Noveldexis

Noveldexis is intended for the treatment of:

- advanced or metastasised testicular cancer

- advanced or metastasised ovarian cancer

- advanced or metastasised bladder carcinoma

- advanced or metastasised squamous cell carcinoma of the head and neck

- advanced or metastasised non-small cell lung carcinoma

- advanced or metastasised small cell lung carcinoma.

Noveldexis is indicated in the treatment of cervical carcinoma in combination with other chemotherapeutics or with radiotherapy.

Noveldexis can be used as monotherapy and in combination therapy

Noveldexis 1 mg/ml concentrate for solution for infusion is to be diluted before administration. For instructions on dilution of the product before administration.

The diluted solution should be administered only intravenously by infusion (see below). For administration, any device containing aluminium that may come in contact with Noveldexis (sets for intravenous infusion, needles, catheters, syringes) must be avoided.

Adults and children:

The Noveldexis dosage depends on the primary disease, the expected reaction, and on whether Noveldexis is used for monotherapy or as a component of combination chemotherapy. The dosage directions are applicable for both adults and children.

For monotherapy, the following two dosage regimens are recommended:

<< Single dose of 50 to 120 mg/m² body surface every 3 to 4 weeks;

< 15 to 20 mg/m²/day for five days, every 3 to 4 weeks.

If Noveldexis is used in combination chemotherapy, the dose of Noveldexis must be reduced. A typical dose is 20 mg/m² or more once every 3 to 4 weeks.

For treatment of cervical cancer Noveldexis is used in combination with radiotherapy. A typical dose is 40 mg/m² weekly for 6 weeks.

For warnings and precautions to be considered prior to the start of the next treatment cycle.

In patients with renal dysfunction or bone marrow depression, the dose should be reduced adequately.

The Noveldexis solution for infusion prepared according to instructions should be administered by intravenous infusion over a period of 6 to 8 hours.

Adequate hydration must be maintained from 2 to 12 hours prior to administration until minimum 6 hours after the administration of Noveldexis. Hydratation is necessary to cause sufficient diuresis during and after treatment with Noveldexis. It is realised by intravenous infusion of one of the following solutions:

sodium chloride solution 0.9%;

mixture of sodium chloride solution 0.9% and glucose solution 5% (1:1).

Hydration prior to treatment with Noveldexis:

Intravenous infusion of 100 to 200ml/hour for a period of 6 to 12 hours, with a total amount of at least 1L.

Hydration after termination of the administration of Noveldexis:

Intravenous infusion of another 2 litres at a rate of 100 to 200 ml per hour for a period of 6 to 12 hours.

Forced diuresis may be required should the urine secretion be less than 100 to 200 ml/hour after hydration. Forced diuresis may be realised by intravenously administering 37.5g mannitol as a 10% solution (375 ml mannitol solution 10%), or by administration of a diuretic if the kidney functions are normal.

The administration of mannitol or a diuretic is also required when the administrated Noveldexis dose is higher than 60 mg/m2 of body surface.

It is necessary that the patient drinks large quantities of liquids for 24 hours after the Noveldexis infusion to ensure adequate urine secretion.

- with pre-existing renal impairment*

- in dehydrated condition (pre- and post-hydration is required to prevent serious renal dysfunction);

- with myelosuppression;

- with pre-existing hearing impairment*;

- with neuropathy caused by Noveldexis

- who are breastfeeding

- in combination with live vaccines, including yellow fever vaccine.

- in combination with phenytoin in prophylactic use

* Due to the fact that Noveldexis is nephrotoxic and neurotoxic (in particular ototoxic). These toxicities may be cumulative if disorders of this type pre-exist.

Noveldexis reacts with metallic aluminium to form a black precipitate of platinum. All aluminium containing IV sets, needles, catheters and syringes should be avoided.

Noveldexis may only be administered under the supervision of a physician qualified in oncology with experience in the use of antineoplastic chemotherapy. Supportive equipment should be available to control anaphylactic reactions.

