Amsacrine

Amsacrine is an aminoacridine cytotoxic agent. It binds to DNA by intercalation and by external electrostatic forces and inhibits DNA synthesis, while RNA synthesis is not affected. The SmPC adds that another mode of action, a change in cell membrane function, might be involved.

Mechanism of Action

• DNA binding: amsacrine intercalates into DNA and also binds to its outside, with a preference for A-T base pairs.
• Topoisomerase II: it inhibits topoisomerase II and appears to cause double-strand DNA breaks. Cytotoxicity is greatest in the S phase of the cell cycle, when topoisomerase levels peak.
• Cell sensitivity: rapidly dividing cells are two to four times more sensitive to amsacrine than resting cells.

Pharmacokinetics

• Absorption: amsacrine is given intravenously. Peak plasma levels depend on the dose, from 0.18 µg/mL after an intravenous dose of 10 mg/m² to 4.8 µg/mL after 90 mg/m².
• Distribution: 96 to 98% bound to plasma proteins, so it can be displaced from albumin by other highly protein-bound medicines.
• Metabolism: extensive, mainly hepatic. In animals the main products are glutathione thioethers and acridine derivatives.
• Elimination: in animals most of the metabolised product is excreted in bile and faeces (about 80%) and the rest in urine (20%). About 20% of the dose (free and metabolised) is eliminated in urine within the first 8 hours and about 42% within 72 hours. The elimination half-life is about 8 to 9 hours.
• Special populations: renal or hepatic impairment can increase toxicity at recommended doses (see Administration and Dosage).

• Acute leukaemias: induction and maintenance treatment of acute lymphoblastic and myeloblastic leukaemias.
• Setting: it is mainly indicated in relapse or after failure of conventional treatments.

• Hypersensitivity to amsacrine, to acridine derivatives or to any other component.
• Marked myelosuppression following cytostatic agents or radiotherapy.
• Breastfeeding.
• Live attenuated vaccines (against yellow fever, varicella and zoster, measles, mumps, rubella, tuberculosis, rotavirus, influenza), also during the 6 months after chemotherapy is stopped: risk of generalised, possibly fatal, vaccine-related disease.

The most frequently reported side effects are nausea and vomiting, anaemia, fever and infections. Pain or phlebitis during the infusion has been reported. Myelotoxicity was seen in all patients treated at therapeutic doses; infections and haemorrhage are its main complications. The white cell count is lowest between day 5 and day 12 and usually returns to normal by day 25, and the platelet count follows the same course.

Very common (≥1/10): hypotension; nausea, mild to moderate vomiting, diarrhoea, abdominal pain, stomatitis (inflammation that can affect the whole digestive tract mucosa, grade 1 to 4, and may take weeks to heal); purpura; phlebitis at the injection site; raised liver enzymes.

Common (≥1/100 to <1/10): infection; thrombocytopenia, pancytopenia, haemorrhage; hypokalaemia; emotional lability; epileptic seizure (sometimes with hypokalaemia); cardiotoxicity, arrhythmia, congestive heart failure (particularly in children previously treated with anthracyclines); dyspnoea; hepatitis, jaundice, hepatic failure; alopecia, urticaria and skin rash; haematuria; fever, injection-site irritation, necrosis and skin inflammation (related to the concentration of amsacrine infused).

Rare (≥1/10,000 to <1/1,000): hypersensitivity, anaphylactic reaction, oedema; weight loss, weight gain; lethargy, confusion; headache, hypoaesthesia, dizziness, peripheral neuropathy; visual disturbances; atrial fibrillation, sinus tachycardia, ventricular arrhythmia (fatal or life-threatening, usually in patients with hypokalaemia), cardiomyopathy, bradycardia, ECG abnormalities, reduced ejection fraction; anuria, proteinuria, acute renal failure; raised bilirubin, urea, alkaline phosphatase and creatinine.

Not known: hyperuricaemia.

The SmPC table also lists anaemia, granulocytopenia and leucopenia as rare, which does not agree with its text (anaemia among the most frequent reactions, myelotoxicity in all patients), so they are not placed in a frequency group here; see the SmPC.

• Live attenuated vaccines: contraindicated (see Contraindications).
• Phenytoin and fosphenytoin: not recommended. The cytotoxic can reduce the digestive absorption of phenytoin, with a risk of convulsions, or phenytoin and fosphenytoin can increase the cytotoxic’s hepatic metabolism, raising toxicity or causing loss of efficacy.
• Vitamin K antagonists: precautions for use. Cancer already raises the risk of thrombosis and bleeding, and chemotherapy may interact with these medicines, so the INR is checked more often.
• Immunosuppressants (ciclosporin, everolimus, sirolimus, tacrolimus, temsirolimus): to be taken into account, as excessive immunosuppression with a risk of lymphoproliferative syndrome is possible.
• Other highly protein-bound medicines: amsacrine may be displaced from serum albumin, increasing its free fraction and toxicity.
• Other cytotoxic agents: their use may potentiate side effects. With cytarabine or azacitidine, the total amsacrine dose per course should not exceed 750 mg/m² (digestive toxicity was less marked).
• Other vaccines: influenza or pneumococcal vaccination during immunosuppressive therapy has been associated with an inadequate vaccine response.

