Drugs List

Administration

Tasonermin is administered by mild hyperthermic isolated limb perfusion. The perfusion circuit should be prepared before surgery and primed with 700-800ml of perfusate, with haematocrit of 0.25 to 0.30.

Perfusion level should be chosen to adequately encompass the affected tissue and catheters should be introduced. Thermal blankets should be applied and limb temperature continuously monitored by thermistor probes inserted into subcutaneous tissue and muscle to prevent external heat loss. If the hands and feet are not affected they should be protected by Esmarch (expulsion) bandages. A tourniquet should be applied to the proximal limb.

Once the limb is connected to the isolated circuit, the flow rate should be adjusted to 35-40 ml/litre limb volume per minute and leakage from the limb to systemic circulation checked using a radioactive tracer technique. Adjustment of flow rate and tourniquet may be necessary to ensure that leakage from the perfusion circuit to systemic circulation is stable (systemic level of radioactivity has reached a plateau) and does not exceed 10%. Tasonermin should only be administered if leakage is less than 10%.

When the temperature in the distal subcutaneous tissue of the limb has reached greater than 38 degrees C, (not exceeding 39 degrees C), and pH of the perfusate is between 7.2 and 7.35, tasonermin should be injected as a bolus into the arterial line of the circuit. After 30 minutes melphalan should be introduced as a bolus into the reservoir of the circuit, or slowly into the arterial line of the circuit. The temperature should be increased to greater than 39 degrees C (but not exceeding 40 degrees C) in 2 different sites of measurement in the tumour area. The duration of this perfusion should last for 60 minutes, making 90 minutes in total.

At the end of perfusion, the perfusate should be collected into the reservoir while washout fluid is added simultaneously to the circuit and circulated at a rate of 35-40 ml/litre limb volume per minute. A standard wash-out procedure using dextran 70 intravenous infusion or similar fluid is recommended. 3-6 litres should be used after lower limb perfusion and 1-2 litres after upper limb perfusion. Popliteal and brachial perfusions may not need more than 1 litre. Washout should continue until a clear (pink, transparent) venous outflow is obtained.

Surgical resection of the tumour remnant should be undertaken whenever possible. If necessary isolated limb perfusion can be repeated 6-8 weeks after the first treatment. If a second ILP is indicated, physicians should take into account the leakage rate of the previous ILP.

Handling

Standard guidelines on handling cytotoxic drugs should be followed:
1. Trained personnel should reconstitute cytotoxics;
2. Reconstitution should be carried out in designated areas;
3. Protective clothing (including gloves) should be worn;
4. The eyes should be protected and means of first aid should be specified;
5. Pregnant staff should not handle cytotoxics;
6. Adequate care should be taken for the disposal of waste material, including syringes, containers and absorbent material.

Reconstitution

Tasonermin should be reconstituted by adding 5ml of solvent for parenteral use (sodium chloride 0.9% solution for injection). A homogenous solution will be obtained by shaking gently. The solution of the reconstituted product should be inspected visually for particulate matter prior to administration. The solution has a clear to light yellow colour.

The formulation does not contain a preservative and is for single use only. Once opened, the content of a vial should normally be used immediately.

Reconstituted solution
Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 degrees C.

From microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 degrees C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Contraindications

Significant cardiovascular disease e.g. congestive heart failure (New York Heart Association Class II, III or IV), severe angina pectoris, cardiac arrhythmias, myocardial infarction within a 3 month period prior to treatment, venous thrombosis, occlusive peripheral arterial disease, recent pulmonary embolism.

Severe pulmonary dysfunction

Recent history of, or active peptic ulcer

Severe ascites

Significant haematological dysfunction, e.g. leucocytes less than 2.5 x 10 to the power of 9 per litre, haemoglobin less than 9g/dL, platelets less than 60 x 10 to the power of 9 per litre, haemorrhagic diathesis or active bleeding disorder.

Significant renal dysfunction (see Dosage Renal Impairment )

Significant hepatic dysfunction (see Dosage Hepatic Impairment )

Hypercalcaemia greater than 12 mg/dL (2.99 mmol/L)

Pregnancy (see Pregnancy section)
Breastfeeding (see Lactation section)
Children under 18 years

Contraindications to the isolated limb perfusion procedure
Severe lymphoedema of the limb

Patients in whom the blood supply to the extremity distal to the tumour is thought to be highly dependent on tumour associated blood vessels. This can be clarified by an arteriogram.

