Rx Prescription information
CYCLOPHOSPHAN - BELMED
(Information for patients)
Trade name: Cyclophosphan - Belmed
International nonproprietary name: Cyclophosphamide.
Description: White or almost white crystalline powder.
Composition: Each vial contains: active substance:cyclophosphamide – 200.0 mg.
Pharmaceutical form: Powder for preparing solution for injections.
Pharmaceutical group: Anti-tumor agents. Alkylating compounds.
Being an anti-tumor agent with the alkylating action it has the chemical structure close the nitrogen mustards (NMs). It has cytostatic and immunosuppressive effects. It is an inactive transport form degrading under the phosphatase action and producing the active component immediately in the tumor cells, it “attacks” the nucleophilic centers of protein molecules, breaks the DNA and RNA synthesis, blocks the mitotic division.
Small cell carcinoma of the lung, ovarian carcinoma, breast cancer, cancer of the neck and of the body of the uterus, urinary bladder cancer, prostate cancer, neuroblastoma, retinoblastoma, lymphogranulomatosis, lymphosarcoma, non-Hodgkin lymphoma, reticulosarcoma, osteogenous sarcoma, multiple myeloma, chronic lympholeukemia and myeloleukemia and monoblastic leukemia, Wilms’ tumor, Ewing’s tumor, granulosarcoid, pulpy testis; autoimmune disease: rheumatoid arthritis, psoriatic arthritis, systemic disorders of the connective tissue, autoimmune hemolytic anemia, nephritic syndrome, suppression of the host-against-transplant reaction.
Mode of administration and dosage
To prepare a solution for injection, dissolve 200 mg of the drug in 10 ml of water for injections (do not use NaCl 0.9%).
Infuse the drug parenterally (intravenously), intramuscular injections are allowed when it is necessary. Other methods of parenteral administration, such as the intrapleural, intraperitoneal, etc. may be practiced depending on the indications. The dose should be prescribed individually considering the general state of the patient and the blood composition. The following treatment schemes are possible:
· daily intravenous administration in the dose 2 – 8 mg/kg/day (200 – 400 mg);
· regular intravenous administration in the dose 10 – 15 mg/kg/day (500 – 1000 mg) with 2 – 6 days intervals;
· regular intravenous administration in the dose 20 – 40 mg/kg/day with 10 – 20 days intervals.
Other doses and schemes of administration are allowed. The dose for course administration is 8 – 14 g followed by the supportive treatment – 100 – 200 mg twice a week.
When fluid has been accumulated in the abdominal and/or pleural cavities caused by the carcinomatous process the intravenous injections are supplemented with 0.4 – 1.0 g (for every centesis) cavities injections of Cyclophosphan - Belmed. The dose of the drug to be administered intravenously should be reduced appropriately in those cases.
When Cyclophosphan - Belmed is administered as an immunosuppressive agent the dose is calculated as 1.0 – 1.5 mg/kg (50 – 100 mg per day), when it is well tolerated the dose may be increased up to 3 – 4 mg/kg. Cyclophosphan - Belmed is recommended to be injected in the morning provided that the patient has taken a large amount of liquid immediately before or after the administration.
Haematopoietic organs: leucopenia, neutropenia, thrombocytopenia, anemia. The most evident leucopenia and thrombocytopenia are observed on Day 7 – 17 (the incremental recovery occurs in 7 – 10 days after the treatment completion).
Digestive system: nausea, vomiting, anorexia, stomatitis, abdominal discomfort or pain, diarrhea or constipation, hemorrhagic colitis, jaundice, liver function abnormality including an intensified liver transaminases, alkaline phosphatase activities, hyperbilirubinemia; when it is administered in high doses combined with busulphan administration and total irradiation at the time of the bone marrow allogenic transplantation as well as when it is administered in high doses to patients suffering from aplastic anemia obliterating endophlebitis of hepatic vein (Chiari disease) (the body mass acute gain, hepatomegalia, ascitis, hyperbilirubinemia, hepatic encephalopathy) is used to develop in 1 – 3 weeks after the bone marrow transplantation.
Skin integument: alopecia (reversible after the treatment completion or during a long-time treatment; the hair structure and color can differ), skin eruption, skin pigmentation, nails alteration, regeneration disorders.
Urinary system: hemorrhagic urethritis/cystitis, renal tubules necrosis (up to a lethal outcome), urinary bladder fibrosis (including a widespread one) accompanied by cystitis or without it, atypical urinary bladder epithelial cells in the urine. When it is administered in high doses a compromised renal function, hyperuricemia, nephropathy (on the background of hyperuricemia) can be observed.
Cardiovascular system: cardiotoxicity (when 4.5 – 10 g/sq. m or 120 – 270 mg/kg of the drug have been injected for several days as a part of an intensive combined cytostatic or another treatment following the organ transplantation), including an evident heart failure (including resulted in a lethal outcome) on the background of hemorrhagic myocarditis.
Respiratory system: interstitial pulmonary fibrosis (when high doses have been administered for a long time).
Reproductive system: spermatogenesis and oogenesis disorders (infertility can be irreversible), amenorrhea (reversible within several months after the therapy has been stopped), olygospermia or azospermia (associated with the elevated gonadotropic hormone the testosterone secretion being normal; can be reversible in some years after the treatment course in some cases), testis atrophy (of various severity).
