Cyclophosphamide

Cyclophosphamide - also known as cytophosphorus or CP - is an anticancer drug belonging to the class of alkylating agents.

Cyclophosphamide - Chemical Structure

Given its importance, cyclophosphamide is included in the list of essential drugs compiled by the World Health Organization, a list of all the drugs that must be present in a basic health system.

Indications

For what it uses

Cyclophosphamide is indicated for the treatment of tumors, including:

Malignant lymphomas;
Chronic lymphocytic leukemia;
Ovarian adenocarcinoma;
Multiple myeloma;
Breast cancer;
Brain cancer;
Bladder cancer;
Other types of solid tumors.

At high doses, it can be used for preparatory therapy for hematopoietic stem cell transplantation (progenitor cells from which blood cells originate).

Thanks to its powerful immunosuppressive action, cyclophosphamide is also indicated in the treatment of autoimmune diseases such as:

Multiple sclerosis;
Systemic lupus erythematosus;
Autoimmune hemolytic anemia;
Rheumatoid arthritis;
Wegener's granulomatosis.

Cyclophosphamide is also used in the treatment of primary systemic amyloidosis (or PSA).

Warnings

Because cyclophosphamide has renal and urinary tract toxicity, it is necessary to monitor these features carefully and constantly in patients being treated with the drug. Where required, the administered dose is reduced; in some cases, however, treatment must be stopped.

Particular attention should be paid to the administration of cyclophosphamide in weak and / or elderly subjects and in patients who have recently received treatment with radiotherapy.

Even patients who have a weakened immune system or who have liver dysfunction should be monitored before, during and after treatment with the drug.

Patients with a history of cardiac disorders should be carefully monitored because of the cardiotoxicity that cyclophosphamide possesses.

Interactions

Cyclophosphamide is a prodrug, which means that before performing its cytotoxic (cell-toxic) action it must undergo changes that turn it into active metabolites. These changes occur following hepatic metabolism. However, there are drugs that can delay the activation of cyclophosphamide, thereby reducing its activity. These drugs are:

Tiotepa, an anticancer medicine;
Aprepitant, an antiemetic used to prevent nausea and vomiting induced by antineoplastic chemotherapy;
Bupropion, a drug once used as an antidepressant, is now used to stop smoking;
Chloramphenicol, a bacteriostatic antibiotic;
Fluconazole and itraconazole, antifungal drugs;

Administration of cyclophosphamide at high doses shortly after the administration of busuflfano at high doses, may decrease the rate of excretion of cyclophosphamide itself, increasing its toxic effects.

The intake of fluoroquinolone antibiotics - such as, for example, ciprofloxacin - may result in reduced efficacy of cyclophosphamide with consequent worsening of the primary pathology.

During treatment with cyclophosphamide, an increase in the concentration of cytotoxic metabolites may occur following the intake of:

Allopurinol, a drug used to treat gout;
Cimetidine, a drug used for the therapy of gastric ulcer;
Disulfiram, a drug used to treat alcoholism;

Attention should be paid to the administration of cyclophosphamide together with drugs inducing hepatic and extrahepatic microsomal enzymes (such as, for example, cytochrome P450). Among these drugs we find:

Rifampicin, an antibiotic;
Phenobarbital, a barbiturate;
Carbamazepine and phenytoin, drugs used to treat epilepsy;
Benzodiazepines ;
St. John's wort (or St. John's wort ), a medicinal plant with antidepressant and antiviral properties;
Corticosteroids .

Even the antiemetic drug ondansetron seems to interfere with cyclophosphamide administered at high doses.

Patients taking cyclophosphamide should not eat grapefruit or drink the juice because this fruit contains substances that can reduce the effectiveness of the drug.

The administration of cyclophosphamide together with other drugs with similar toxicity can cause combined toxic effects, therefore greater. Therefore, attention should be paid to the simultaneous administration of cyclophosphamide to nephrotoxic (kidney toxic) or cardiotoxic drugs .

