Holoxan  is a cytotoxic drug for the treatment of malignant disease. As a single agent it has successfully produced objective remissions in a wide range of malignant conditions. Holoxan  is also frequently used in combination with other cytotoxic drugs, radiotherapy and surgery.

Children and adolescents - see section 5.1-Paediatric population

Holoxan  should only be administered when there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during and after administration and under the direction of a specialist oncology service by physicians experienced with this drug.

 

Dosage must be individualised. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring.

 

In combination with other agents of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary.

 

Method of administration

 

A guide to the dosage regimens used for most indications is given below:

 

a)         8 - 12 g/m² equally fractionated as single daily doses over 3 - 5 days every 2 - 4 weeks.

 

b)         5 - 6 g/m² (maximum 10 g) given as a 24 hour infusion every 3 – 4 weeks.

 

The frequency of dosage is determined by the degree of myelosuppression and the time taken to recover adequate bone marrow function.  The usual number of courses given is 4, but up to 7 (6 by 24 hour infusion) courses have been given. Re-treatment has been given following relapse.

 

During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity. See Section 4.4.

 

For prophylaxis of haemorrhagic cystitis, Holoxan  should be used in combination with mesna.

 

Use in Patients with Renal Impairment

 

In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of Holoxan  and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients. See section 4.3.

Holoxan  and its metabolites are dialyzable. Use in Patients with Hepatic Impairment

 

Hepatic impairment, particularly if severe, may be associated with decreased activation of Holoxan . This may alter the effectiveness of Holoxan  treatment. Low serum albumin and hepatic impairment are also considered risk factors for the development of CNS toxicity. Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to CNS toxicity and also contribute to nephrotoxicity. This should be considered when selecting the dose and interpreting response to the dose selected. See section

4.3.

 

Use in Paediatric Patients

 

In children, the dosage and administration should be determined by the tumour type, tumour stage, the general condition of the patient, any previous cytotoxic therapy, and whether chemotherapy or radiotherapy is to be administered concurrently. Clinical trials have involved doses of:

 

a)                       5 g/m² over 24 hours

 

b)                       9 g/m² equally fractionated as single daily doses over 5 days

 

c)                       9 g/m² as a continuous infusion over 72 hours repeated at three weekly intervals.

 

Use in Elderly Patients

 

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (See Section 5.2).

 

Administration:

 

Holoxan  is inert until activated by enzymes in the liver. However, safe handling is required and advice is included under Pharmaceutical Precautions. The dry contents of a vial should be dissolved in Water for Injections as follows:

 

1 g vial: add 12.5 ml of Water for Injections

 

The resultant solution of 8% of Holoxan  should not be injected directly into the vein.  The solution may be:

 

1.         diluted to less than a 4% solution and injected directly into the vein, with the patient supine.

 

2.                      infused in 5% dextrose-saline or normal saline over 30-120 mins.

 

3.                      injected directly into a fast-running infusion,

 

4.         made up in 3 x 1 litres of dextrose-saline or normal saline and infused over 24 hours. Each litre should be given over eight hours, and should be freshly made up immediately before infusion.

 

Care should be taken that extravasation does not take place, however, should it occur local tissue damage is unlikely and no specific measures need be taken. Repeated intravenous injections of large doses of Holoxan  have resulted in local irritation.

 

Mesna  should be used to prevent urothelial toxicity.

 

Where Holoxan  is used as an i.v. bolus, increased dosages of mesna are recommended in children, patients whose urothelium may be damaged from previous therapies and those who are not adequately protected by the standard dose of mesna.

 

The patient should be well hydrated and maintained in fluid balance, replacement fluids being given as necessary to achieve this. The fluid intake of patients on the intermittent regimen should be at least 2 litres in 24 hours. As Holoxan  may exert an antidiuretic effect, a diuretic may be necessary to ensure an adequate urinary output.

 

Urine should be sent for laboratory analysis before, and at the end of, each course of treatment, and the patient should be monitored for output and evidence of proteinuria and haematuria at regular intervals (4-hourly if possible) throughout the treatment period. The patient should be instructed to report any signs or symptoms of cystitis.  Holoxan  should be avoided in patients with cystitis from any cause until it has been treated.

 

Antiemetics given before, during and after therapy may reduce nausea and vomiting.  Oral hygiene is important.