Noveldexis reacts with metallic aluminium to form a black precipitate of platinum. All aluminium containing IV sets, needles, catheters and syringes should be avoided.

The solution for infusion should not be mixed with other drugs or additives (see 6.2).

Appropriate monitoring and management of the treatment and its complications are only possible if adequate diagnosis and exact treatment conditions are available.

Noveldexis is proven to be cumulative ototoxic, nephrotoxic, and neurotoxic. The toxicity caused by Noveldexis may be amplified by the combined use with other medicinal products, which are toxic for the said organs or systems.

Before, during and after administration of Noveldexis, the following parameters resp. organ functions must be determined:

- renal function;

- hepatic function;

- hematopoiesis functions (number of red and white blood cells and blood platelets);

- serum electrolytes (calcium, sodium, potassium, magnesium).

These examinations must be repeated every week over the entire duration of the treatment with Noveldexis.

Repeating administration of Noveldexis must be delayed until normal values are achieved for the following parameters:

- Serum creatinine < 130 µmol/l rsp. 1.5 mg/dl

- Urea < 25 mg/dl

- White blood cells > 4.000/µl resp. > 4.0 x 109/l

- Blood platelets > 100.000/µl resp. > 100 x 109/l

- Audiogram: results within the normal range.

1. Nephrotoxicity

Noveldexis causes severe cumulative nephrotoxicity. A urine output of 100 mL/hour or greater will tend to minimize Noveldexis nephrotoxicity. This can be accomplished by prehydration with 2 litres of an appropriate intravenous solution, and similar post Noveldexis hydration (recommended 2,500 mL/m2/24 hours). If vigorous hydration is insufficient to maintain adequate urinary output, an osmotic diuretic may be administered (eg, mannitol). Hyperuricaemia and hyperalbuminaemia may predispose to Noveldexis-induced nephrotoxicity.

2.Neuropathies

Severe cases of neuropathies have been reported.

These neuropathies may be irreversible and may manifest by paresthesia, areflexia and a proprioceptive loss and a sensation of vibrations. A loss of motor function has also been reported. A neurologic examination must be carried out at regular intervals.

Special caution must be exercised for patients with peripheral neuropathy not caused by Noveldexis. Prior to each course, the absence of symptoms of peripheral neuropathy should be established.

3. Ototoxicity

Ototoxicity has been observed in up to 31% of patients treated with a single dose of Noveldexis 50mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000Hz). Decreased ability to hear conversational tones may occur occasionally. Ototoxic effect may be more pronounced in children receiving Noveldexis. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses; however, deafness after initial dose of Noveldexis has been reported rarely. Ototoxicity may be enhanced with prior simultaneous cranial irradiation and may be related to peak plasma concentration of Noveldexis. It is unclear whether Noveldexis induced ototoxicity is reversible. Careful monitoring by audiometry should be performed prior to initiation of therapy and prior to subsequent doses of Noveldexis. Vestibular toxicity has also been reported..

4. Allergic phenomena

As with other platinum-based products, hypersensitivity reactions appearing in most cases during perfusion may occur, and necessitate discontinuation of the perfusion and an appropriate symptomatic treatment. Cross reactions, sometimes fatal, have been reported with all the platinum compounds (See "Side Effects" and “Contraindications”).

Anaphylactic-like reactions to Noveldexis have been observed. These reactions can be controlled by administration of antihistamines, adrenaline and/or glucocorticoids.

5. Hepatic function and haematological formula

The haematological formula and the hepatic function must be monitored at regular intervals.

6. Carcinogenic potential

In humans, in the rare cases the appearance of acute leukaemia has coincided with use of Noveldexis, which was in general associated with other leukaemogenic agents. Noveldexis is a bacterial mutagen and causes chromosome aberrations in cultures on animal cells. Carcinogenicity is possible but has not been demonstrated. Noveldexis is teratogenetic and embryo toxic in mice.

7. Injection site reactions

Injection site reactions may occur during the administration of Noveldexis. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.