Alcohol may increase the emetic effects induced by cyclophosphamide.

Cyclophosphamide can reduce the anticoagulant power of warfarin .

Cyclophosphamide intake can interfere with intestinal absorption of digoxin (a drug used to increase the strength of cardiac contraction) and verapamil (a drug used to treat hypertension).

You need to tell your doctor if you are taking, if you have recently taken or if you plan to take any type of medication, including over-the-counter medications, herbal products and / or homeopathic products.

Cyclophosphamide and vaccines

Cyclophosphamide has immunosuppressive effects, ie it is able to suppress the immune system. This suppression could lead to a reduced response to vaccinations. Furthermore, patients vaccinated with live attenuated virus vaccines can contract infections and show more pronounced side effects to the vaccine due to the suppression of the body's natural defenses.

Side effects

Cyclophosphamide can induce various side effects depending on the amount of drug administered, the route of administration chosen, the type of pathology to be treated and the patient's condition. The side effects that can occur and their intensity vary from individual to individual, this is because each patient responds differently to therapy.

Myelosuppression

Cyclophosphamide can induce myelosuppression, ie it suppresses bone marrow activity; this causes a reduction in the production of blood cells which can lead to:

Anemia (decrease in hemoglobin blood levels), the main symptom of the onset of anemia is the feeling of physical exhaustion ;
Leukopenia (decreased white blood cell levels), with increased susceptibility to contraction of infections ;
Plateletopenia (decrease in the number of platelets), this leads to the appearance of bruising and abnormal bleeding with an increased risk of bleeding .

Gastrointestinal disorders

Cyclophosphamide can cause nausea, vomiting and diarrhea .

Vomiting can occur from a few hours to a few days after taking the drug. Antiemetic drugs are used to control this symptom. If the symptom persists, it is necessary to inform the oncologist.

Diarrhea can be treated with anti-diarrheal drugs and it is necessary to drink a lot to replenish lost fluids.

Cyclophosphamide can also cause colitis, enteritis, stomatitis and constipation .

Skin disorders

Cyclophosphamide therapy can cause erythema, hives, dermatitis and blisters .

Alopecia

Cyclophosphamide treatment can lead to hair and hair loss in general. This side effect generally disappears after the end of the treatment.

Oral cavity disorders

Cyclophosphamide therapy can lead to the appearance of small ulcers of the oral cavity, the sensation of a dry mouth and pain . To prevent these symptoms, it is important to take plenty of fluids and clean your teeth regularly with a soft toothbrush.

It is also possible to incur a temporary loss of the sense of taste that is usually regained at the end of the therapy.

Toxicity of the urinary tract

Cyclophosphamide presents toxicity to the kidneys and urinary tract in general. The treatment with the drug can, in fact, favor the onset of:

Hemorrhagic cystitis;
Macro- and micro-hematuria (blood in the urine, visible or not);
Edema of the bladder wall;
Fibrosis and bladder sclerosis;
Hemorrhagic urethritis;
Ulcerative cystitis;
Kidney failure;
Necrosis of the renal tubules;
Toxic nephropathy;
Increased blood levels of creatinine and urea nitrogen.

Lung diseases

Cyclophosphamide can cause various lung disorders such as, for example, bronchospasm, dyspnea, cough, interstitial pneumonia, pulmonary edema, chronic pulmonary fibrosis, respiratory failure and hypoxia.

Hepatobiliary disorders

Cyclophosphamide treatment can cause liver and biliary tract damage. Among the main side effects we find liver function disorders, hepatitis, hepatomegaly, veno-occlusive liver disease and jaundice .

Cardiovascular disorders

Cyclophosphamide has toxicity to the cardiovascular system. It can trigger:

Changes in blood pressure (hypertension or hypotension);
Arrhythmias (tachycardia or bradycardia);
Palpitations;
Ventricular failure;
Angina pectoris;
pericarditis;
Myocardial infarction;
Cardiac arrest.

