Cyclophocil (Powder) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Nord, JSC (Russia)

Manufactured By

Pharmasintez, JSC (Russia)

ATC Code

L01AA01 (Cyclophosphamide)

Active Substance

Cyclophosphamide (Rec.INN WHO registered)

Dosage Forms

	Cyclophocil	Powder for solution for intravenous and intramuscular administration 200 mg: vial 1 pc.
		Powder for solution for intravenous and intramuscular administration 500 mg: vial 1 pc.
		Powder for solution for intravenous and intramuscular administration 1000 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Powder for solution for intravenous administration white or almost white crystalline.

200 mg – vials (1) – carton packs.
200 mg – vials (5) – carton packs (for hospitals).
200 mg – vials (10) – carton packs (for hospitals).
200 mg – vials (15) – carton packs (for hospitals).
200 mg – vials (20) – carton packs (for hospitals).
200 mg – vials (25) – carton packs (for hospitals).
200 mg – vials (30) – carton packs (for hospitals).
200 mg – vials (35) – carton packs (for hospitals).
200 mg – vials (40) – carton packs (for hospitals).
200 mg – vials (45) – carton packs (for hospitals).
200 mg – vials (50) – carton packs (for hospitals).
200 mg – vials (55) – carton packs (for hospitals).
200 mg – vials (60) – carton packs (for hospitals).
200 mg – vials (65) – carton packs (for hospitals).
200 mg – vials (70) – carton packs (for hospitals).
200 mg – vials (75) – carton packs (for hospitals).
200 mg – vials (80) – carton packs (for hospitals).
200 mg – vials (85) – carton packs (for hospitals).
200 mg – vials (90) – carton packs (for hospitals).
200 mg – vials (95) – carton packs (for hospitals).
200 mg – vials (100) – carton packs (for hospitals).

Powder for solution for intravenous administration white or almost white crystalline.

200 mg – vials (1) – carton packs.
200 mg – vials (5) – carton packs (for hospitals).
200 mg – vials (10) – carton packs (for hospitals).
200 mg – vials (15) – carton packs (for hospitals).
200 mg – vials (20) – carton packs (for hospitals).
200 mg – vials (25) – carton packs (for hospitals).
200 mg – vials (30) – carton packs (for hospitals).
200 mg – vials (35) – carton packs (for hospitals).
200 mg – vials (40) – carton packs (for hospitals).
200 mg – vials (45) – carton packs (for hospitals).
200 mg – vials (50) – carton packs (for hospitals).
200 mg – vials (55) – carton packs (for hospitals).
200 mg – vials (60) – carton packs (for hospitals).
200 mg – vials (65) – carton packs (for hospitals).
200 mg – vials (70) – carton packs (for hospitals).
200 mg – vials (75) – carton packs (for hospitals).
200 mg – vials (80) – carton packs (for hospitals).
200 mg – vials (85) – carton packs (for hospitals).
200 mg – vials (90) – carton packs (for hospitals).
200 mg – vials (95) – carton packs (for hospitals).
200 mg – vials (100) – carton packs (for hospitals).

Powder for solution for intravenous administration white or almost white crystalline.

200 mg – vials (1) – carton packs.
200 mg – vials (5) – carton packs (for hospitals).
200 mg – vials (10) – carton packs (for hospitals).
200 mg – vials (15) – carton packs (for hospitals).
200 mg – vials (20) – carton packs (for hospitals).
200 mg – vials (25) – carton packs (for hospitals).
200 mg – vials (30) – carton packs (for hospitals).
200 mg – vials (35) – carton packs (for hospitals).
200 mg – vials (40) – carton packs (for hospitals).
200 mg – vials (45) – carton packs (for hospitals).
200 mg – vials (50) – carton packs (for hospitals).
200 mg – vials (55) – carton packs (for hospitals).
200 mg – vials (60) – carton packs (for hospitals).
200 mg – vials (65) – carton packs (for hospitals).
200 mg – vials (70) – carton packs (for hospitals).
200 mg – vials (75) – carton packs (for hospitals).
200 mg – vials (80) – carton packs (for hospitals).
200 mg – vials (85) – carton packs (for hospitals).
200 mg – vials (90) – carton packs (for hospitals).
200 mg – vials (95) – carton packs (for hospitals).
200 mg – vials (100) – carton packs (for hospitals).