 

If leucocyte count is below 4,000/mm³ or the platelet count is below

100,000/mm³, treatment with Holoxan  should be withheld until the blood count returns to normal.

 

There should be no signs or symptoms of urothelial toxicity or renal or hepatic impairment prior to the start of each course of Holoxan .

Holoxan is contra-indicated in patients with: • known hypersensitivity to Holoxan . See section 4.4 • urinary outflow obstruction • severely impaired bone-marrow function (especially in patients previously treated with cytotoxic agents or radiotherapy) • inflammation of the urinary bladder (cystitis) • impaired renal function - serum creatinine greater than 120 mcmol/l or 1.5 mg/100 ml • hepatic impairment - bilirubin greater than 17 mcmol/l or 1 mg/100 ml, or serum transaminases or alkaline phosphatase more than 2.5 times the upper limit of normal • acute infections

In individual patients, risk factors for Holoxan  toxicities and their sequelae described here and in other sections may constitute contraindications. In such situations, individual assessment of risk and expected benefits is necessary. Adverse reactions, depending on their severity, may require dosage modification or discontinuation of treatment

 

 

 

 

WARNINGS

 

Myelosuppression, Immunosuppression, Infections

 

Treatment with Holoxan  may cause myelosuppression and significant suppression of immune responses, which can lead to severe infections. Fatal outcome of Holoxan -associated myelosuppression has been reported.

 

Administration of Holoxan  is normally followed by a reduction in the leukocyte count. The nadir of the leukocyte count tends to be reached

 

approximately during the second week after administration. Subsequently, the leukocyte count rises again.

 

Severe myelosuppression and immunosuppression must be expected particularly in patients pre-treated with and/or receiving concomitant chemotherapy/haematotoxic agents, immunosuppressants and/or radiation therapy( See Section 4.5).

 

Where indicated, use of haematopoiesis-stimulating agents (colonystimulating factors and erythropoiesis-stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing. For information on a potential interaction with G-CSF and

GM-CSF (granulocyte colonystimulating factor, granulocyte macrophage colony-stimulating factor) (See section 4.5).

 

The risk of myelosuppression is dosedependent and is increased with administration of a single high dose compared to fractionated administration.

 

The risk of myelosuppression is increased in patients with reduced renal function.

 

Severe immunosuppression has led to serious, sometimes fatal, infections. Infections reported with Holoxan  include pneumonias, as well as other bacterial, fungal, viral, and parasitic infections. Sepsis and septic shock also have been reported.

 

Latent infections can be reactivated. In patients treated with Holoxan , reactivation has been reported for various viral infections.

 

Close haematologic monitoring is recommended. White blood cell count, platelet count, and haemoglobin levels should be obtained prior to each administration and at appropriate intervals after administration.

 

Central Nervous System Toxicity, Neurotoxicity

 

Administration of Holoxan  can cause CNS toxicity and other neurotoxic effects (see Section 4.8).

 

Holoxan  neurotoxicity may become manifest within a few hours to a few days after first administration and in most cases resolves within 48 to 72 hours of Holoxan  discontinuation. Symptoms may persist for longer periods of time. Occasionally, recovery has been incomplete. Fatal outcome of CNS toxicity has been reported.

 

Recurrence of CNS toxicity after several uneventful treatment courses has been reported.

 

CNS toxicity appears to be dose dependent.

 

Other risk factors that have been demonstrated or discussed in the literature include:

 

– Renal dysfunction, elevated serum creatinine

 

– Low serum albumin

 

– Hepatic dysfunction

 

– Low bilirubin, low haemoglobin levels, decreased white blood cell count

 

– Acidosis, low serum bicarbonate

 

– Electrolyte imbalances, hyponatraemia and inappropriate ADH (vasopressin)

secretion, low fluid intake

 

– Presence of brain metastases, prior CNS disease, brain irradiation

 

– Cerebral sclerosis, peripheral vasculopathy

 

– Presence of tumour in lower abdomen, bulky abdominal disease

 

– Poor performance status, advanced age

 

– Obesity, female gender

 

– Interactions with other medicines (e.g., aprepitant, CYP 3A4 inhibitors), alcohol, drug abuse, or pretreatment with cisplatin

 

If encephalopathy develops, administration of Holoxan  should be discontinued.

