Fytosid

Overdose

Overdose can lead within one-two weeks to severe myelosuppression. Total doses of 2.4-3.5 g/m2 of Fytosid administered intravenously over 3 days have caused mucositis and myelotoxicity. Metabolic acidosis and severe hepatic toxicity have been reported after the administration of doses that were higher than recommended. There is no specific antidote available. Treatment should therefore be symptomatic and supportive, and patients should be closely monitored.

Contraindications

- Severe liver impairment

- Severe myelosuppression

- Breastfeeding

- Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see 4.5 interaction with other medicinal products and other forms of interaction).

Pharmaceutical form

Undesirable effects

The following adverse events have been reported in association with Fytosid therapy:

Frequencies are defined using the following convention:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000),

not known (cannot be estimated from the available data)

Hematological Toxicity:

The dose-limiting effect of Fytosid is myelosuppression. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported.

Granulocyte and platelet nadirs tend to occur about 10-14 days after administration of Fytosid depending on the way of administration and treatment scheme. Nadirs tend to occur earlier with intravenous administration compared to oral administration.

Leucopenia in 60-91%, severe leucopenia (< 1,000/µl) in 7-17% of patients, thrombocytopenia in 28-41%, severe thrombocytopenia (< 50,000/µl) in 4-20% of patients. The reports of fever and infection were also very common in patient with neutropenia treated with Fytosid.

Gastrointestinal Toxicity

Nausea and vomiting are the main gastrointestinal undesirable effects and occur in 31-43% of patients given intravenous. Loss of appetite was observed with a frequency of 10-13% of patients.

Stomatitis has been observed in approximately 1-6% of patients. Diarrhea is noted in 1-13% of these patients.

Alopecia:

Reversible alopecia, sometimes progressing to toal baldness has been observed in upto 66% of patients.

Blood pressure changes

Hypotension:

Transient hypotension followingrapid intravenous administration has been reported in patients treated with Fytosid and has not been associated with cardiac toxicity or electrocardiographic changes. Hypotension usually responds to cessation of infusion of Fytosid and/or other supportive therapy as appropriate. When resulting the infusion, a slower administration rate should be used.No delayed hypotension has been noted.

Hypertension:

In clinical studies involving Fytosid injection, hypertension has been reported. If clinically significant hypertension occurs in patients receiving Fytosid injection, appropriate supportive therapy should be initiated.

Allergic reactions:

Anaphylactic type reactions have also been reported to occur during or immediately after intravenous administration of Fytosid. The role that concentration or rate of infusion plays in the development of anaphylactic type reactions is uncertain. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic type-reactions can occur with the initial dose of Fytosid.

Actual fatal reactions associated with bronchospasm have been reported with Fytosid. Facial flushing was reported in 2% and skin rashes in 3% patients.

Metabolic complications:

Tumour lysis syndroms (sometime fatal) has been reported following the use of Fytosid in association with other chemotherapeutic drugs.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard..

Preclinical safety data

Fytosid has been shown to be embryotoxic and teratogenic in experiments with rats and mice. There are positive results from in vitro and in vivo trials with regard to genetic and chromosomal mutations caused by Fytosid. These results justify the suspicion of a mutagenic effect in humans. No animal tests with regard to carcinogenicity were performed. Fytosid is viewed as a potentially carcinogenic drug, as it damages DNA and has mutagenic potential.

Therapeutic indications

Fytosid Injection is indicated in adults for the management of:

- resistant non-seminomatous testicular tumours in combination with other chemotherapeutic agents

- small cell lung cancer, in combination with other chemotherapeutic agents

- acute monoblastic leukaemia (AML M5) and acute myelomonoblastic leukaemia (AML M4) when standard induction therapy has failed (in combination with other chemotherapeutic agents).

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agent—podophyllotoxin derivatives

ATC code: L01CB01

Fytosid is a semi-synthetic podophyllotoxin derivative. Its main effect seems to occur during the G2 phase of the cell cycle. Two dose-dependent reactions occur: at high concentrations (> 10 µg/ml), lysis can be observed of the cells entering mitosis; at low concentrations (0.3-10 µg/ml), the cells are prevented from entering the prophase. The main macromolecular effect appears to be inhibition of DNA synthesis.

Pharmacokinetic properties

Following intravenous infusion plasma levels of Fytosid declines bi-exponentially with a distribution half-life of approximately 1.5 hours followed by a terminal elimination half-life of 4-11 hours. The total body clearance is 16-36 ml/minute/m2 and is dose-independent within the dose interval 100-600 mg/m2. The terminal half-life is also dose-independent in this dose interval. Fytosid does not accumulate in plasma when given as a daily intravenous administration of 100 mg/m2 over 4-6 days. The steady state distribution volume is 7-17 l/m2. The distribution to CSF is low and variable. In vitro studies shows that Fytosid is extensively bound to human plasma proteins (97%).