WARNING

This cytostatic agent had a more marked toxicity than is usually found in antineoplastic chemotherapy.

Renal toxicity, which is above-all cumulative, is severe and requires particular precautions during administration (see "Side Effects" and "Administration").

Nausea and vomiting may be intense and require adequate antiemetic treatment.

Close supervision must also be carried out with regard to ototoxicity, myelodepression and anaphylactic reactions (see "Side Effects").

Preparation of the intravenous solution

Warning

As with all other potentially toxic products, precautions are essential when handling the Noveldexis solution. Skin lesions are possible in the event of accidental exposure to the product. It is advisable to wear gloves. In the event the Noveldexis solution comes into contact with the skin or mucous membranes, wash the skin or mucous membranes vigorously with soap and water.

Conforming to the procedures appropriate for the manipulation and elimination of cytostatic agents is recommended.

Before administering the solution to the patient, verify the clarity of the solution and the absence of particles.

Special care is required for patients with acute bacterial or viral infections.

Male and female patients have to use effective contraception during and for at least 6 months after the treatment with Noveldexis.

No studies on the effects on the ability to drive and use machines have been performed.

However, the profiles of undesirable effects (central nervous system and special senses) may lead to minor or moderate influence on the ability to drive and use machines. Patients who suffer from these effects (e.g. sleepy or vomiting) must avoid driving and operating machinery.

Undesirable effects depend on the used dose and may have cumulative effects.

The most frequently reported adverse events (>10%) of Noveldexis were haematological (leukopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, hyperuricaemia) and fever.

Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to about one third of patients given a single dose of Noveldexis; the effects are generally dose-related and cumulative. Ototoxicity may be more severe in children.

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).

Hypersensitivity may present as rash, urticaria, erythema, or pruritus allergic.

Table of Adverse Drug Events Reported During Clinical or Postmarketing Experience (MedDRA terms).

* Source of frequencies: Noveldexis Injection Company Core Data Sheet (CCDS), BMS Pharmacovigilance & Epidemiology, 02 August 2010. Frequencies not reported in the CCDS, have been added from the assessment report

a: Infectious complications have led to death in some patients.

b: Symptoms reported for anaphylactoid reaction such as facial edema (PT-face oedema), wheezing, bronchospasm, tachycardia, and hypotension will be included in the parentheses for anaphylactoid reaction in the AE frequency table.

c: Elevations in BUN and creatinine, serum uric acid, and/or a decrease in creatinine clearance are subsumed under renal insufficiency/failure.

d: Local soft tissue toxicity including tissue cellulitis, fibrosis, and necrosis (common) pain (common), oedema (common) and erythema (common) as the result of extravasation.

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Symptoms of overdose involve above mentioned side effects in an excessive manner. Efficient hydration and osmotic diuresis can aid in reduction of toxicity, provided this is applied immediately after overdose.

In case of overdose (> 200 mg/m²), direct effects on the respiratory centre are possible, which might result in life threatening respiratory disorders and acid base equilibrium disturbance due to passage of the blood brain barrier.

An acute overdose of Noveldexis may result in renal failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, untreatable nausea and vomiting and/or neuritis. An overdose may be fatal.

There is no specific antidote in the event of an overdose of Noveldexis. Even if haemodialysis is initiated 4 hours after the overdose it has little effect on the elimination of Noveldexis from the body following a strong and rapid fixation of Noveldexis to proteins.

Treatment in the event of an overdose consists of general support measures.

Pharmacotherapeutic group: Other antineoplastic agents, Platinum compounds, ATC code: L01XA01

Noveldexis is an inorganic compound which contains a heavy metal [cis- diamminedichloridoplatinum (II)]. It inhibits DNA-synthesis by the formation of DNA cross- links. Protein and RNA synthesis are inhibited to a lesser extent.