 

Publications report both successful and unsuccessful use of methylene blue for the treatment and prophylaxis of Holoxan -associated encephalopathy.

 

Due to the potential for additive effects, drugs acting on the CNS (such as antiemetics, sedatives, narcotics, or antihistamines) must be used with particular caution or, if necessary, be discontinued in case of Holoxan  induced encephalopathy.

 

Renal and Urothelial Toxicity

 

Holoxan  is both nephrotoxic and urotoxic.

 

Glomerular and tubular kidney function must be evaluated and checked before commencement of therapy, as well as during and after treatment.

 

Close clinical monitoring of serum and urine chemistries, including phosphorus, potassium, and other laboratory parameters appropriate for identifying nephrotoxicity and urothelial toxicity is recommended, see section

4.3.

 

Nephrotoxic Effects

 

Fatal outcome from nephrotoxicity has been documented.

 

Disorders of renal function (glomerular and tubular) following Holoxan  administration are very common. ( See 4.8).

 

Development of a syndrome resembling SIADH (syndrome of inappropriate antidiuretic hormone secretion) has been reported with Holoxan .

 

Tubular damage may become apparent during therapy, months or even years after cessation of treatment.

 

Glomerular or tubular dysfunction may resolve with time, remain stable, or progress over a period of months or years, even after completion of Holoxan  treatment.

 

The risk of developing clinical manifestations of nephrotoxicity is increased with, for example:

 

– large cumulative doses of Holoxan

 

– pre-existing renal impairment

 

– prior or concurrent treatment with potentially nephrotoxic agents

 

– younger age in children

 

– reduced nephron reserve as in patients with renal tumours and those having undergone renal radiation or unilateral nephrectomy.

 

Urothelial Effects

 

Holoxan  administration is associated with urotoxic effects, which can be reduced by prophylactic use of mesna.

 

Haemorrhagic cystitis requiring blood transfusion has been reported with Holoxan .

 

The risk of haemorrhagic cystitis is dose-dependent and increased with administration of single high doses compared to fractionated administration.

Haemorrhagic cystitis after a single dose of Holoxan  has been reported. Before starting treatment, it is necessary to exclude or correct any urinary tract

obstructions.

 

During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity.

 

Holoxan  should be used with caution, if at all, in patients with active urinary tract infections.

 

Past or concomitant radiation of the bladder or busulfan treatment may increase the risk for haemorrhagic cystitis.

 

Cardiotoxicity, Use in Patients With Cardiac Disease

 

Fatal outcome of Holoxan -associated cardiotoxicity has been reported.

 

The risk of developing cardiotoxic effects is dose-dependent. It is increased in patients with prior or concomitant treatment with other cardiotoxic agents or radiation of the cardiac region and, possibly, renal impairment.

 

Particular caution should be exercised when Holoxan  is used in patients with risk factors for cardiotoxicity and in patients with pre-existing cardiac disease.

 

Manifestations of cardiotoxicity reported with Holoxan  treatment (see

Section 4.8) and include:

 

– Supraventricular or ventricular arrhythmias, including atrial/supraventricular tachycardia, atrial fibrillation, pulseless ventricular tachycardia

 

– Decreased QRS voltage and STsegment or T-wave changes

 

– Toxic cardiomyopathy leading to heart failure with congestion and hypotension

 

– Pericardial effusion, fibrinous pericarditis, and epicardial fibrosis

 

Pulmonary Toxicity

 

Pulmonary toxicity leading to respiratory failure as well as fatal outcome has been reported.Interstitial pneumonitis and pulmonary fibrosis have been reported with Holoxan  treatment.

 

Secondary Malignancies

 

As with all cytotoxic therapy, treatment with Holoxan  involves the risk of secondary tumours and their precursors . The secondary malignancy may develop several years after chemotherapy has been discontinued.

 

The risk of myelodysplastic alterations, some progressing to acute leukaemias, is increased.

 

Veno-occlusive Liver Disease

 

Veno-occlusive liver disease has been reported with chemotherapy that included Holoxan  and also is a known complication with another oxazaphosphorine cytotoxic agent.

Genotoxicity

See section 4.6.

Effects on Fertility

 

See section 4.6.