The elimination of Fytosid is both renal and non-renal. Following intravenous administration of 3H-Fytosid (70-290 mg/m2) 42-67% of the dose was recovered in urine and 0-16% in faeces. 8-35% of the dose was excreted in the urine as unchanged drug within 24 hours. The main non-renal elimination route of Fytosid is metabolism. Less than 6% of the given dose is excreted in the bile. In adults the total body clearance Fytosid correlated with creatinine clearance, low serum albumin concentration and non-renal clearance. In children, elevated serum GPT has been associated with decreased Fytosid clearance. Impaired hepatic or renal function may increase Fytosid concentration in tissues due to metabolic and excretion routes.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Fytosid should be administered under the supervision of qualified physician experienced in the use of cancer chemotherapeutic agents. Physicians should be aware that the treatment with Fytosid may be an anaphylactic reaction manifested as chills, fever, flushing, tachycardia, bronchospasm, dyspnea and hypotension, which may be fatal. Treatment is symptomatic. The infusion must be stopped and followed by administration of pressor agents, corticosteroids, antihistamines or volume expanding resources by physician. There may be reactions at injection site during administration.

If Fytosid is to be administered intravenously, paravenous injection must be carefully avoided. It is recommended to monitor the infusion site closely for possible infiltration during drug administration. There is no known specific treatment for extravasation at this time.

There may be severe myelosuppression with resultant infection or bleeding.

There have been reports of fatal myelosuppression after administration of Fytosid. Patients treated with Fytosid should be monitored closely and frequently for myelosuppression both during and after treatment. Dose limiting bone marrow suppression is the most significant toxicity associated with Fytosid treatment. The following observations should be made at the start of treatment and before each subsequent dose Fytosid: platelet count, hemoglobin and total and differential count of leukocytes. If radiotherapy or chemotherapy was carried out before the start of Fytosid treatment, a suitable interval must elapse for the bone marrow to recover.

After the initial dose, subsequent doses adjusted if the neutrophil count below 500 cells/mm3 occurring in more than 5 days or associated with fever or infection, if there is platelet counts below 25,000 cells/mm3 if they develop any other toxicity of grade 3 or 4, or if the renal clearance is below 50 ml / min. The dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of previous radiation therapy or chemotherapy which may have compromised bone marrow reserve.

Occurrence of acute leukemia, which can occur with or without a pre-leukaemic phase, has been reported rarely in patients treated with Fytosid in combination with other antineoplastic drugs.

Neither the cumulative risk, nor the predisposing factors related to the development of secondary leukaemia are known. The roles of both administration schedules and cumulative doses of Fytosid have been suggested, but have not been clearly defined.

An 11q23 chromosome abnormality has been observed in some cases of secondary leukaemia in patients who have received epipodophyllotoxins. This abnormality has also been seen in patients developing secondary leukaemia after being treated with chemotherapy regimens not containing epipodophyllotoxins and in leukaemia occurring de novo. Another characteristic that has been associated with secondary leukaemia in patients who have received epipodophyllotoxins appears to be a short latency period, with average median time to development of leukaemia being approximately 32 months.

Before Fytosid treatment is started, bacterial infections should be brought under control.

The infusion should be given slowly, during 30 to 60 minutes, to avoid hypotension or bronchospasm.

In all instances where the use of Fytosid is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Fytosid therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity

In patients with a lower serum albumin level, the risk of toxicity caused by Fytosid can be elevated. Before the start of therapy, during the therapy, and before each course of treatment, a peripheral blood panel (white blood cells, platelets, haemoglobin), renal function, and hepatic function should be checked, and neurological functions should be investigated. Courses of therapy with Fytosid should in generally be carried out only if the patient's liver and kidneys are functioning normally. If the patient is suffering from hepatic or renal dysfunction, renal and hepatic function should regularly monitored due to the risk of accumulation. Furthermore, courses of therapy with Fytosid should be carried out only if the peripheral nervous system is functioning normally.

Fytosid is mutagenic and carcinogenic. This should be taken into account when a long-term treatment is performed.

In view of Fytosid mutagenic potential, both male and female patients use effective contraception during treatment and up to 6 months after treatment.

It is recommended to seek genetic counseling if the patient wants to have children after treatment. Since Fytosid may reduce fertility in men, may be considered to allow sperm storage for subsequent paternity.

Paediatric population

Safety and efficacy in children has not been systematically studied.

Anaphylactic reactions have been reported in paediatric patients who received Fytosid Injection

Excipient (s ) that the clinician should be aware of :

Ethanol

Fytosid Injection contains 30.5% alcohol (ethanol), which corresponds to 240.64 mg of ethanol per ml of concentrate i.e up to 1.2 gm of ethanol per 5 ml vial, equivalent to 30 ml of beer or 12.55 ml of wine and up to 3 gm of ethanol per 12.5 ml vial, equivalent to 75 ml of bear or 31.4 ml of wine.

There is a health risk to hepatic patients, alcoholics, epileptics, patients with organic brain diseases, pregnant women, breastfeeding women, and children, amongst others. The effect of other drugs may be reduced or increased.