Precautions and Warnings

This treatment should carried out in specialised centres by surgical teams experienced in the management of limb sarcomas and isolated limb perfusion, with an intensive care unit available and with the facilities for continuous monitoring for medicinal leakage into the systemic circulation.

Tasonermin must not be administered systemically.

Significant caution should be applied when using in patients with any level of cardiac, renal, hepatic or haematological impairment or disorder.

A constant level of anaesthesia should be maintained to prevent large fluctuations in systemic blood pressure, which can affect leakage between systemic circulation and perfusion circuit.

Central venous pressure and arterial pressure should be monitored during ILP.
Routine monitoring of blood pressure, urine output and electrocardiogram should be undertaken in the first 24-48 hours after ILP, or longer if indicated. A Swan-Ganz catheter may be considered for monitoring pulmonary artery pressure and wedge pressure during the ILP and in the post-operative period.

Perfusion rate should not exceed 40 ml/litre limb volume per minute in order to minimise the risk of leakage of the perfusate into the systemic circulation. The perfusion should be terminated if the cumulative leakage into the systemic circulation is greater than 10% (see Administration ).

The maximum tolerated dose (MTD) of tasonermin for ILP is 4mg, which is 10 times the systemic MTD. Therefore, whenever there is significant systemic leakage of tasonermin, serious undesirable effects are to be expected.

Prophylaxis and treatment of fever, chills and other influenza-like symptoms associated with tasonermin administration, can be achieved by pre-ILP administration of paracetamol (oral or by suppository) or an alternative analgesic/antipyretic.

For the prophylaxis of shock, patients should be maximally hydrated prior to, during and after the perfusion procedure, to ensure optimal haemodynamic conditions and high urinary output, especially after the perfusion, to allow for rapid clearance of any residual tasonermin. Additional resuscitation fluids should be available for volume expansion in case of a significant fall in blood pressure. In cases of severe shock discontinue the limb perfusion and administer the appropriate therapy.

Deprivation of oxygen supply to the limb should not exceed 20 minutes in duration.

Tasonermin may enhance cardiotoxicity. Avoid in combinations with other cardiotoxic agents.

If signs of systemic toxicity appear e.g. fever, cardiac arrhythmias, shock/hypotension, adult respiratory distress syndrome, general supportive measures should be employed and the patient transferred to an Intensive Care Unit for monitoring. Renal and hepatic function should be closely monitored. Haematological disorders, in particular leucopenia, thrombocytopenia and clotting dysfunction, might be expected.

Cases of compartment syndrome characterised by pain, swelling and neurological symptoms, as well as muscle damage affecting the perfused limb have been observed in isolated patients treated with tasonermin. Therefore patients should be monitored during the first 3 days after the ILP.

The literature regarding melphalan use should be consulted before commencing an isolated limb perfusion (ILP) procedure.

Medicinal product contains sodium. Take into consideration if patient is on a controlled sodium diet.

Pregnancy and Lactation

Pregnancy

Tasonermin is contraindicated during pregnancy.

There is no information on the use of tasonermin in pregnant women. Data from animal studies are insufficient to conclude from about the effects on pregnancy, embryonal development and postnatal development.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - Contraindicated in pregnancy.

Lactation

Tasonermin is contraindicated in breastfeeding.

It is unknown whether tasonermin in excreted in human milk. Breastfeeding is contraindicated within 7 days of isolated limb perfusion.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Side effects may be related to tasonermin, to melphalan or to the isolated limb perfusion procedure and associated measures, or to a combination of these factors.

Fever
Nausea
Vomiting
Cardiac arrhythmias
Fatigue
Chills
Liver toxicity
Infections
Constipation
Thrombocytopenia
Night sweats
Peripheral neurotoxicity
Proteinuria
Shock
Hypotension
Myalgia
Impaired consciousness
Headache
Diarrhoea
Adult respiratory distress syndrome
Leucopenia
Acute renal failure
Cutaneous manifestations
Oedema
Pain
Nerve damage
Wound infection
Thrombosis
Nail disorders
Tissue damage
Hypersensitivity reactions
Compartment syndrome
Skin necrosis
Muscle necrosis
Sepsis
Upper abdominal pain
Gastritis
Pulmonary oedema
Increase in creatinine
Cardiac failure
Peripheral oedema

Presentation

Powder for solution for infusion containing 1 mg tasonermin per 5 ml vial.

1 mg tasonermin (TNFa-1a) corresponds to 3.0-6.0 x 10 to the power 7 IU.