 

Female Patients

 

Amenorrhea has been reported in patients treated with Holoxan . In addition, with another oxazaphosphorine cytotoxic agent, oligomenorrhea has been reported, see section 4.6.

 

Male Patients

 

Men treated with Holoxan  may develop oligospermia or azoospermia, see section 4.6.

 

Anaphylactic/Anaphylactoid Reactions, Cross-sensitivity

 

Anaphylactic/anaphylactoid reactions have been reported in association with Holoxan .

 

Cross-sensitivity between oxazaphosphorine cytotoxic agents has been reported.

 

Impairment of Wound Healing

 

Holoxan  may interfere with normal wound healing. Paravenous Administration

The cytotoxic effect of Holoxan  occurs after its activation, which takes place mainly in the liver. Therefore, the risk of tissue injury from accidental paravenous administration is low.

 

In case of accidental paravenous administration of Holoxan , the infusion should be stopped immediately, the extravascular Holoxan  solution should be aspirated with the cannula in place, and other measures should be instituted as appropriate.

 

Use in Patients With Renal Impairment

 

In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of Holoxan  and its metabolites. This may result in increased toxicity (e.g., neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients.

 

Use in Patients With Hepatic Impairment

 

Hepatic impairment, particularly if severe, may be associated with decreased activation of Holoxan . This may alter the effectiveness of Holoxan  treatment. Low serum albumin and hepatic impairment are also considered risk factors for the development of CNS toxicity. Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to CNS toxicity and also contribute to nephrotoxicity.

 

This should be considered when selecting the dose and interpreting response to the dose selected.

Planned co administration or sequential administration of other substances or treatments that could increase the likelihood or severity of toxic effects (by means of pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of the expected benefit and the risks. Patients receiving such combinations must be monitored closely for signs of toxicity to permit timely intervention.

 

Patients being treated with Holoxan  and agents that reduce its activation should be monitored for a potential reduction of therapeutic effectiveness and the need for dose adjustment.

 

Increased haematotoxicity and/or immunosuppression may result from a combined effect of Holoxan  and, for example:

 

– ACE inhibitors: ACE inhibitors can cause leukopenia.

 

– Carboplatin

 

– Cisplatin

 

– Natalizumab

 

Increased cardiotoxicity may result from a combined effect of Holoxan  and, for example:

 

– Anthracyclines

 

– Irradiation of the cardiac region

 

Increased pulmonary toxicity may result from a combined effect of Holoxan  and, for example:

 

– Amiodarone

 

– G-CSF, GM-CSF (granulocyte colonystimulating factor, granulocyte macrophage colony-stimulating factor)

 

Increased nephrotoxicity may result from a combined effect of Holoxan  and, for example:

 

– Acyclovir

 

– Aminoglycosides

 

– Amphotericin B

 

– Carboplatin

 

– Cisplatin

 

An increased risk of developing haemorrhagic cystitis may result from a combined effect of Holoxan  and, for example:

 

– Busulfan

 

– Irradiation of the bladder

 

Additive CNS effects may result from a combined effect of Holoxan  and, for example:

 

– Antiemetics

 

– Antihistamines

 

– Narcotics

 

– Sedatives

 

Inducers of human hepatic and extrahepatic microsomal enzymes

(e.g.,cytochrome P450 enzymes):

 

The potential for increased formation of metabolites responsible for cytotoxicity and other toxicities (depending on the enzymes induced) must be considered in case of prior or concomitant treatment with, for example:

 

– Carbamazepine

 

– Corticosteroids

 

– Rifampin

 

– Phenobarbital

 

– Phenytoin

 

– St. John’s Wort

 

See also aprepitant below.

 

Inhibitors of CYP 3A4: Reduced activation and metabolism of Holoxan  may alter the effectiveness of Holoxan  treatment. Inhibition of CYP 3A4 can also lead to increased formation of an Holoxan  metabolite associated with CNS and nephrotoxicity. CYP 3A4 inhibitors include:

 

– Ketoconazole

 

– Fluconazole

 

– Itraconazole

 

– Sorafenib

 

See also aprepitant below.

 

Aprepitant: Reports suggest increased Holoxan  neurotoxicity in patients receiving antiemetic prophylaxis with aprepitant, which is both an inducer and a moderate inhibitor of CYP 3A4.

 

Docetaxel: Increased gastrointestinal toxicity has been reported when Holoxan  was administered before docetaxel infusion.