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; alkylating agents; nitrogen mustard analogues

Pharmacological Action

Antineoplastic agent of alkylating action. The cytotoxic effect of cyclophosphamide is based on the interaction of its alkylating metabolites with DNA. Alkylation leads to strand breaks and the formation of cross-links between DNA strands, as well as between proteins and DNA strands. As a result, the progression of cells into the G2 phase of the cell cycle is slowed down. The cytotoxic effect is not specific to a particular phase of the cell cycle; it acts throughout its entire duration.

Acrolein does not possess antineoplastic activity; nevertheless, it is the cause of side effects on the urinary tract. There is also an assumption about the immunosuppressive effect of cyclophosphamide.

Pharmacokinetics

Cyclophosphamide is almost completely absorbed from the gastrointestinal tract. Bioequivalent levels of cyclophosphamide in the blood are observed after intravenous and oral administration.

Cyclophosphamide was detected in the cerebrospinal fluid and breast milk. Cyclophosphamide and its metabolites cross the placental barrier.

The mean T_1/2 is approximately 7 hours in adults and approximately 4 hours in children.

Cyclophosphamide is not characterized by significant binding to plasma proteins. However, the binding of its metabolites to plasma proteins is approximately 50%.

Cyclophosphamide and its metabolites are excreted primarily by the kidneys.

Indications

As monotherapy or as part of combination therapy with other antineoplastic drugs for the following diseases: acute lymphoblastic or chronic lymphocytic leukemia, myeloid/myelogenous leukemia; malignant lymphomas: Hodgkin’s disease, non-Hodgkin’s lymphoma; multiple myeloma, macroglobulinemia; metastatic and non-metastatic malignant solid tumors: ovarian cancer, small cell lung cancer, neuroblastoma, Ewing’s sarcoma; adjuvant therapy for breast cancer after tumor resection or mastectomy; palliative therapy for metastatic breast cancer; germ cell tumors, soft tissue sarcoma, reticulosarcoma. Treatment of transplant rejection reaction. Conditioning before allogeneic bone marrow transplantation. Progressive autoimmune diseases (rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus (including severe forms of lupus nephritis), scleroderma, systemic vasculitis (e.g., with nephrotic syndrome), certain types of glomerulonephritis (e.g., with nephrotic syndrome), Myasthenia gravis, autoimmune hemolytic anemia, cold agglutinin syndrome, Wegener’s granulomatosis).

ICD codes

Dosage Regimen

Determine the dosage regimen individually based on the specific malignancy, disease stage, chemotherapy protocol, and patient’s hematological status.

Administer orally, intravenously, or intramuscularly. Use as monotherapy or within a combination chemotherapy regimen.

For oral administration, take the total daily dose as a single intake. For intravenous use, reconstitute the powder with Sterile Water for Injection or Sodium Chloride 0.9%. Administer as a slow intravenous injection or infusion.

For intramuscular injection, dissolve the powder in 0.5% Procaine Hydrochloride solution or Water for Injection. Inject deeply into the gluteal muscle.

Adjust the dose based on white blood cell count and platelet count. Withhold therapy if leukocytes fall below 2,000/mm³ or platelets below 50,000/mm³.

For adult monotherapy, initiate with an initial intravenous dose of 40-50 mg/kg, divided into 2-5 daily doses. Alternatively, use 10-15 mg/kg intravenously every 7-10 days, 3-5 mg/kg intravenously twice weekly, or 1-5 mg/kg orally daily.