Drugs List

Dosage

Adults

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

Tasonermin is administered by mild hyperthermic isolated limb perfusion. The perfusion circuit should be prepared before surgery and primed with 700-800ml of perfusate, with haematocrit of 0.25 to 0.30.

Perfusion level should be chosen to adequately encompass the affected tissue and catheters should be introduced. Thermal blankets should be applied and limb temperature continuously monitored by thermistor probes inserted into subcutaneous tissue and muscle to prevent external heat loss. If the hands and feet are not affected they should be protected by Esmarch (expulsion) bandages. A tourniquet should be applied to the proximal limb.

Once the limb is connected to the isolated circuit, the flow rate should be adjusted to 35-40 ml/litre limb volume per minute and leakage from the limb to systemic circulation checked using a radioactive tracer technique. Adjustment of flow rate and tourniquet may be necessary to ensure that leakage from the perfusion circuit to systemic circulation is stable (systemic level of radioactivity has reached a plateau) and does not exceed 10%. Tasonermin should only be administered if leakage is less than 10%.

When the temperature in the distal subcutaneous tissue of the limb has reached greater than 38 degrees C, (not exceeding 39 degrees C), and pH of the perfusate is between 7.2 and 7.35, tasonermin should be injected as a bolus into the arterial line of the circuit. After 30 minutes melphalan should be introduced as a bolus into the reservoir of the circuit, or slowly into the arterial line of the circuit. The temperature should be increased to greater than 39 degrees C (but not exceeding 40 degrees C) in 2 different sites of measurement in the tumour area. The duration of this perfusion should last for 60 minutes, making 90 minutes in total.

At the end of perfusion, the perfusate should be collected into the reservoir while washout fluid is added simultaneously to the circuit and circulated at a rate of 35-40 ml/litre limb volume per minute. A standard wash-out procedure using dextran 70 intravenous infusion or similar fluid is recommended. 3-6 litres should be used after lower limb perfusion and 1-2 litres after upper limb perfusion. Popliteal and brachial perfusions may not need more than 1 litre. Washout should continue until a clear (pink, transparent) venous outflow is obtained.

Surgical resection of the tumour remnant should be undertaken whenever possible. If necessary isolated limb perfusion can be repeated 6-8 weeks after the first treatment. If a second ILP is indicated, physicians should take into account the leakage rate of the previous ILP.

Handling

Standard guidelines on handling cytotoxic drugs should be followed:
1. Trained personnel should reconstitute cytotoxics;
2. Reconstitution should be carried out in designated areas;
3. Protective clothing (including gloves) should be worn;
4. The eyes should be protected and means of first aid should be specified;
5. Pregnant staff should not handle cytotoxics;
6. Adequate care should be taken for the disposal of waste material, including syringes, containers and absorbent material.

Reconstitution

Tasonermin should be reconstituted by adding 5ml of solvent for parenteral use (sodium chloride 0.9% solution for injection). A homogenous solution will be obtained by shaking gently. The solution of the reconstituted product should be inspected visually for particulate matter prior to administration. The solution has a clear to light yellow colour.

The formulation does not contain a preservative and is for single use only. Once opened, the content of a vial should normally be used immediately.

Reconstituted solution
Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25 degrees C.

From microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 degrees C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Contraindications

Significant cardiovascular disease e.g. congestive heart failure (New York Heart Association Class II, III or IV), severe angina pectoris, cardiac arrhythmias, myocardial infarction within a 3 month period prior to treatment, venous thrombosis, occlusive peripheral arterial disease, recent pulmonary embolism.

Severe pulmonary dysfunction

Recent history of, or active peptic ulcer

Severe ascites

Significant haematological dysfunction, e.g. leucocytes less than 2.5 x 10 to the power of 9 per litre, haemoglobin less than 9g/dL, platelets less than 60 x 10 to the power of 9 per litre, haemorrhagic diathesis or active bleeding disorder.

Significant renal dysfunction (see Dosage Renal Impairment )

Significant hepatic dysfunction (see Dosage Hepatic Impairment )

Hypercalcaemia greater than 12 mg/dL (2.99 mmol/L)

Pregnancy (see Pregnancy section)
Breastfeeding (see Lactation section)
Children under 18 years

Contraindications to the isolated limb perfusion procedure
Severe lymphoedema of the limb

Patients in whom the blood supply to the extremity distal to the tumour is thought to be highly dependent on tumour associated blood vessels. This can be clarified by an arteriogram.