 

Coumarin derivatives: Increased INR (increased international normalized ratio)

has been reported in patients receiving Holoxan  and warfarin.

 

Vaccines: The immunosuppressive effects of Holoxan  can be expected to reduce the response to vaccination. Use of live vaccines may lead to vaccine induced infection.

 

Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

 

Cisplatin: Cisplatin-induced hearing loss can be exacerbated by concurrent Holoxan  therapy (see also interactions above).

 

Irinotecan: Formation of the active metabolite of irinotecan may be reduced when irinotecan is administered with Holoxan .

 

Alcohol: In some patients, alcohol may increase Holoxan -induced nausea and vomiting.

 

Concurrent administration of antidiabetic agents, such as sulfonylureas and Holoxan  may enhance the hypoglycaemic effects of the former drugs.

 

Theoretical interactions of Holoxan  and allopurinol resulting in an increased severity of bone marrow depression.

Pregnancy

 

The administration of Holoxan  during organogenesis has been shown to have a fetotoxic effect in mice, rats, and rabbits and therefore may cause fetal damage when administered to pregnant women.

 

There are only very limited data available on the use of Holoxan  during pregnancy in humans. Fetal growth retardation and neonatal anaemia have been reported following exposure to Holoxan -containing chemotherapy regimens during pregnancy. Multiple congenital deviations have been reported after use during the first trimester of pregnancy. Animal data generated with cyclophosphamide, another oxazaphosphorine cytotoxic agent suggest that an

 

increased risk of failed pregnancy and malformations may persist after discontinuation of the agent as long as oocytes/follicles exist that were exposed to the agent during any of their maturation phases.

 

In addition, exposure to cyclophosphamide has been reported to cause miscarriage, malformations (following exposure during the first trimester), and neonatal effects, including leukopenia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.

 

Based on the results of animal studies, human case reports and the substance's mechanism of action, the use of Holoxan  during pregnancy, particularly in the first trimester, is advised against.

 

In every individual case, the benefits of the treatment will have to be weighed against possible risks for the fetus.

 

If Holoxan  is used during pregnancy, or if the patient becomes pregnant while taking this drug or after treatment, the patient should be apprised of the potential hazard to a fetus.

 

Breast-feeding

 

Holoxan  is passed into the breast milk and may cause neutropenia, thrombocytopenia, low haemoglobin concentrations and diarrhea in children. Holoxan  is contra-indicated for breast-feeding (see section 4.3).

 

Fertility

 

Holoxan  interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes.

 

Development of sterility appears to depend on the dose of Holoxan , duration of therapy, and state of gonadal function at the time of treatment.

 

Holoxan  may cause transient or permanent amenorrhea in women and oligospermia or azoospermia in men.

 

Female Patients

 

Women treated with Holoxan  should be informed prior to treatment about the possibility to save and preserve their eggs.

 

The risk of permanent chemotherapy-induced amenorrhea is increased in older women.

 

Girls treated with Holoxan  during prepubescence may develop secondary sexual characteristics normally and have regular menses.

 

Girls treated with Holoxan  during prepubescence subsequently have conceived.

 

Girls who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

 

Male Patients

 

Men treated with Holoxan  should be informed prior to treatment about the possibility to save pre-produced sperm kept in proper conditions.

 

Sexual function and libido generally are unimpaired in these patients.

 

Boys treated with Holoxan  during prepubescence may develop secondary sexual characteristics normally, but may have oligospermia or azoospermia.

 

Some degree of testicular atrophy may occur.

 

Azoospermia may be reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.

 

Men treated with Holoxan  have subsequently fathered children.

 

Genotoxicity

 

Holoxan  is genotoxic and mutagenic in male and female germ cells. Therefore, women should not become pregnant and men should not father a child during therapy with Holoxan .

 

Women treated with Holoxan  should take contraceptive measures for at least

1 year after discontinuation of Holoxan  therapy.

Men should not father a child for up to 6 months after the end of therapy. Sexually active women and men should use effective methods of contraception

during these periods of time.

Potential side-effects on the central nervous system may transiently impair the ability to operate machinery and motor vehicles.

The adverse reactions and frequencies below are based on publications describing clinical experience with fractionated administration of Holoxan  as monotherapy with a total dose of 4 to 12 g/m2 per course.