Eye disorders

Cyclophosphamide therapy can cause eye changes, increased lacrimation, conjunctivitis and ocular edema accompanied by hypersensitivity.

Toxicity of the ear

Cyclophosphamide can cause hearing disorders and tinnitus, which is a ringing sensation in the ears that can be perceived as a pulsating noise, like a whistle, a clink or a rustling sound.

Infertility

Cyclophosphamide can cause damage - sometimes irreversible - to the female and male reproductive systems.

In women, cyclophosphamide can alter ovarian function and induce oligomenorrhea or amenorrhea (respectively, a reduction or a halt in the menstrual cycle).

In men, however, cyclophosphamide can lead to testicular atrophy, oligospermia or azoospermia (respectively, reduced quantity or absence of spermatozoa in the ejaculate).

Nervous system disorders

Cyclophosphamide treatment can cause dizziness, convulsions, tremors, paraesthesia (altered sensitivity in the limbs or other parts of the body); it can also generate confusion and encephalopathies .

Carcinogenesis

It appears that treatment with cyclophosphamide may induce the formation of secondary tumors, both benign and malignant. The tumors that may arise following treatment with the drug are leukemias, lymphomas, skin cancers, kidney tumors and bladder tumors.

Overdose

Symptoms of cyclophosphamide overdose include manifestations of dose-dependent toxicity such as myelosuppression, urotoxicity, cardiotoxicity, veno-occlusive hepatic disease and stomatitis. There is no antidote but - as cyclophosphamide can be dialyzed - in the event of an overdose or accidental intoxication, rapid hemodialysis is indicated.

Action mechanism

As mentioned above, cyclophosphamide is a prodrug, ie it must be activated by hepatic metabolism to carry out its action. Only after being transformed into its active and cytotoxic metabolites will it be able to perform its action.

Cyclophosphamide is an alkylating agent, so - as such - it is able to intercalate alkyl groups within the double strand of DNA through the formation of very strong bonds that are difficult to break. The alterations thus induced on the DNA prevent the cell from replicating correctly, condemning it to undergo the process of programmed cell death called apoptosis .

Mode of Use - Posology

Cyclophosphamide is available for oral and intravenous administration.

For oral administration it is formulated as white or pink tablets. The tablets should be taken without chewing while drinking plenty of water.

For intravenous administration the drug comes in the form of a powder that must be dissolved in an adequate amount of solvent before the infusion. It can be administered through three different routes:

Through a cannula (a thin tube) that is inserted into a vein of an arm or hand;
Through a central venous catheter that is inserted subcutaneously into a vein near the clavicle;
Through the PICC line ( Peripherally Inserted Central Catheter ), in this case, the catheter is inserted into a peripheral vein, usually of an arm. This technique is used for the administration of anticancer drugs for a prolonged time.

The administration of cyclophosphamide should be carried out under the strict supervision of a doctor who specializes in the administration of anticancer drugs.

The dosage is established by the doctor based on the type of pathology to be treated, based on the patient's condition and his / her clinical picture. In patients with liver dysfunctions it must be taken into account that there may be reduced cyclophosphamide activation.

Dose adjustment is often necessary in patients with previous myelosuppression and / or renal failure. Even in the case of elderly patients, the dose of the drug must be adapted according to the patient's condition.

Pregnancy and breastfeeding

The use of cyclophosphamide in pregnancy is not recommended - especially during the first trimester - because the drug can pass the maternal placenta.

The use of cyclophosphamide can cause termination of pregnancy, fetal growth retardation and toxic effects on the fetus that occur in the newborn, such as pancytopenia, severe bone marrow hypoplasia and gastroenteritis.

During treatment with cyclophosphamide and for at least six months after the end of treatment, precautions must be taken to avoid possible pregnancies.

Cyclophosphamide is also capable of being distributed in breast milk. Therefore, women on medication should not breastfeed.