Cyclophosphanum

General characteristics. Structure:

Active ingredient: Cyclophosphanum (cyclophosphamide) sterile in terms of 100% substance of 200 mg.

Pharmacological properties:

Pharmacodynamics. Cyclophosphamide is cytostatics of group of oksazafosforin. In vitro cyclophosphamide is inactive. Its activation happens by means of mikrosomny enzymes in a liver where it turns into 4-gidrokso-cyclophosphamide which is in balance with its tautomer – aldophosphamide. Cytotoxic effect of cyclophosphamide is based on its interaction between its alkylating metabolites and DNA. This alkylation is led to a gap by those to coupling of cross bonds of DNA and DNA-proteins threads. In a cellular cycle transfer through G2 a phase is slowed down. Cytotoxic action is not characteristic of a phase of a cellular cycle, but it is specific to a cellular cycle. It is impossible to exclude mutual counteraction, especially with cytostatics of similar structure as, for example, with ifosfamidy, and also with other alkilant.

Pharmacokinetics. Cyclophosphamide is almost completely soaked up from a gastro intestinal path. After a single intravenous injection of cyclophosphamide for 24 hours there is a considerable decrease in concentration of cyclophosphamide and its metabolites in a blood plasma, but the levels determined in a blood plasma can be in existence till 72 o'clock. The cyclophosphamide elimination half-life from blood serum averages 7 hours for adults and 4 hours – for children. Removal of cyclophosphamide and its metabolites happens preferential kidneys. Levels in blood after an intravenous and peroral dosage of a bioekvivalentna.
Pharmaceutical characteristics.
Main physical and chemical properties: crystal powder of white or almost white color. Incompatibility. The solutions containing benzyl alcohol can reduce stability of cyclophosphamide.

Indications to use:

Циклофосфан® it is applied to mono - or polychemotherapy at treatment:
– leukoses: acute or chronic lymphoblastoid/lymphocytic and myeloid/myelogenetic leukoses;
– malignant lymphoma: Hodzhkin's (lymphogranulomatosis) diseases, nekhodzhkinsky lymphoma, plasmacytoma;
– big malignant tumors with existence of metastasises or without them: ovary cancer, cancer of testicles, a breast cancer, small-celled lung cancer, a neuroblastoma, Ewing's sarcoma, a rhabdomyosarcoma at children, an osteosarcoma;
– the progressing "autoimmune diseases", such as pseudorheumatism, psoriasis arthropathy, system lupus erythematosus, scleroderma, system vasculitis (for example with a nephrotic syndrome), certain types of a glomerulonephritis (for example with a nephrotic syndrome), a myasthenia гравис, autoimmune hemolitic anemia, a disease of cold agglutinins, Wegener's granulomatosis. Циклофосфан® it is applied also to suppression of immunity at organ transplantation and to conditioning before bone marrow transplantation at heavy aplastic anemia, acute myeloid and acute lymphoblastoid leukoses, a chronic myeloid leukosis.

Route of administration and doses:

Intravenous infusion. Only the experienced oncologist can appoint drug. The dosage should be selected individually for each patient. The following recommendations concerning a dosage can be used for monotherapy by cyclophosphamide. At joint purpose of other tsitostatik of similar toxicity the dose decline or extension of pauses at treatment can be necessary drug.
If another is not appointed, such dosages are recommended:
– for continuous treatment of adults and children – from 3 to 6 mg/kg of body weight, daily (from 120 to 240 mg / кг2 are equivalent to body surface area);
– for discontinuous therapy of adults and children – from 10 to 15 mg/kg of body weight (from 400 to 600 mg/sq.m of surface area of a body are equivalent), bucketed from 2 to 5 days;
– for discontinuous therapy of adults and children with a high dose – from 20 to 40 mg/kg (from 800 to 1600 mg/sq.m of surface area of a body are equivalent), or with a bigger dose
(for example, when conditioning before bone marrow transplantation), bucketed from 21 to 28 days.
Solution preparation
Just before use with a dosage of 200 mg add 10 ml of 0,9% of solution of sodium of chloride to contents of one bottle. Substance is easily dissolved at vigorous stirring after solvent addition. If substance is not dissolved at once and completely, it is recommended to allow to stand to a bottle several minutes. Solution suitable for intravenous appointment, at the same time is better to carry out introduction in the form of intravenous infusion. At short-term intravenous administration Tsiklofosfana® solution is added to Ringer's solution, by 0,9% of solution of sodium of chloride or solution of glucose to total amount about 500 ml. Infusion duration – of 30 minutes till 2 o'clock, depending on volume.
The medical cycles at discontinuous therapy can be repeated each 3–4 weeks. Duration of therapy and intervals between courses depend on indications, use of a combination of chemotherapeutic drugs, the general state of health of the patient, laboratory indicators and recovery of quantity of uniform elements of blood.
Special recommendations about a dosage
Recommendations concerning a dose decline for patients with oppression of function of marrow:
– leukocytes> 4000 мкл, and thrombocytes> 100000 мкл – 100% of the planned dose;
– leukocytes 4000-2500 мкл, and thrombocytes 100000-50000 мкл – 50% of a dose;
– leukocytes <2500 мкл, and thrombocytes <50000 мкл – selection of a dose before normalization of indicators or adoption of the hotel decision.
Use in a combination with other substances which oppress blood circulation demands adjustment of a dose. It is necessary to use the corresponding tables of adjustment of a dose for cytotoxicity of medicines on quantitative structure of uniform elements of blood at the beginning of a cycle and adjustment of a dose on the minimum level of cytostatic substances. The recommendation concerning selection of a dose for patients with a liver failure the Heavy liver failure demands a dose decline. The dose decline for 25% at the content in serum of bilirubin from 3,1 to 5 mg / 100 ml is the general recommendation.
Recommendations about selection of a dose at patients with a renal failure
The dose decline for 50% is recommended at a speed of glomerular filtering at the level of less than 10 ml/min. Cyclophosphamide can be removed from an organism by means of dialysis.
Children and teenagers
Dosage – according to the accepted treatment planning; recommendations about selection of a dose and use of drug for treatment of children and teenagers same, as well as for adult patients.
Patients of advanced age and physically weakened patients
Generally, in view of the increased frequency of cases of decrease in hepatic, renal or cordial function, and also existence of associated diseases and use of other medicamentous therapy, selection of a dose for this group of patients should be carried out with care.

Features of use:

To apply only to destination and under strict control of the doctor! Before an initiation of treatment it is necessary to eliminate possible barriers to removal of urine from urinary tract, disturbances of electrolytic balance, to sanify possible infections (cystitis). From system of blood and lymphatic system. It is necessary to expect serious oppression of function of marrow, especially at patients who before it were treated with the help himio-and/or radiotheraphy, and also at patients with an impaired renal function. Therefore for all patients during treatment constant hematologic control with regular calculation of uniform elements of blood is shown. Calculation of leukocytes and thrombocytes, and also definition of a hemoglobin content should be carried out before each administration of drug, and also with certain intervals. In the course of treatment it is necessary to control quantity of leukocytes systematically: at the beginning of a course of treatment – with an interval of 5-7 days if their quantity decreases to <3000 in mm3, then time in two days or daily. At prolonged treatment it is usually enough to carry out the analysis
blood of times in two weeks. Without urgent need of Tsiklofosfan® patients cannot appoint at quantity of leukocytes less 2500/mkl and/or quantity of thrombocytes less than 50 000/mkl. In case of an agranulocytic fever and/or a leukopenia it is necessary to appoint antibiotics and/or antifungal drugs preventively. It is regularly necessary to analyze the uric rest on the maintenance of erythrocytes. From immune system. Patients with the weakened immune system, for example patients on a diabetes mellitus, with a chronic renal or liver failure, also require special attention. In general Tsiklofosfan®, as well as other cytostatics, it is necessary to apply with care
at treatment of the weakened patients and people of advanced age, and also after carrying out radiotheraphy. From kidneys and an urinary system. Before an initiation of treatment it is necessary to pay attention to a condition of an urinary system. The corresponding treatment uroprotektory uromiteksany, and also reception of enough liquid can significantly reduce the frequency and weight of toxic influence of drug. Regular bladder emptying is important.
If at treatment of Tsiklofosfanom® emergence of cystitis with a micro or gross hematuria is noted, therapy by drug should be stopped before normalization of a state. The patients having diseases of kidneys during treatment of Tsiklofosfanom® demand careful leaving. Cardial disturbances. Patients have data on strengthening of cardiotoxic effect of Tsiklofosfana® after the previous radiotheraphy of area of heart and/or the accompanying treatment by anthracyclines or pentostatiny. It is necessary to remember need of regular checks of electrolytic composition of blood, to pay special attention to patients with heart diseases in the anamnesis. Gastrointestinal frustration. For the purpose of reduction of frequency and weight of such effects as nausea and vomiting it is necessary to appoint antiemetic drugs. Alcohol can strengthen these by-effects therefore patients who receive treatment of Tsiklofosfanom® should recommend to refuse alcohol intake. For decrease in frequency of emergence of stomatitis it is necessary to pay attention to hygiene
oral cavities.
From gepatobiliarny system. It is necessary to use drug for treatment of patients with an abnormal liver function only after careful assessment in each case. Such patients demand careful supervision. The alcohol abuse can increase risk of development of hepatic dysfunction. Frustration of reproductive system / genetic disorders. Treatment of Tsiklofosfanom® can cause genetic anomalies in men and women. Therefore during treatment by drug and for six months after its termination it is necessary to avoid pregnancy. Throughout this time sexually active men and women have to apply effective methods of contraception. At men treatment can increase risk of development of irreversible infertility therefore they have to be informed on need of preservation of sperm prior to treatment. The general disturbances / disturbances in an injection site. As the cytostatic effect of Tsiklofosfana® is defined after its bioactivation which occurs in a liver, risk of damage of fabrics at inadvertent paravenous administration of solution drug insignificant. At patients with a diabetes mellitus it is regularly necessary to check sugar level in blood timely to modify antidiabetic therapy. Ability to influence speed of response at control of motor transport or work with other mechanisms. Owing to possibility of side effects at use of Tsiklofosfana® the doctor has to warn the patient about need of respect for care during the driving of motor transport or occupations potentially unsafe types of activity which require special attention.

Side effects:

The patients receiving Tsiklofosfan® depending on a dosage can have following side reactions which in most cases are reversible. Infections and invasions. Usually heavy oppression of marrow can lead to agranulocytic fever and consecutive infections like pneumonia progressing in sepsis (infections, life-threatening) which in isolated cases can come to an end letalno. Disturbances from immune system. The hypersensitivity reactions which are followed by rashes, a fever, a fever, tachycardia, a bronchospasm, short wind, hypostasis, rush of blood and a lowering of arterial pressure can seldom take place. In isolated cases anaphylactoid reactions can progress to an acute anaphylaxis.
From system of blood and lymphatic system. Depending on a dosage different forms of oppression of marrow, such as leukopenia, neutropenia can be noted. thrombocytopenia with the increased risk of bleeding and anemia. It is necessary to take in attention that heavy oppression of marrow can lead to agranulocytic fevers and to development secondary (sometimes life-threatening) infections. The minimum quantity of leukocytes and thrombocytes is usually noted for the 1st and 2nd week of treatment. Marrow is recovered rather quickly, and a blood picture
it is normalized, as a rule, in 20 days after an initiation of treatment. Anemia usually can develop only after several cycles of treatment. The heaviest oppression of function of marrow should be expected at patients who before it were treated with the help himio-and/or radiation therapy, and also at patients with a renal failure. Simultaneous treatment with other substances which oppress a hemopoiesis demands adjustment of a dose. It is necessary to use the corresponding tables of adjustment of doses for cytotoxicity of medicines on quantitative composition of blood at the beginning of a cycle of treatment and adjustment of doses on the lowest levels of cytostatic substances.
From a nervous system. In isolated cases it was reported about neurotoxic reactions, such as paresthesia, peripheral neuropathy, polyneuropathy, and also about neuropathic pain, disturbance of taste and spasms.
From a digestive tract. Such side reactions as nausea and vomiting are very frequent and dozozavisimy. Averages and severe forms of their manifestations are noted approximately at 50% of patients. Anorexia, diarrhea, a lock and an inflammation of mucous membranes from stomatitis before formation of ulcers are noted with a smaller frequency. It was in some cases reported about hemorrhagic colitis, acute pancreatitis. It was in some cases reported about gastrointestinal bleeding. In case of nausea and
vomitings dehydration can sometimes develop. It was reported about isolated cases of abdominal pain because of gastrointestinal frustration.
From gepatobiliarny system. It was seldom reported about an abnormal liver function (increase in level of serumal transaminases, gamma глутамил - transpeptidases, an alkaline phosphatase, bilirubin).
The obliterating endophlebitis of hepatic veins was noted approximately at 15-50% of patients who received high doses of cyclophosphamide in total with busulfany or radiation of all body at allogenic transplantation of marrow. To the contrary, this complication was noted at patients with aplastic anemia who received only high doses of Tsiklofosfana®. The syndrome usually develops in 1-3 weeks after transplantation and is shown by sharp increase in body weight, a hepatomegalia, ascites and a hyperbilirubinemia and portal hypertensia. Very seldom hepatic encephalopathy can develop. The known risk factors which promote development in the patient of an obliterating endophlebitis of hepatic veins are disturbance of hepatic function, therapy by gepatotoksichny drugs in total with chemotherapy high doses, and especially if an element of the conditioning therapy is the alkylating connection бисульфан.
From kidneys and urinary system. After allocation in urine metabolites of cyclophosphamide cause changes of an urinary system, namely in a bladder. Hemorrhagic cystitis, a microhematuria and a gross hematuria are the most widespread dozozavisimy complications at treatment of Tsiklofosfanom® and demand therapy cancellation. Cystitis develops very often, in the beginning they sterile, but there can be a secondary infection. Also were noted hypostasis of walls uric
bubble, bleeding from a cellular sphere, an intersticial inflammation with fibrosis, and sometimes – a bladder sclerosis. Dysfunction of kidneys (especially in cases of a renal failure in the anamnesis) is not frequent side reaction at use in high doses. Treatment uromiteksany or reception of a large amount of liquid can reduce the frequency and weight of urotoksichesky side reactions. It was in some cases reported about hemorrhagic cystitis with lethal outcomes. The acute or chronic renal failure, a toxic nephropathy, especially at patients with reduced function of kidneys in the anamnesis can be noted.