 

ADR frequency is based upon the following scale: Very common (≥1/10); Common (≥1/100 - <1/10), Uncommon (≥1/1,000 - <1/100), Rare (≥1/10,000 - <1/1,000), Very rare (<1/10,000), Not known (adverse reactions reported in the post-marketing experience).

System Organ Class (SOC)	Adverse Reaction	Frequency Category
INFECTIONS AND INFESTATIONS	Infections (including reactivation of latent infections) Sepsis (septic shock)*	Common   Not known
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYCTS AND POLYPS)	Secondary tumors* (including Urinary tract carcinoma, Myelodysplastic syndrome, Acute leukaemia, Acute lymphocytic leukaemia, Lymphoma [Non-Hodgkin’s lymphoma], Sarcomas, Renal cell carcinoma, Thyroid cancer) Progressions of underlying malignancies*	Not known       Not known
BLOOD AND LYMPHATIC SYSTEM DISORDERS	Myelosuppression   - Leukopenia   - Thrombocytopenia*   - Anaemia   - Agranulocytosis Haematotoxicity*   - Haemolytic anaemia   - Methaemoglobinaemia Febrile bone marrow aplasia Disseminated intravascular coagulation Haemolytic uremic syndrome Neonatal anaemia	Very common Very common Very common Not known Not known Not known Not known Not known Not known Not known Not known Not known
IMMUNE SYSTEM DISORDERS	Angioedema* Anaphylactic reaction Immunosuppression Urticaria Hypersensitivity reaction	Not known Not known Not known Not known Not known
ENDOCRINE DISORDERS	Syndrome of inappropriate antidiuretic hormone secretion (SIADH)	Not known
METABOLISM AND NUTRITION DISORDERS	Decreased Appetite Tumor lysis syndrome Metabolic acidosis Hypokalaemia Hypocalcaemia Hypophosphataemia Hyperglycaemia Polydipsia	Common Not known Not known Not known Not known Not known Not known Not known
PSYCHIATRIC DISORDERS	Mutism Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack) Echolalia Perseveration	Not known Not known   Not known Not known
NERVOUS SYSTEM DISORDERS	Central nervous system toxicity   - Encephalopathy   - Faecal incontinence  - Status epilepticus* (convulsive and nonconvulsive)   - Movement disorder   - Extrapyramidal disorder   - Gait disturbance   - Dysarthria Peripheral neuropathy   - Hypoesthesia  - Paresthesia Asterixis Neuralgia	Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known
EYE DISORDERS	Visual impairment Conjunctivitis Eye irritation	Not known Not known Not known
EAR AND LABYRINTH DISORDERS	Deafness Vertigo Tinnitus	Not known Not known Not known
CARDIAC DISORDERS	Cardiotoxicity* Arrythmia (including supraventricular and ventricular arrhythmia) Atrial fibrillation Premature atrial contractions Bradycardia Cardiac arrest* Myocardial infarction Cardiac failure* Myocardial haemorrhage Angina pectoris Cardiomyopathy* (including congestive cardiomyopathy ) Electrocardiogram ST-segment abnormal Electrocardiogram T- wave inversion Electrocardiogram QRS complex abnormal	Uncommon Not known   Not known Not known Not known Not known Not known Not known Not known Not known Not known   Not known Not known Not known
VASCULAR DISORDERS	Hypotension Pulmonary embolism Deep vein thrombosis Capillary leak syndrome Vasculitis Hypertension Flushing	Uncommon Not known Not known Not known Not known Not known Not known
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS	Respiratory failure* Acute respiratory distress syndrome* Pulmonary hypertension Interstitial lung disease* (as manifested by Pulmonary fibrosis) Pneumonitis* Pulmonary oedema* Pleural effusion Dyspnea Hypoxia Cough	Not known Not known Not known Not known   Not known Not known Not known Not known Not known Not known
GASTROINTESTINAL DISORDERS	Nausea/Vomiting Diarrhoea Stomatitis Enterocolitis Pancreatitis Ileus Gastrointestinal haemorrhage Mucosal ulceration Constipation Abdominal pain Salivary hypersecretion	Very common Uncommon Uncommon Not known Not known Not known Not known Not known Not known Not known Not known
HEPATOBILIARY DISORDERS	Hepatotoxicity   - Hepatic failure Veno-occlusive liver disease Portal vein thrombosis Cytolytic hepatitis	Common Not known Not known Not known Not known
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	Alopecia Dermatitis Papular rash Toxic epidermal necrolysis Stevens-Johnson syndrome Palmar-plantar erythrodysesthesia syndrome Radiation recall dermatitis Skin necrosis Facial swelling Rash Pruritus Erythema Skin hyperpigmentation Hyperhidrosis Nail disorder	Very common Rare Rare Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS	Rhabdomyolysis Osteomalacia Rickets Growth retardation Myalgia Arthralgia Muscle twitching	Not known Not known Not known Not known Not known Not known Not known
RENAL AND URINARY DISORDERS	Haemorrhagic cystitis Haematuria Renal dysfunction*   - Acute renal failure   - Chronic renal failure   - Aminoaciduria   - Phosphaturia   - Fanconi syndrome  - Tubulointerstitial nephritis Renal structural damage Nephrogenic diabetes insipidus Polyuria Enuresis Feeling of residual urine	Very common Very common Very common Very common Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known
REPRODUCTIVE SYSTEM AND BREAST DISORDERS	Infertility Ovarian failure Premature menopause Amenorrhea Ovulation disorder Azoospermia Oligospermia	Not known Not known Not known Not known Not known Not known Not known
CONGENITAL, FAMILIAL AND GENETIC DISORDERS	Fetal growth retardation	Not known
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS	Phlebitis Fatigue Malaise Multiorgan failure* General physical deterioration Injection/Infusion site reactions Oedema Pain Pyrexia Chills	Common Uncommon Not known Not known Not known   Not known Not known Not known Not known

