Cyclovid

CYCLOVID^®
DRY INJECTION

COMPOSITION
Cyclovid 200 mg
Each vial contains Cyclophosphamide 200 mg

Cyclovid 500 mg
Each vial contains Cyclophosphamide 500 mg

Cyclovid 1 g
Each vial contains Cyclophosphamide 1000 mg


INDICATION

1.  Malignant lymphomas
2. Multiple myeloma
3. Leukemias
4. Neuroblastoma
5. Adenacardinoma of the ovary
6. Retinoblastoma
7. Carcinoma of the breast

POSOLOGY
Dosage and administration
The drug should be used only under constant supervision by physicians experienced, because concomitant therapy with other neoplastic agents may occur potential risks and fatal complication.
The drug is used for continuous reduction or reduction-induction of disease.

1. Induction dosage
   1. The initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 40 to 50 mg/kg given intravenously in divided dose over a period of 2 to 5 days.
   2. For the treatment of patients who were previously under X-ray therapy or antineoplastic agents which can decrease bone marrow function like cytotoxic drugs, and patients whose bone marrow are infiltrated tumor through, the recommended dose is 1/2 to 1/3 of the initial dose.
   3. Although leukopenia, related to the above dosage, may occur, generally it will disappear 7 - 10 days after the administration. White blood cell count should be monitored in the induction duration.
2. Maintenance dosage
   1. The recommended dose for delay or suppression of tumor growth is the following.
      • 10 to 15 mg/kg/day given every 2 to 10 days intravenously .
      • 3 to 5 mg/kg/day twice a week intravenously
   2. It is generally advisable to administer the largest maintenance dose that reasonably can be tolerated by the patients, unless the disease is unusually sensitive to cyclophosphamide.
   3. Measure of total white blood cell account is a good objective guide for maintenance dosage control. If Decreases in the total white blood cell count to 3000 to 4000 cells/mm3 develops commonly in patients, the drug can be used without risk of serious infection or other complication.
3. Preparation and handling of Solution
   1. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
   2. Cyclophosphamide for injection should be prepared for parenteral use by adding Sterile water for Injection to the vial. Use the quantity of diluent shown below to reconstitute the product.
   
   

   Dosage Strength	Quantity of Diluent
   200 mg	10 mL
   500 mg	25 mL
   1 g	50 mL

   
   
   3. Solutions of Cyclophosphamide for Injection may be injected intravenously, intramuscularly, intraperitoneally, or intrapleurally or the may be infused intravenously in the following:
      • Diluent: Dextrose Injection (5% dextrose), Dextrose and Sodium Chloride Injection (5% dextrose and 0,9% sodium chloride), 5% Dextrose and Ringer's Injection, Sodium Chloride Injection (0.45% sodium chloride), Sodium injection (1/6 molar sodium lactate).
   4. Reconstituted Cyclophosphamide for Injection does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. The Reconstitutes solution should be immediately, not exceeding 6 hours.
   5. Extemporaneous liquid preparations of for oral administration may be prepared by dissolving Cyclophosphamide for Injection in Aromatic Elixir. The concentration of the solution is 1 - 5 mg of Cyclophosphamide per mL. Such preparations should be stored under refrigeration and used within 14 days

WARNINGS AND PRECAUTIONS
General Special attention to the possible development of toxicity should be exercised in patients being treated with cyclophosphamide if any of the following conditions are presents:

1. Leukopenia
2. Thrombocitopenia
3. Tumor cell infiltration of bone marrow
4. Previous x-ray therapy
5. Previous therapy with other cytotoxic agents
6. Impaired renal function
7. Impaired hepatic function

CONTRAINDICATIONS

• Patient who have demonstrated a previous hypersensitivity to cyclophosphamide.
• Continued use of cyclophosphamide contra indicated in patients with severely depressed bone marrow function.