For pediatric patients, calculate the dose based on body surface area. Common regimens include 2-8 mg/kg orally or intravenously daily, or 10-15 mg/kg intravenously every 7-10 days.

In autoimmune diseases, typical doses range from 1-3 mg/kg/day orally. For bone marrow transplantation conditioning, use high doses of 50-60 mg/kg/day intravenously for 2-4 days.

Ensure adequate hydration and consider mesna co-administration with high-dose regimens to prevent hemorrhagic cystitis.

Monitor blood counts, liver function, and renal function before and during therapy. Dose reduction is necessary for patients with renal impairment or hepatic impairment.

Adverse Reactions

Infections and infestations: frequent – reactivation of latent bacterial, fungal, viral, protozoal and parasitic infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leukoencephalopathy (including fatal cases), Pneumocystis jirovecii, Herpes zoster, Strongyloides; infrequent – pneumonia, sepsis; very rare – septic shock

Benign, malignant and unspecified neoplasms (including polyps and cysts): rare – acute leukemia, myelodysplastic syndrome, bladder cancer, urethral cancer; very rare – tumor lysis syndrome; frequency unknown – lymphomas, progression of underlying malignant diseases, sarcomas, renal cell carcinoma, transitional cell carcinoma of the renal pelvis, thyroid cancer; carcinogenic effects in offspring.

Blood and lymphatic system disorders very common – leukopenia, thrombocytopenia, anemia, neutropenia, agranulocytosis, pancytopenia, decreased hemoglobin; common – febrile neutropenia, neutropenic fever; very rare – disseminated intravascular coagulation, hemolytic-uremic syndrome; frequency unknown – granulocytopenia, lymphopenia.

Immune system disorders: very common – immunosuppression; infrequent – hypersensitivity reactions; very rare – anaphylactic shock, anaphylactic/anaphylactoid reactions.

Endocrine disorders: very rare – syndrome of inappropriate antidiuretic hormone secretion; frequency unknown – water intoxication.

Metabolism and nutrition disorders: common – anorexia, rare – dehydration; very rare – hyponatremia, fluid retention; frequency unknown – changes in blood glucose levels.

Nervous system disorders: infrequent – peripheral neuropathy, polyneuropathy, neuralgia; rare – dizziness; very rare – impaired consciousness, convulsions, encephalopathy, paresthesia; frequency unknown – dysgeusia, hypogeusia, posterior reversible leukoencephalopathy syndrome, myelopathy, dysesthesia, hypoesthesia, tremor, parosmia.

Eye disorders rare – blurred vision; very rare – visual disturbances, conjunctivitis, eyelid edema; frequency unknown – increased lacrimation.

Ear and labyrinth disorders infrequent – deafness; frequency unknown – tinnitus, hearing impairment.

Cardiac disorders infrequent – cardiomyopathy, myocarditis, heart failure (including isolated cases with fatal outcome), tachycardia, flushing, decreased blood pressure; rare – ventricular arrhythmia (including ventricular tachycardia and ventricular fibrillation), supraventricular arrhythmia; very rare – atrial fibrillation, cardiac arrest, myocardial infarction, pericarditis, thromboembolism, arterial hypertension, arterial hypotension; frequency unknown – cardiogenic shock, pericardial effusion/cardiac tamponade, myocardial hemorrhage, left ventricular failure, bradycardia, cardiac arrhythmia, QT interval prolongation on ECG, decreased cardiac output, carditis, palpitations, pulmonary embolism, venous thrombosis, vasculitis, peripheral ischemia, hyperemia.

Respiratory, thoracic and mediastinal disorders: rare – pneumonitis; frequency unknown – acute respiratory distress syndrome, chronic interstitial pulmonary fibrosis, pulmonary edema, pulmonary hypertension, bronchospasm, dyspnea, hypoxia, cough, unspecified lung function disorders, nasal congestion, nasal discomfort, oropharyngeal pain, nasal discharge, sneezing, pulmonary veno-occlusive disease, obliterative bronchiolitis, hospital-acquired pneumonia, allergic alveolitis, pleural effusion, respiratory arrest.