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

*  including fatal outcomes

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of Holoxan is important. It allows continued monitoring of the benefit/risk balance of Holoxan. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system as per following contact details:

·    Saudi Arabia:

-     The National Pharmacovigilance and Drug Safety Centre (NPC) ·         Fax: +966-11-205-7662 ·         Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. ·         Toll free phone: 8002490000 ·         E-mail: npc.drug@sfda.gov.sa ·         Website: www.sfda.gov.sa/npc

 

·    Other GCC States:

-     Please contact the relevant competent authority.

Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression, and mucositis. See Section 4.4.

 

Patients who received an overdose should be closely monitored for the development of toxicities.

 

No specific antidote for Holoxan  is known.

 

Overdosage should be managed with supportive measures, including appropriate, state-of-the-art treatment for any concurrent infection, myelosuppression, or other toxicity, should it occur.

 

Holoxan  as well as Holoxan  metabolites are dialyzable. Consider haemodialysis in cases of severe overdose presenting early, particularly in patients with renal impairment.

 

Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose.

Holoxan  is an antineoplastic, a cytotoxic alkylating agent. It is a prodrug and shows no in vitro cytotoxic activity until activated by microsomal enzymes.

The cytotoxic activity of Holoxan  (alkylation of the nucleophilic centres in the cells) is associated with the activated oxazaphosphorine ring hydroxylated at the C4 atom which interacts with DNA-DNA cross linking.  This activity manifests itself by blocking the late S and early G2 phases of the cell cycle.

 

Paediatric population

 

Ewing’s sarcoma

 

In a randomized controlled trial, 518 patients (87% under 17 years of age) with Ewing’s Sarcoma, primitive neuroectodermal tumour of bone or primitive sarcoma of bone were randomized to Holoxan /etoposide alternating with standard treatment, or to standard treatment alone. In those with no metastases at baseline, there was a statistically significant improvement in 5 year survival for those receiving Holoxan  /etoposide (69%) compared to those on standard treatment alone (54%). Overall survival at 5 years was 72% in the Holoxan /etoposide group compared to 61% in the standard treatment group. Similar toxicities were observed in both treatment arms. In those with

metastases at baseline, there was no difference in 5 year event-free survival or 5 year overall survival between treatment groups.

 

In a randomized comparative study of Holoxan  (VAIA regimen) and cyclophosphamide (VACA regimen) in 155 patients with standard risk Ewing’s

 

sarcoma (83% under 19 years of age), no difference in event free survival or overall survival was demonstrated. Less toxicity was demonstrated for the Holoxan  regimen.