Allergic reactions: skin eruption, urticaria, skin itching, rarely – anaphylactic reactions; cross sensitivity with other alkylating compounds is possible.
Others: development of severe infections; syndrome resembling the adrenocorticotropic hormone inadequate secretion syndrome; rush of blood to the face or face hyperemia, headache, hyperhidrosis; development of secondary malignant tumors.
Hypersensitivity, the bone marrow function severe suppression (anemia, leucopenia, thrombocytopenia), cystitis, urinary retention, pregnancy, lactation.
The patient should be monitored thoroughly during treatment as toxic effects can develop under any of the states specified: leucopenia, thrombocytopenia, bone marrow infiltration by tumor cells, beam-therapy or chemotherapy in the anamnesis, renal/hepatic insufficiency.
The blood count (especially neutrophils and platelets numbers) should be controlled twice a week during the therapy main course for determining the myelosuppression degree and once a week when the therapy is supportive; the urine should be assayed for erythrocyturia presence as it can precede hemorrhagic cystitis development. When symptoms of cystitis accompanied by micro- or macrohematuria appear and when the leukocyte number has reduced to 2500/µl and/or the platelet number has reduced to 100,000/µl the drug administration should be cancelled.
Both women and men should use reliable methods of contraception during the period of treatment.
Ethanol drinking and grapefruit (including juice) consumption should be avoided during treatment.
When Cyclophosphan - Belmed is to be administered within the first decade after the surgical interference under general anesthesia the anesthesiologist should be informed about this. After an adrenalectomy has been performed the doses of both the glucocorticosteroids (administered as a replacement therapy) and cyclophosphamide should be adjusted. The drug can increase the anticoagulant activity due to the blood coagulation factors synthesis reduction in liver and platelets production disorders as well as due to an unknown mechanism, too.
For preventing hemorrhagic cystitis consumption of liquid adequate volume and uroprorectors (mesna) administration are recommended. Hematuria is reported to stop in some days after the Cyclophosphan - Belmed administration has been completed. When hemorrhagic cystitis is severe the Cyclophosphan - Belmed administration should be cancelled.
In accordance with the results of electrocardiogram and echocardiogram patients having survived episodes of cardiotoxic effect of the cyclophosphamide high doses exposure did not manifest any myocardial symptoms afterwards.
Secondary sexual characters progressed normally and menstrual cycles were normal in girls having been treated with Cyclophosphan - Belmed during the prepubertal period; in future they could get pregnant successfully. Male’s sexual interest and potency do not alter. Secondary sexual characters progressed normally in boys treated with Cyclophosphan - Belmed during the prepubertal period, however, oligospermia or azospermia can occur and the gonadotropic hormone secretion can intensify.
After the drug has been administered earlier secondary malignant tumors, the urinary bladder tumors most often (usually it is observed in patients having hemorrhagic cystitis in the anamnesis), as well as myelo- or lymphoproliferative disorders can develop. Secondary tumors were found in patients having been treated for primary myeloproliferative malignant or benign diseases on the background of immune disorders most often. In a number of cases the secondary tumor appeared in several years after the drug administration had been discontinued.
Administration during pregnancy and lactation
The drug administration is contraindicated during pregnancy (it has embryotoxic and teratogenic effects). Breast feeding should be interrupted for the treatment period.
Interaction with other drug products
It aggravates the succinylcholine effect (suppressing the cholinesterase activity for a long time), reduces or inhibits the cocaine metabolism, intensifies and/or prolongs its action increasing the risk of toxicity. Cyclophosphamide suppresses the cholinesterase activity thus potentiating the acetylcholine effect. It aggravates the doxorubicin and daunorubicin cardiotoxic effects. The liver microsomal oxidation inducers elevate the cyclophosphamide alkylating metabolites production, reduce its half-elimination and aggravate its activity. Myelotoxic medicinal agents including allopurinol, beam therapy cause intensification of the cyclophosphamide myelotoxic effect. Uricosuric medicinal agents increase the risk of nephropathy development (the uricosuric drug dose may need being corrected). Grapefruit juice disrupts the cyclophosphamide activation and therefore the drug effect. Other immune depressants (including azathioprine, chlorambucil, glucocorticosteroids, cyclosporine, mercaptopurine) elevate the risk of infections and secondary tumors development. Concurrent lovastatin administration in case the heart is transplanted increases the risk of skeletal muscle acute necrosis and of acute renal insufficiency. Concurrent cytarabine high dose administration leads to the cardiomyopathy frequency increase with a possibility of a lethal outcome when the patient is prepared for the bone marrow transplantation.
Measures of precaution
Cyclophosphan - Belmed should be prescribed with caution to patients with decompensated heart, liver or kidney disorders; after adrenalectomy, podagra (in the anamnesis), nephrourolithiasis, bone marrow depression, bone marrow infiltration by tumor cells, after previous chemotherapy or beam therapy.
Cyclophosphan - Belmed is not recommended to be prescribed earlier than in a decade after the surgery performed under anesthesia.
Store in protected from light place at temperature below 25°C.
Keep out of reach of children.
Do not use after expiration of a shelf life.
200 mg vials. Vial together with leaflet is placed in a cardboard pack. Packing for hospitals: 40 vials together with appropriate number of leaflets are put into a cardboard multipack.
Republic of Belarus,
30, Fabritsius str.