From reproductive system. Because of ankiliruyushchy action cyclophosphamide can seldom cause disturbance of a spermatogenesis (sometimes non-turnaround) and to lead to an azoospermism and/or a resistant oligospermatism. Disturbances of an ovulation were occasionally noted. It was in some cases reported about an amenorrhea and decrease in level of female sex hormones.
From cardiovascular system. Cardiotoxicity: from minor changes of arterial pressure, changes of EKG, arrhythmias, to a secondary cardiomyopathy with reduced function of a left ventricle and heart failure which in some cases can cause a lethal outcome.
Clinical symptoms of cardiotoxicity can be shown, for example, in the form of a stethalgia and stenocardia attacks. It was occasionally reported about ventrikulyarny, supraventricular arrhythmia. Very seldom at therapy by Cyclophosphanum can develop fibrillation of auricles or ventricles, and also a cardiac standstill. It was seldom or never reported about myocarditis, a pericardis and a myocardial infarction.
Cardiotoxicity especially amplifies after use of drug in high doses (120-240 mg/kg of body weight) and/or at the combined its use with other cardiotoxic drugs, for example anthracyclines or pentostatiny. Strengthening of cardiotoxicity can also arise after preliminary radiotheraphy of area of heart.
From a respiratory organs. A bronchospasm, short wind or cough that leads to a hypoxia. Very seldom the obliterating endophlebitis of lungs, sometimes as a pneumosclerosis complication can develop. It was very seldom reported about a toxic fluid lungs, pulmonary hypertensia, an embolism of lungs and a pleural exudate. In some cases the pneumonitis and intersticial pneumonia, passing can develop in an intersticial pneumofibrosis, it was also reported about respiratory a distress syndrome and respiratory insufficiency with a lethal outcome. High-quality and malignant new growths (including cysts and polyps). As well as always at cytostatic treatment, use of Tsiklofosfana® is followed by risk of development of secondary tumors and their predecessors as late complications.
The risk of development of cancer of an uric path, and also miyelodisplastichesky changes which can partially progress in acute leukoses increases. Researches on animals showed that the threat of cancer of bladder can be reduced considerably by the corresponding use of an uromiteksan. In isolated cases it was reported about a syndrome of disintegration of tumors owing to bystry corresponding reaction of tumors, big, sensitive to chemotherapy.
From skin and its appendages / allergic reactions. The focal allopecia which is frequent side reaction (can progress to total baldness), has, as a rule, reverse character. It was reported about cases of change of a xanthopathy of palms, nails and fingers of hands, and also soles; the dermatitis which is shown an inflammation of skin and mucous membranes. An eritrodizestiya syndrome (feeling of a pricking in palms and soles, up to severe pain). Very seldom, later
radiation therapy and the subsequent treatment by cyclophosphamide it was reported about the general irritation and an erythema on the irradiated area (beam dermatitis). In isolated cases – Stephens-Johnson's syndrome and a toxic epidermal necrosis, fever, shock.
From a musculoskeletal system and connecting fabric. Muscular weakness, рабдомиолиз.
From endocrine system and a metabolism. Very seldom – SISAH (syndrome of inadequate secretion of antidiuretic hormone), a syndrome Schwartz-Barttera with a hyponatremia and a delay of removal of liquid, and also the corresponding symptoms (confusion of consciousness, a spasm). It was in some cases reported about anorexia, it is rare about dehydration and is very rare - about a delay of removal of liquid and a hyponatremia. Disturbances from organs of sight. Deterioration in sight. Owing to reaction of the raised guvstvitelnost very seldom it was reported about such symptoms as conjunctivitis and a swelling a century. Vascular disorders. The basic disease can cause some rare complications, such as a thrombembolia and peripheral ischemia, the disseminated intravascular turning of blood or a hemolitic and uraemic syndrome; frequency
these complications can increase at chemotherapy cyclophosphamide. General frustration. Fever at treatment by Cyclophosphanum – very frequent side reaction in the conditions of development of the hypersensitivity or a neutropenia (associated with an infection). Asthenic states, the general weakness – frequent complications at oncological patients. Very seldom owing to an ekstravazation reactions in a drug injection site in the form of an erythema, an inflammation or phlebitis can be noted.