 

Other paediatric cancers

 

Holoxan  has been widely investigated in uncontrolled prospective exploratory studies in children. Various dosage schedules and regimens, in combination with other antitumour agents, have been used. The following paediatric cancers have been investigated: rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcoma, germ cell tumours, osteosarcoma, non-Hodgkins lymphoma, Hodgkins Lymphoma , acute lymphoblastic leukaemia, neuroblastoma, Wilms tumour, and malignant CNS tumours.

 

Favourable partial responses, complete responses and survival rates have been documented.

 

A variety of dosage schedules and regimens of Holoxan  in combination with other antitumor agents, are used. The prescriber should refer to chemotherapy regimens for specific tumour type  in choosing a specific dosage, mode of administration and schedules.

 

Usually the doses of Holoxan  in pediatric tumors range from 0.8 to 3 g/m2/day for 2-5 days for a total dose of 4-12 g/m2 for chemotherapy course.

 

Fractionated administration of Holoxan  is performed as intravenous infusion over a period ranging between 30 minutes and 2 hours, depending on the infusion volume or recommendations of protocol:

 

Uroprotection with mesna is mandatory during Holoxan  administration with a dose equivalent to 80-120 % of Holoxan . It is recommended to prolong

Mesna infusion to 12-48 hours after the end of Holoxan  infusion. 20 % of the whole Mesna dose should be given as i.v start bolus. Hyperhydration with at least 3000 ml/m2 is required during Holoxan  infusion and for 24-48 hours after the end of Holoxan  administration.

 

Under treatment with Holoxan , especially in case of long-term treatment, sufficient diuresis and regular control of renal function will be required. Children 5 years of age or younger may be more susceptible to Holoxan - induced renal toxicity than older children or adults. Severe nephrotoxicity leading to Fanconi’s syndrome has been reported. Progressive tubular damage resulting in potentially debilitating hypophosphataemia and rickets has been reported rarely but should be taken into consideration.

 

Paediatric data from randomized controlled clinical studies are limited.

 

Holoxan  is rapidly absorbed from the site of administration, activation of Holoxan  is primarily in the liver by microsomal mixed function oxidases. Elimination of metabolised Holoxan  is primarily via the kidneys.  The serum half-life ranges between 4 - 8 hours depending on the dose and dosage regimen. Over 80% of a single dose of Holoxan  was excreted in the urine within 24 hours. Approximately 80% of the dose was excreted as parent compound. Significant quantities of unchanged Holoxan  were found in the cerebrospinal fluid consistent with the high lipid solubility of the drug.

Not relevant

None

Benzyl alcohol-containing solutions can reduce the stability of Holoxan .

3 years. The reconstituted solution should be used immediately. The product does not contain a preservative, therefore microbial stability cannot be guaranteed. When prepared under strict aseptic conditions, Holoxan is, as a 4% solution, however, chemically stable for 7 days at room temperature with Water for Injections, 0.9% saline, dextrose/saline and dextrose solutions. Holoxan and mesna when prepared under strict aseptic conditions at the recommended dilutions are chemically stable with: (i) 0.9% saline and dextrose/saline solution for one week at room temp. (ii) Water for Injections for one week under refrigeration. (iii) 5% dextrose solution for 24 hours at room temperature, and (iv) 0.9% saline solution for 28 days at room temperature.

Do not store above 25°C.

 

Keep container in outer carton.

Type I or Type III clear glass injection vial with bromobutyl rubber closure and beading cap. Vials are packed singly in a cardboard box.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Before parenteral administration, the substance must be completely dissolved. The following protective recommendations are advised during handling due to

the toxic nature of the substance:

 

Reconstitution and administration must be undertaken only by trained personnel. Pregnant staff and breastfeeding mothers should be excluded.

 

Protective clothing, goggles, masks and disposable PVC or latex gloves should be worn.

 

A designated area should be defined for reconstitution (preferably under a laminar-airflow system).  The work surface should be protected by a

disposable, plastic backed absorbent paper. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water. Soap and water should then be used on non-mucous membranes. Spillage should be removed by dry or moist disposable towels.

 

Care must be taken in the disposal of all waste material (syringes, needles and disposable towels etc.) Used items should be placed in appropriate secure

 

containers in readiness for destruction in an appropriate high-temperature incinerator with an after-burner.