Although the most important mechanism of action seems to be inhibition of DNA synthesis, other mechanisms can also contribute to the antineoplastic activity of Noveldexis, including the increase of tumour immunogenicity. The oncolytic properties of Noveldexis are comparable to the alkylating agents. Noveldexis also has immunosuppressive, radiosensitising, and antibacterial properties. Noveldexis seems to be cell-cycle non-specific. The cytotoxic action of Noveldexis is caused by binding to all DNA-bases, with a preference for the N-7 position of guanine and adenosine.

After intravenous administration Noveldexis quickly distributes across all tissues; Noveldexis badly penetrates in the central nervous system. The highest concentrations are reached in the liver, kidneys, bladder, muscle tissue, skin, testes, prostate, pancreas and spleen.

After intravenous administration the elimination of filterable, non-protein bound Noveldexis runs biphasic, with an initial and terminal half life of 10-20 minutes and 32-53 minutes, respectively. The elimination of the total quantity of platinum runs triphasic with half lives of 14 minutes, and 274 minute and 53 days respectively.

Noveldexis is bound to plasma proteins for 90%.

The excretion primarily takes place via the urine: 27-43% of the administered dose is recovered in the urine in the first five days after the treatment. Platinum is also excreted in the bile.

Chronic toxicity

In chronic toxicity models indications for renal damage, bone marrow depression, gastro- intestinal disorders and ototoxicity have been observed.

Mutagenicity en carcinogenity

Noveldexis is mutagenic in numerous in vitro and in vivo tests (bacterial test systems, chromosomal disorders in animal cells and in tissue cultures). In long-term studies it has been shown that Noveldexis is carcinogenic in mice and rats.

Reproductive toxicity

In mice, gonadal suppression, resulting in amenorrhoea or azoospermia has been observed, which can be irreversible and result in infertility. In female rats Noveldexis induced morphological changes in the ovaries, causing partial and reversible infertility.

Studies in rats have shown that exposure during pregnancy can cause tumours in adult offspring.

Noveldexis is embryotoxic in mice and rats, and in both species deformities have been reported. Noveldexis is excreted in the breast milk.

Do not bring in contact with aluminium.

Preparation and handling of the product

Like with all anti-neoplastic products caution is needed with the processing of Noveldexis. Must be diluted before use. Dilution should take place under aseptic conditions by trained personnel in an area specifically intended for this. Protective gloves should be worn for this. Precautions should be taken to avoid contact with the skin and mucous membranes. If skin contact did occur anyway, the skin should be washed with soap and water immediately. With skin contact tingling, burns and redness have been observed. In case of contact with the mucous membranes they should be copiously rinsed with water. After inhalation dyspnoea, pain in the chest, throat irritation and nausea have been reported.

Pregnant women must avoid contact with cytostatic drugs.

Bodily waste matter and vomit should be disposed with care.

If the solution is cloudy or a deposit that does not dissolve is noticed, the bottle should be discarded.

A damaged bottle must be regarded and treated with the same precautions as contaminated waste. Contaminated waste must be stored in waste containers specifically marked for this. See section “Disposal”.

Preparation of the intravenous administration

Take the quantity of the solution that is needed from the bottle and dilute with at least 1 litre of the following solutions:

- sodium chloride 0.9%

- mixture of sodium chloride 0.9% / glucose 5% (1:1), (resulting final concentrations:

sodium chloride 0.45%, glucose 2.5%)

- sodium chloride 0.9% and 1.875% mannitol, for injection

- sodium chloride 0.45%, glucose 2.5% and 1.875% mannitol for injection

Always look at the injection before use. If the solution is not clear or an undissolvable precipitate is formed the solution must not be used. Only a clear solution, free from particles should be administered.

DO NOT bring in contact with injection material that contains aluminium

DO NOT administer undiluted

With respect to microbiological, chemical and physical stability with use of the undiluted solutions.

Disposal

All materials that have been used for the preparation and administration, or which have been in contact with Noveldexis in any way, must be disposed of according to local cytotoxic guidelines. Medicines should not be disposed of via wastewater or household waste.