Amsacrine must be given under strict medical supervision. It is a cytotoxic, so the solution must be prepared by specialised, trained staff in a dedicated area, with protective equipment (long-sleeved gown, mask, cap, goggles, sterile single-use gloves). Excreta and vomit are handled with care, pregnant women should avoid handling cytotoxics, a broken container is treated as contaminated waste, and contaminated waste is incinerated in labelled rigid containers.

Preparation and Administration

• Add 50 mL of water for injections to the vial of lyophilisate, swirl moderately without shaking and leave for about 15 minutes. Repeat if needed until a clear, intense orange solution is obtained.
• For the infusion, withdraw 50 mL from a 500 mL bag of isotonic glucose and replace it with the reconstituted solution. Isotonic saline must not be used, because amsacrine may precipitate.
• Give only as an intravenous infusion over at least 60 minutes, to prevent local irritation and phlebitis. For a daily or continuous 24-hour infusion a central catheter is advised to prevent venous inflammation. Stop the infusion immediately if extravasation occurs.

Recommended Doses

The dose is left to the practitioner, according to the indication, the age and condition of the patient and above all the haematological and clinical monitoring, in single-agent or combination chemotherapy. Doses may be lowered when amsacrine is combined with other cytostatic or cytolytic agents. Average doses are:

• Induction, myeloblastic leukaemias: usually 90 to 150 mg/m² a day for 5 consecutive days.
• Induction, lymphoblastic leukaemias: 150 to 200 mg/m² a day for 5 consecutive days.
• Maintenance: 150 to 250 mg/m², as a single infusion or spread over 3 consecutive days, repeated every 3 weeks.

Dose Adjustments

• Blood counts: treatment may need to be interrupted or the dose lowered if white cell or platelet counts fall abruptly.
• Renal or hepatic impairment: toxicity at recommended doses can be increased, so the dose must be adapted, especially in hepatic impairment. A reduction of 20 to 30% of the usual doses can be advised.
• With cytarabine or azacitidine: no more than 750 mg/m² per course.

Special Populations

The SmPC gives no separate doses for elderly patients or children; the dose is set according to age and condition. After previous high-dose anthracycline treatment, heart failure should be looked for, particularly in children (see Special Instructions).

Strict Medical Supervision and Myelosuppression

Amsacrine can cause severe myelosuppression, so blood counts are needed often, particularly during induction, and bone marrow checks are done periodically. Infections and haemorrhage can be fatal. Extra checks are needed when myelosuppression is already drug-induced. Red cell and platelet concentrates and suitable equipment must be available to manage bone marrow toxicity.

Hyperuricaemia

Rapid destruction of tumour cells can raise uric acid. Strict monitoring of blood levels is recommended, particularly because of the risk to kidney function, and the level may need to be lowered prophylactically before or during treatment.

Kidney and Liver Impairment

Toxicity can be increased by renal or hepatic impairment. Liver and kidney function is checked before and during treatment, and the dose is adapted (see Administration and Dosage).

Allergic Reactions, Seizures and Extravasation

Watch for allergic reactions (anaphylaxis, oedema, skin reactions), gastrointestinal disorders and epilepsy; seizures due to amsacrine can be managed with standard treatment. Extravasation can cause local necrosis. Irritation at the injection site can be avoided by diluting amsacrine in a larger volume of 5% glucose and lengthening the infusion time to at least 1 hour.

Heart and Potassium

Strict monitoring of heart rhythm is recommended to detect cardiotoxicity. Patients with hypokalaemia are at increased risk of ventricular fibrillation, and the risk of arrhythmia can be reduced by keeping potassium normal before and during treatment. Hypokalaemia must be corrected before administration. After previous high-dose anthracyclines, heart failure should be looked for, particularly in children, and cardiac function kept under special surveillance.

Laboratory Monitoring

Blood count, liver and kidney function and electrolytes are checked regularly, and electrolytes are reassessed before each treatment.

Pregnancy, Breastfeeding and Fertility

• Contraception: sexually active patients of both sexes must use effective contraception during treatment and for 3 months afterwards (women) or 6 months afterwards (men).
• Pregnancy: animal studies showed teratogenic and other reproductive effects. There are no human data, but given its mechanism amsacrine may harm the foetus. It must not be used in pregnancy, particularly in the first trimester, unless the woman’s clinical situation justifies it; the benefit is weighed case by case.
• Breastfeeding: contraindicated during treatment; passage into breast milk is unknown.
• Fertility: reversible azoospermia has been seen in men.

Effect on Driving

The effect on the ability to drive and use machines is not known. Given the side effects reported, patients should take care when driving or using machines after administration.

Store at a temperature not exceeding 30 °C. After reconstitution, physico-chemical stability was shown for 5 days at 25 °C, but from a microbiological point of view the solution should be used immediately; otherwise storage times and conditions are the responsibility of the user. Presentation: powder in a 50 mL brown type I glass vial with a bromobutyl stopper, in boxes of 5.

3 years. After reconstitution, see Storage Conditions.

Prescription only (Rx). Amsacrine is a cytotoxic given as an intravenous infusion under strict medical supervision, and the solution is prepared by specialised, trained staff. It is supplied to the hospital or clinic that administers it.