Interaction with other medicines:

At simultaneous use of Allopyrinolum or hydrochlorothiazide the hypoglycemic effect under the influence of a sulfonilureaza as well as oppression of function of marrow can amplify. Preliminary or parallel treatment by phenobarbital, Phenytoinum, benzodiazepines or hydrochloride can cause microsomal induction of liver enzymes. Ftorkhinolonovy antibiotics (like ciprofloxacin) which were accepted prior to treatment by cyclophosphamide (especially when conditioning before bone marrow transplantation), can reduce effect of drug and by that to lead to a recurrence of a basic disease.
As cyclophosphamide possesses immunosuppressive action, it is necessary to expect on decrease in reaction at the patient to any vaccination; the injection with an aktivorovanny vaccine can be followed by the infection induced by a vaccine. If the depolarizing drugs relaxing muscles are at the same time used (for example halogenides of suktsinilkholin), then the apnoea owing to decrease in concentration of pseudo-cholinesterase can become result long. Simultaneous use of chloramphenicol leads to increase in an elimination half-life of cyclophosphamide and to a metabolization delay.
Treatment by anthracyclines, pentostatiny and trastuzumaby can increase potential cardiotoxicity of drug. The intensification of cardiotoxic effect can be observed also after preliminary radiotheraphy of area of heart. Parallel use of indometacin should be carried out very carefully, посколько in one case the liquid delay was noted. As grapefruit contains connection which is capable to weaken effect of cyclophosphamide, patients cannot eat grapefruits and to drink grapefruit juice. At animals with tumors decrease in antineoplastic activity at the use of ethanol (alcohol) and simultaneous treatment was noted by low doses of peroral cyclophosphamide.
Separate messages confirm the increased risk of pulmonary toxicity (pneumonia, alveolar fibrosis) at patients who received the cytotoxic chemotherapy including cyclophosphamide and G-CSF or GM-CSF. Interaction with Azathioprinum is possible that can lead to a liver necrosis, it was noted at three patients after administration of cyclophosphamide to which treatment by Azathioprinum preceded.
It is known that azolny antifungal drugs (флуконазол, итраконазол) inhibit P450 cytochrome enzymes which metabolize cyclophosphamide. It was reported about higher influence of toxic metabolites of cyclophosphamide among the patients treated itrakonazoly. At patients who receive high doses of cyclophosphamide less than in 24 hours after treatment by high doses of a busulfan, lower clearance and longer elimination half-life of cyclophosphamide can be noted. It can lead to increase in frequency of a venookklyuzionny disease and an inflammation of a mucous membrane (mukotsit).
Concentration of cyclosporine in serum of the patients receiving cyclophosphamide and cyclosporine in a combination was lower, than at the patients receiving only cyclosporine. It can lead "a transplant against the owner" to increase in frequency of a disease. Introduction of a high dose of cyclophosphamide and Cytarabinum in the same day (with very short time interval) will increase cardial toxicity, in view of cardial toxicity of each active agent. It was reported about pharmacokinetic interaction between ondansetrony and cyclophosphamide (in a high dose) that it was shown in decrease in AUCs for cyclophosphamide. It was reported about strong inhibition of bioactivation of cyclophosphamide of tiotepy high-dose chemotherapy in the mode when Thiotepum it was entered in one hour prior to cyclophosphamide. Definition of the sequence and terms of introduction of these two components can have critical value.

Contraindications:

– the known hypersensitivity to cyclophosphamide;
– heavy disturbances of functions of marrow (especially at patients who before that underwent treatment by cytotoxic drugs / or radiotheraphy);
– bladder inflammation (cystitis);
– urination delay;
– active infections.

Use during pregnancy or feeding by a breast. Циклофосфан® it is contraindicated during pregnancy. At the vital indications for
uses of Tsiklofosfana® in the first 3 months of pregnancy it is necessary to resolve an issue about
abortion. In the future, if treatment cannot be postponed and the patient wishes to continue to bear a fruit, the chemotherapy can be carried out only after the message of the patient on possible
risk of teratogenic effects. As cyclophosphamide gets into breast milk, feeding by a breast during treatment it is necessary to stop.
Children. Recommendations about selection of a dose and to use of drug for treatment of children and teenagers same, as well as for adult patients.
Special security measures. At use of Tsiklofosfana® and preparation of solution it is necessary to follow the rules safety measures during the work with cytotoxic substances.

Overdose:

As any specific antidote is not known, it is necessary to adhere to extra care at its use. Cyclophosphamide can be removed from an organism by means of dialysis therefore at overdose the bystry hemodialysis is shown. The clearance of dialysis of 78 ml/min. was calculated from concentration of cyclophosphamide which was not metabolized in dialyzates (the normal renal clearance makes
about 5-11 ml/min.). Other sources reported about the size of 194 ml/min. After 6 hours of dialysis of 72% of the entered dose of cyclophosphamide it was found in dialyzate. At overdose, among other reactions, it is necessary to expect oppression of function of marrow, is more often to a leykotsitopeniye. Weight and duration of oppression of function of marrow depends on extent of overdose. Necessary careful control of indicators of blood and condition of the patient. At development of a neutropenia it is necessary to hold events for prevention of infections; the infection should treat by means of the corresponding antibiotics. At emergence of thrombocytopenia it is necessary to provide replenishment of thrombocytes. It is necessary to take measures for prevention of cystitis by means of an uromiteksan for the prevention of the urotoksichesky phenomena.

Storage conditions:

Period of storage. 3 years. In original packaging at a temperature not above 10 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 200 mg in a bottle, on 40 bottles place in a box for group packaging.