ADVERSE REACTIONS

1. Cardiac Toxicity :
   • Although a few instances of cardiac dysfunction have been reported following use of recommended doses of cyclophosphamide, no casual relationship has been established.
   • Cardiotoxocity has been observed in some patients receiving high doses of cyclophosphamide (120 - 270 mg/Kg) administered over a period of a few days, usually as a portion of an intensive antineoplastic multidrug regimen or in conjunction with transplantation procedures.
   • In a few instances with high doses of cyclophosphamide, severe, and sometimes fatal, congestive heart failure occurred within a few days after the first cyclophosphamide dose.
   • Histopathologic examination has primarily shown hemorrhagic myocarditis. No residual cardiac abnormalities, as evidenced by electrocardiogram or echocardiogram appear to be present in patients surviving episodes of apparent cardiac toxicity associated with high doses of cyclophosphamide.
   • Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity.
2. Second malignancies:
   • Second malignancies have developed in some patients treated with cyclophosphamide used alone or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative, or lymphoproferative malignancies
   • Second malignancies most frequently were detected in patients treated for primary myeloproliferative malignancies or lymphoproferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically.
   • Second urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis.
   • Although the clear relationship between the drug and malignancy in a patients has not established, the possibility of cyclophosphamide-induced malignancy' has been known on the basis of reliable data, therefore the possibility of cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.
3. Hematopoietic:
   • Leukopenia is used as a guide for the expected effect and treatment.
   • Thrombocytopenia or anemia may occur in a few patients and those symptoms reversible occur.
4. Gastrointestinal tract:
   • Anorexia, nausea, vomiting are generally related to individual susceptibility to the drug as well as the dose of cyclophosphamide.
   • Oral mucosa ulcer, jaundice, hemorrhagic colitis during the therapy have been reported.
5. Urinary System:
   • Hemorrhagic cystitis may develop in patients treated with cyclophosphamide, and it is considered to be due to urinary metabolite
   • Non-hemorrhagic cystitis, fibrosis of the urinary bladder related to cyclophosphamide administration have been reported, and atypical urinary bladder epithelial cell have appeared in urine participate
   • Sufficient water intake and frequent acceleration of urination prevent cystitis, and generally, although they occur, the administration doesn't have to discontinued
   • Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist for several months, and in severe case, supplementation of lost bleed may be needed. Protracted cases are successfully treated with application of electrocautery to telangiectatic areas of urinary bladder, diversion of urine flow, or cryosurgary.
   • Renal toxicity such as bleeding, conglobation in renal pelvis has been reported
   • In the patients treated with the drug, gonadal suppression related to the dose and therapy duration has been reported. It may result in amenorrhea or aspermatism and be reversible, therefore, these adverse reactions should be considered.
   • Ovarian fibrosis after the cyclophosphamide administration has been reported.
6. Integument:
   • Alopecia may occur in patients treated with frequent cyclophosphamide therapy. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color.
   • Pigmentation of the skin and changes in nails can occur. General dermatitis may occur
7. Respiratory system:
   • Interstitial pulmonary fibrosis has been reported inpatients receiving high doses of cyclophosphamide over a prolonged period
8. Skin rash occurs occasionally in patients receiving the drug.

DRUG INTERACTIONS

1. Barbiturates: The rate of metabolism and the leukopenia activity of cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital.
2. The patients should be alerted for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even through cyclophosphamide has been used successfully concurrently with the other drugs. In once administration of pentostatin to a patients with cyclophosphamide therapy, confusion, dyspnea, hypotension, pulmonary edema have been developed and death of the patients has been reported. In animal (mouse) studies, concomitant administration with pentostatin (about 10 times of clinical dose), cyclophosphamide (around LD 50) or ephosphamide (around LD 50) have been confirmed that death rate more increased than each separate administration of those drugs.

USE IN PREGNANCY

1. In animal study, cyclophosphamide may occur teratogenesis, or be absorbed in fetus
2. In the Initial pregnancy, the drug should be only when the expected benefits clearly outweigh the potential risk
3. Girls and boys who are possible to be parents should be informed of mutagenic potential of this drug and adequate methods of contraception

USE IN LACTATION
Cyclophosphamide is excreted in breast milk. Breast-feeding should be discontinued prior to the drug therapy.

OVERDOSAGE
No specific antidote for cyclophosphamide is known. Overdosage should be managed with general supportive measure. Including appropriate treatment for any concurrent injection, myelosupression, or cardiac toxicity should be occur.

OTHER
Acute leukemia. urinary bladder tumor, malignant lymphoma, renal pelvic and utheral tumor have been reported in patients receiving long-term cyclophosphamide therapy. In intraperitonial or intravenous administration to rats, and intraperitonial or hypodermic administration to mouse studies, there have been reports of tumors of several internal organs.

STORAGE
Preserve in hermetic containers.
Store at room temperature (below 30°C).

PRESENTATION
Cyclovid 200 mg
Box, 1 vial @ 200mg
Reg. No.: DKI0616200344A1

Cyclovid 500 mg
Box, 1 vial @ 500 mg
Reg. No.: DKI0616200344B1

Cyclovid 1 g
Box, 1 vial @ 1000 mg
Reg. No. DKI0916200344C1

HARUS DENGAN RESEP DOKTER 
ON MEDICAL PRESCRIPTION ONLY

Manufactured by:
KOREA UNITED PHARM. INC.

Imported and Marketed by:
NOVELL
PHARMACEUTICAL
LABORATORIES
BOGOR - INDONESIA

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