Precautions and Warnings

This treatment should carried out in specialised centres by surgical teams experienced in the management of limb sarcomas and isolated limb perfusion, with an intensive care unit available and with the facilities for continuous monitoring for medicinal leakage into the systemic circulation.

Tasonermin must not be administered systemically.

Significant caution should be applied when using in patients with any level of cardiac, renal, hepatic or haematological impairment or disorder.

A constant level of anaesthesia should be maintained to prevent large fluctuations in systemic blood pressure, which can affect leakage between systemic circulation and perfusion circuit.

Central venous pressure and arterial pressure should be monitored during ILP.
Routine monitoring of blood pressure, urine output and electrocardiogram should be undertaken in the first 24-48 hours after ILP, or longer if indicated. A Swan-Ganz catheter may be considered for monitoring pulmonary artery pressure and wedge pressure during the ILP and in the post-operative period.

Perfusion rate should not exceed 40 ml/litre limb volume per minute in order to minimise the risk of leakage of the perfusate into the systemic circulation. The perfusion should be terminated if the cumulative leakage into the systemic circulation is greater than 10% (see Administration ).

The maximum tolerated dose (MTD) of tasonermin for ILP is 4mg, which is 10 times the systemic MTD. Therefore, whenever there is significant systemic leakage of tasonermin, serious undesirable effects are to be expected.

Prophylaxis and treatment of fever, chills and other influenza-like symptoms associated with tasonermin administration, can be achieved by pre-ILP administration of paracetamol (oral or by suppository) or an alternative analgesic/antipyretic.

For the prophylaxis of shock, patients should be maximally hydrated prior to, during and after the perfusion procedure, to ensure optimal haemodynamic conditions and high urinary output, especially after the perfusion, to allow for rapid clearance of any residual tasonermin. Additional resuscitation fluids should be available for volume expansion in case of a significant fall in blood pressure. In cases of severe shock discontinue the limb perfusion and administer the appropriate therapy.

Deprivation of oxygen supply to the limb should not exceed 20 minutes in duration.

Tasonermin may enhance cardiotoxicity. Avoid in combinations with other cardiotoxic agents.

If signs of systemic toxicity appear e.g. fever, cardiac arrhythmias, shock/hypotension, adult respiratory distress syndrome, general supportive measures should be employed and the patient transferred to an Intensive Care Unit for monitoring. Renal and hepatic function should be closely monitored. Haematological disorders, in particular leucopenia, thrombocytopenia and clotting dysfunction, might be expected.

Cases of compartment syndrome characterised by pain, swelling and neurological symptoms, as well as muscle damage affecting the perfused limb have been observed in isolated patients treated with tasonermin. Therefore patients should be monitored during the first 3 days after the ILP.

The literature regarding melphalan use should be consulted before commencing an isolated limb perfusion (ILP) procedure.

Medicinal product contains sodium. Take into consideration if patient is on a controlled sodium diet.

Pregnancy and Lactation

Pregnancy

Tasonermin is contraindicated during pregnancy.

There is no information on the use of tasonermin in pregnant women. Data from animal studies are insufficient to conclude from about the effects on pregnancy, embryonal development and postnatal development.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - Contraindicated in pregnancy.

Lactation

Tasonermin is contraindicated in breastfeeding.

It is unknown whether tasonermin in excreted in human milk. Breastfeeding is contraindicated within 7 days of isolated limb perfusion.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

None reported however, ability to drive or operate machinery may be affected by patients clinical condition and by side effects.

Side Effects

Side effects may be related to tasonermin, to melphalan or to the isolated limb perfusion procedure and associated measures, or to a combination of these factors.

Fever
Nausea
Vomiting
Cardiac arrhythmias
Fatigue
Chills
Liver toxicity
Infections
Constipation
Thrombocytopenia
Night sweats
Peripheral neurotoxicity
Proteinuria
Shock
Hypotension
Myalgia
Impaired consciousness
Headache
Diarrhoea
Adult respiratory distress syndrome
Leucopenia
Acute renal failure
Cutaneous manifestations
Oedema
Pain
Nerve damage
Wound infection
Thrombosis
Nail disorders
Tissue damage
Hypersensitivity reactions
Compartment syndrome
Skin necrosis
Muscle necrosis
Sepsis
Upper abdominal pain
Gastritis
Pulmonary oedema
Increase in creatinine
Cardiac failure
Peripheral oedema

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Reference Sources

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.