiotepa.
    • Streptozocin – blood levels or side effects of Streptozocin may be increased by Thiotepa.
    • Carboplatin – blood levels or side effects of Carboplatin may be increased by Thiotepa.
    • Carmustine – blood levels or side effects of Carmustine may be increased by Thiotepa.
    • Certolizumab as it increases the risk of infections.
    • Cidofovir may increase the risk of nephrotoxicity and renal impairment.
    • Clozapine as it may lower the WBC count.
    • Deferiprone as it may lower the WBC count.
    • Ditrizoate may increase the risk of nephrotoxicity, nephropathy and renal impairment.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Infliximab as it increases the risk of infections.
    • Iodamide may increase the risk of nephropathy and renal impairment.
    • Iodipamide may increase the risk of nephrotoxicity and renal impairment.
    • Iodixanol may increase the risk of nephrotoxicity and renal impairment.
    • Iohexol may increase the risk of nephrotoxicity and renal impairment.
    • Iopamidol may increase the risk of nephropathy and renal impairment.
    • Iopromide may increase the risk of nephropathy and renal impairment.
    • Iothalamate may increase the risk of nephrotoxicity and renal impairment.
    • Ioversol may increase the risk of nephropathy and renal impairment.
    • Ioxagalate may increase the risk of nephrotoxicity and renal impairment.
    • Ioxilan may increase the risk of nephropathy and renal impairment.
    • Leflunomide as it increases the risk of infections.
    • Melphalan – blood levels or side effects of Melphalan may be increased by Thiotepa.
    • Nalidixic acid as the combination may cause unusual bruising or bleeding, nausea, stomach pain, unusual weakness, low fever and loss of appetite.
    • Natalizumab as it increases the risk of infections.
    • Oprelvekin may cause abnormally low levels of potassium in blood.
    • Paclitaxel causes increased hematotoxicity.
    • Talimogene as it increases the risk of herpes infections.
    • Teriflunomide as it increases the risk of infections.
    • Thalidomide may increase the risk of dangerous blood clots.
    • Thiazide diuretics
    • Thiotepa may increase the side effects of Ifosfamide.
    • Tofacitinib as it increases the risk of infections.
  • Concomitant use of live and attenuated vaccines should be avoided until immunosuppressive effects have resolved in patients treated with Thiotepa.

Click here to go to Thiotepa forums.

Reference

  • “Product information. Tepadina (Thiotepa). Adienne SA, Switzerland

Evaluation of parenterals

October 12th, 2018|Comments Off on Evaluation of parenterals

Evaluation test of Parenterals The following tests are performed on the finished parenteral products to maintain quality control: Leakage test Clarity test Pyrogen test Sterility test Evaluation of Parenterals or quality control [...]

advance directive

September 5th, 2018|Comments Off on advance directive

Advance directives Contents of the post Overview Other names Types of advance directives The need for a living will Important aspects related to a durable power of attorney for a health care Living will [...]

Is omeprazole addictive

August 28th, 2018|Comments Off on Is omeprazole addictive

Is omeprazole addictive? Is Omeprazole addictive? Contents of the post Indications Examples of PPI's (Proton Pump Inhibitors) Purpose of recommending or prescribing or consuming omeprazole or any other PPI Is omeprazole and other [...]

COPD

August 9th, 2018|Comments Off on COPD

COPD (Chronic Obstructive Pulmonary Disease) Index of the post Introduction Some numbers and facts on COPD Causes Risk factors Symptoms Diagnosis Treatment Treatment of symptoms Treatment of flare-ups Oxygen therapy Pulmonary rehabilitation Other [...]

Pulmonary embolism

August 6th, 2018|Comments Off on Pulmonary embolism

Pulmonary embolism Contents of the post Overview Causes Symptoms Diagnosis Prevention Treatment Prognosis Factors which predisposes a person  to blood clots References and further reading Overview Pulmonary embolism is the sudden blocking of an [...]

By |2018-12-29T07:42:17+00:00April 25th, 2017|medicines|Comments Off on thiotepa

About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

WE NEED YOUR HELP IN CREATING AWARENESS ABOUT DISEASES AND MEDICINES

In today's fast paced life, we often come across minor health issues that we often neglect due to lack of time for paying a visit to a doctor, which usually takes away 2-3 hours of a person's time and are expensive too. Further more, such minor conditions may grow big at any time if neglected. Our aim in setting up this platform is that any person can search for any health condition or medicines and can get all the needed information within hardly 10-15 minutes, which saves a lot of time and money. After going through every information, if the person has any questions, he/she can go to our forums section and raise a topic. This will help him/her decide better whether he/she needs to pay an immediate visit to a doctor or can it wait for a day or two? Help us in bringing awareness about diseases and medicines by spreading the word to at least 5 of your friends and relatives.