Gastrointestinal disorders: common – stomatitis, diarrhea, vomiting, constipation, nausea; very rare – hemorrhagic enterocolitis, acute pancreatitis, ascites, mucosal ulceration, gastrointestinal bleeding; frequency unknown – abdominal pain, parotid gland inflammation, colitis, enteritis, appendicitis, typhlitis.

Hepatobiliary disorders: common – impaired liver function; rare – hepatic veno-occlusive disease, increased blood bilirubin, increased AST, ALT, GGT, ALP activity; very rare – activation of viral hepatitis, liver enlargement, jaundice; frequency unknown – cholestatic hepatitis, cytolytic hepatitis, cholestasis, hepatic encephalopathy, hepatotoxicity with liver failure.

Skin and subcutaneous tissue disorders: very common – alopecia; rare – exanthema, dermatitis, discoloration of the skin of the palms, soles and nails; very rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme; frequency unknown – radiation skin injury, radiation burn, pruritus, toxic rash, palmar-plantar erythrodysesthesia syndrome, urticaria, blistering, skin redness, facial swelling, hyperhidrosis.

Musculoskeletal system side effects: frequency unknown – rhabdomyolysis, scleroderma, muscle cramps, myalgia, arthralgia.

Urinary system side effects: very common – cystitis, microhematuria; common – hemorrhagic cystitis (including isolated cases with fatal outcome), macrohematuria; very rare – suburothelial hemorrhage, bladder wall edema, interstitial inflammation with bladder fibrosis and sclerosis, renal failure, increased creatinine level, tubular necrosis; frequency unknown – renal tubule disease, toxic nephropathy, hemorrhagic urethritis, ulcerative cystitis, bladder contracture, nephrogenic diabetes insipidus, atypical bladder epithelial cells, increased blood in urine, impaired renal function.

Reproductive system side effects: common – impaired spermatogenesis; uncommon – impaired ovulation; rare – amenorrhea, azoospermia, oligospermia; frequency unknown – impaired ovarian function, infertility, ovarian insufficiency, ovulation discomfort, oligomenorrhea, testicular atrophy, decreased blood estrogen level, increased blood gonadotropin level, premature birth, intrauterine fetal death, fetal deformities, fetal growth retardation, fetotoxicity (including myelosuppression /gastroenteritis).

Laboratory parameters side effects: very rare – hyperuricemia due to tumor lysis syndrome; frequency unknown – increased blood LDH level, increased C-reactive protein level.

Other side effects: very common – fever; common – chills, asthenia, feeling of fatigue, discomfort sensation, mucosal inflammation; rare – chest pain; very rare – headache, pain, multiorgan failure, phlebitis; frequency unknown – edema, flu-like reactions, general mental lability, slow wound healing.

Local reactions with IV administration – reactions at the injection site (thrombosis, necrosis, inflammation, pain, swelling, skin redness).

Contraindications

Hypersensitivity to cyclophosphamide or its metabolites; severe bone marrow function disorders (myelosuppression, especially in patients previously treated with cytotoxic agents and/or radiation therapy); cystitis; urinary tract obstruction; severe infectious process; pregnancy, breastfeeding period.

Use with caution

Heart disease or existing risk factors for cardiotoxicity, acute porphyria, acute urinary tract infections, severe bone marrow function disorders, severe immunosuppression; diabetes mellitus, debilitated patients, elderly age, chronic liver diseases, kidney diseases.

Before starting cyclophosphamide conditioning prior to allogeneic bone marrow transplantation, the presence of general contraindications for allogeneic bone marrow transplantation should be carefully assessed, such as age over 50 years, bone marrow contamination with metastases of a malignant (epithelial) tumor and insufficient HLA compatibility with the donor in chronic myeloid leukemia.

Use in Pregnancy and Lactation

Cyclophosphamide is contraindicated during pregnancy. If use during lactation is necessary, the issue of discontinuing breastfeeding should be decided.