Benzyl alcohol

Because of the presence of benzyl alcohol, Fytosid Injection must not be given to premature babies or neonates. It may cause toxic and allergic reactions in infants and children upto 3 years old.

Polysorbate 80

Fytosid Injection contains polysorbate 80. In newborn infants a life threatening syndrome of liver, cholestasis and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable vitamin E product containing polysorbate 80.

Effects on ability to drive and use machines

No studies on the effects on the ability and use machines have been performed with Fytosid. Fatigue, somnolence, nausea, vomiting and acute hypersensitivity reactions may occur due to a drop in blood pressure, and this may impair the ability to drive and use machines.

Dosage (Posology) and method of administration

Treatment with Fytosid should be initiated by or in consultation with a qualified physician experienced in cancer chemotherapy.

Fytosid Injection is intended for slow intravenous infusion. Fytosid should not be administered as a rapid intravenous injection.

Posology:

Adults

The recommended dose of Fytosid is 60-120 mg/m2 i.v. per day for 5 subsequent days. As Fytosid causes myelosuppression, the course of treatment must not be repeated more often than in intervals of 10 to 20 days. For non-haematological indications courses may not be repeated more frequently than at 21 days intervals. Repeated courses of treatment with Fytosid infusion must not be given before the blood picture has been controlled for signs of myelosuppression and found satisfactory.

Overall, a dosage schedule of 100 mg/m2 for 5 days or 120 mg/m2 every other day on days 1, 3, and 5 is used frequently.

The necessary dose of Fytosid must be diluted either with a 5% glucose solution or a 0.9% sodium chloride solution, in order to achieve a final concentration of 0.2 - 0.4 mg/ml of Fytosid (i.e 1 ml or 2 ml concentrate in 100 ml of diluent to achieve concentration of 0.2 mg/ml and 0.4 mg/ml respectively). This solution is administered as an intravenous solution over a period of no less than 30 minutes and no more than 2 hours.

Administration precautions:

Hypotension after rapid intravenous administration has been reported. Therefore, it is recommended that Fytosid be administered over a 30 to 60 minute period. Longer infusion times may be required depending on the patient's tolerance. As with other potentially toxic compounds, caution should be exercised in the handling and preparation of Fytosid. Skin reactions associated with unintentional exposure to Fytosid may occur. The use of gloves is recommended. If Fytosid Injection comes into contact with skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Dosage adjustment:

The dosage of Fytosid should be adjusted taking into account the myelosuppressive effects of other drugs in combination, or the effects of prior radiation or chemotherapy which may have compromised bone marrow reserve. Fytosid cycles should not be begin if the neutrophil count is less than 1,500 cells/mm3 or the platelet count is less than 100,000 cells/mm3, unless caused by malignant disease.

Doses following the first dose should be adjusted if the neutrophil count is less than 500 cells/mm3 for more than 5 days or if this is associated with fever or infection, if the platelet count is less than 25,000 cells/mm3, if any other grade 3 or 4 toxicity develops or if the clearance is less than 50 ml / min.

In the case of combination therapy, the dosage of Fytosid should be set in accordance with the relevant treatment plan.

The duration of therapy is set by the doctor, taking into account the underlying disease, the combination therapy being administered (if relevant), and the individual therapeutic circumstances. Fytosid should be discontinued if the tumour does not respond to treatment and/or progresses or if intolerable undesirable effects occur.

Paravenous injection must be carefully avoided. Fytosid may not be administered as an intra-arterial and intracavitary injection.

Paediatric population:

Safety and effectiveness in children and adolescents have not been established.

Elderly patients

The dosage does not need to be adjusted.

Patients with impaired renal function

In patients with renal impairment the following initial dose adjustment should be considered based on measured creatinine clearance.

Subsequent dosing should be based on patient tolerance and clinical efficacy.

Special precautions for disposal and other handling

Fytosid Injection should be handled in accordance with instruction for cytotoxic agents.

If solution showing sign of precipitation or contains visible particles, it should be discarded.

Fytosid Injection must be diluted prior to use with Sodium chloride injection (0.9 % w/v) or glucose injection (5% w/v) to concentration of 0.2 mg/mL (i.e 1 ml of concentrate in 100 ml of diluent) to 0.4 mg/mL (i.e 2 ml of concentrate in 100 ml of diluent). The concentration of diluted solution should not exceed 0.4 mg/mL because of risk of precipitation.

For waste-disposal and safety information guidelines on safe-handling of antineoplastic drugs should be followed.

Any contact with the fluid should be avoided. During preparation and reconstitution a strictly aseptic working technique should be used; protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of a vertical laminar airflow (LAF) hood is recommended.

Gloves should be worn during administration. Waste-disposal procedures should take into account the cytotoxic nature of this substance.

Pregnant personnel are advised not to handle chemotherapeutic agents.

If Fytosid contacts skin, mucosae or eyes, immediately wash thoroughly with water. Soap may be used for skin cleansing.

Any unused product or waste material should be disposed of in accordance with local requirements.