Women of childbearing potential should use reliable methods of contraception during therapy and for 6 months after completion of the treatment course.

Experimental studies have established the teratogenic and embryotoxic effects of cyclophosphamide.

Use in Hepatic Impairment

Use with caution in chronic liver diseases.

Use in Renal Impairment

Contraindicated in cystitis, in urinary tract obstruction. Use with caution in acute urinary tract infections, chronic kidney diseases.

Pediatric Use

Can be used in children according to indications, in doses, regimens and dosage forms recommended according to body surface area. It is necessary to strictly follow the instructions in the cyclophosphamide drug prescribing information for use in children.

Geriatric Use

Should be prescribed with caution to elderly patients. Before starting cyclophosphamide conditioning prior to allogeneic bone marrow transplantation, the presence of general contraindications should be carefully assessed in patients over 50 years of age.

Special Precautions

Cyclophosphamide should be prescribed by a physician experienced in the use of antineoplastic agents. The dosage regimen is selected according to the indications and chemotherapy regimen, duration of therapy and/or treatment intervals, the general health status of the patient and the functioning of their individual organs, laboratory parameters (in particular, blood cell counts).

Cyclophosphamide should be used with caution in debilitated and elderly patients who have previously received radiation therapy. In addition, the condition of patients with a weakened immune system, diabetes mellitus, chronic liver or kidney diseases, with a previous heart disease should be carefully monitored. In patients with diabetes mellitus, glucose metabolism should also be carefully monitored during cyclophosphamide treatment.

Caution should be exercised when treating patients with acute porphyria, as Cyclophosphamide has a porphyrinogenic effect.

When using cyclophosphamide in combination with other cytostatics of similar toxicity, dose reduction or increased intervals between drug administrations may be required. The use of hemopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered as reducing the risk of complications associated with bone marrow function suppression and/or facilitating the transition to the planned dose.

Systematic monitoring of the peripheral blood picture is necessary during treatment.

During cyclophosphamide therapy, the activity of liver transaminases and LDH, bilirubin level, plasma uric acid concentration, diuresis and urine specific gravity should be monitored, and tests for microhematuria should also be performed.

Before starting therapy, it is necessary to exclude urinary tract obstruction, inflammation and infection of the bladder, and electrolyte imbalance.

During therapy, patients should not consume grapefruits or grapefruit juice, as this may reduce the effectiveness of cyclophosphamide.

During cyclophosphamide therapy, blood and urine sediment analysis should be performed.

Timely intake of antiemetic drugs should be monitored and proper oral hygiene should be maintained.

During or immediately after cyclophosphamide administration, intake or infusion of a sufficient amount of fluid is required to force diuresis in order to reduce the risk of urotoxicity.

When using cyclophosphamide in higher doses, mesna administration is advisable to prevent hemorrhagic cystitis.

Experimental studies have established the carcinogenic and mutagenic effects of cyclophosphamide.

Effect on ability to drive vehicles and operate machinery

During the use of cyclophosphamide, patients should exercise caution when driving vehicles and operating machinery, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

With simultaneous use, Cyclophosphamide may enhance the effect of hypoglycemic drugs.

Concomitant use with allopurinol may lead to increased myelotoxicity.

With simultaneous use with indirect anticoagulants, a change in anticoagulant activity is possible (as a rule, Cyclophosphamide reduces the synthesis of clotting factors in the liver and impairs the platelet formation process).

With concomitant use with cytarabine, daunorubicin or doxorubicin, an increase in cardiotoxic effects is possible.

With concomitant use with immunosuppressants, the risk of infections and secondary tumors increases.

With simultaneous use of cyclophosphamide with lovastatin, the risk of acute skeletal muscle necrosis and acute renal failure increases.

Drugs that are inducers of microsomal enzymes cause increased formation of active metabolites of cyclophosphamide, leading to an enhancement of its effect.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.