Rubida lyophilizate 5 mg

Antitumor agent from the group of anthracycline antibiotics. Embedded in the DNA molecule, idarubicin interacts with topoisomerase II and inhibits the synthesis of nucleic acids; it is highly lipophilic and has a higher rate of cell penetration and, according to in vitro studies, lower cross-resistance compared to doxorubicin and daunorubicin. The main metabolite of idarubicin, idarubicinol, exhibits antitumor activity and is less cardiotoxic than idarubicin.

Indications

Active ingredient

Composition

How to take, the dosage

The drug is administered by intravenous stream slowly over 5-10 min. To reduce the risk of extravasation it is recommended to administer Rubida through a tube of an IV system during infusion of 0.9% sodium chloride solution.

Acute non-lymphoblastic leukemia

Adults – 12 mg/m2 w/v daily for 3 days (in combination with cytarabine) or 8 mg/m2 daily for 5 days as monotherapy or in combination with other anticancer drugs.

Acute lymphoblastic leukemia

Adults: 12 mg/m2, children: 10 mg/m2 v/v daily for 3 days as monotherapy.

All of the above regimens should be used taking into account the hematologic status of the patient as well as the doses of other cytotoxic drugs used in combination therapy.

There are limited data on the use of Rubida in patients with hepatic or renal dysfunction. In case of elevated bilirubin or creatinine content in blood serum it is recommended to use the drug in reduced doses. If bilirubin content in blood serum is within 1.2-2 mg%, the dose of anthracycline is usually reduced by 50%; above 2 mg% – the drug is discontinued.

Preparation of solution

Only water for injection is used as a solvent for Rubida in the amount of 5 ml for every 5 mg of idarubicin.

Interaction

When concomitant use of Rubida with drugs with cardiotoxic and myelotoxic effects, the side effects are mutually increased.

Additive myelosuppressive effect may be observed if radiation therapy was performed 2-3 weeks before or during therapy with Rubida.

The co-administration with other cardiovascular medications (e.g., calcium channel blockers) requires close monitoring of cardiac function throughout treatment.

Hepatotoxic drugs may result in impaired drug metabolism, pharmacokinetics and therapeutic efficacy and/or toxicity.

The co-administration of Rubida with uricosuric drugs increases the risk of nephropathy.

The drug Rubida should not be mixed with other drugs.

Pharmaceutically incompatible with any solutions with alkaline pH – destruction of idarubicin.

Do not mix with heparin – precipitate formation.

Special Instructions

The drug should only be used under the supervision of a physician experienced in cytotoxic chemotherapy.

Patients must fully recover from signs of acute toxicity resulting from prior cytotoxic drug therapy (stomatitis, neutropenia, thrombocytopenia, generalized infections) before starting treatment.

Before and during each cycle of therapy, a blood count should be performed.

To reduce the risk of severe toxic cardiac damage, regular monitoring of cardiac function (using the same assessment technique throughout follow-up), including evaluation of left ventricular ejection fraction by EchoCG or multichannel radioisotope angiography, and ECG monitoring is recommended before and during therapy with Rubid. Monitoring of cardiac function should be particularly rigorous in patients with risk factors, as well as in patients receiving high cumulative doses of anthracyclines. If signs of cardiotoxicity are detected, treatment with Rubida should be discontinued immediately.

Risk factors for cardiotoxicity include cardiovascular disease in the active or latent phase, prior or concomitant radiotherapy of the mediastinal or pericardial area, prior therapy with other anthracyclines or anthracenediones, concurrent use of other drugs that suppress cardiac contractility. However, cardiotoxicity due to the use of the drug may also develop at lower cumulative doses and regardless of the presence or absence of risk factors for cardiotoxicity. The toxicity of idarubicin and other anthracyclines and anthracenediols is thought to be additive.

Limit cumulative doses have not yet been established with IV administration of the drug. Cardiomyopathy has been reported as a result of treatment with the drug in approximately 5% of patients at an IV cumulative dose of 150-290 mg/m2.

Because impaired hepatic and/or renal function may affect the distribution of idarubicin, hepatic and renal function (with determination of serum bilirubin and creatinine levels) should be monitored before and during treatment.

With regard to the possible development of hyperuricemia, patients during therapy are recommended to determine serum levels of uric acid, potassium, calcium, phosphate and creatinine. Hydration, alkalinization of urine, and prophylaxis with allopurinol minimize the risk of complications associated with tumor lysis syndrome.

Phlebosclerosis may develop after injection into small-diameter veins or after repeated injections into the same vein. The risk of phlebitis/thrombophlebitis at the injection site may be reduced if the recommendations for drug administration are strictly followed.

In case of the first signs of extravasation (burning or soreness at the injection site), the infusion should be stopped immediately, and then the infusion should be resumed in another vein until the full dose is administered.

Men and women receiving therapy with Rubida should use reliable methods of contraception.

The rules for handling cytotoxic substances must be followed when working with Rubida. It is recommended to treat the surface contaminated by the drug with diluted solution of sodium hypochlorite containing 1% chlorine. If the drug gets on the skin – immediately rinse the skin with soap and water or sodium bicarbonate solution; if the drug got into the eyes – pull back the eyelids and rinse the eye (eyes) with plenty of water for at least 15 minutes.

Features

Absorption

In intravenous administration Cmax in plasma is reached within a few minutes. Intracellular Cmax of idarubicin is also reached a few minutes after IV administration of the drug. The concentrations of idarubicin and idarubicinol in nucleated blood cells and bone marrow are more than 100-200 times higher than the corresponding concentrations in plasma.

Distribution

The uptake of idarubicin by nucleated blood and bone marrow cells in patients with leukemia is very rapid and almost coincides with its appearance in plasma.

Metabolism

The metabolism is fast and intense, occurs both in the liver and outside it with the formation of the main metabolite idarubicinol, which is not different in activity from idarubicin.

Elevation

T1/2 of idarubicin after IV administration is 11-25 hrs. T1/2 of idarubicinol when administered by IV is 33-60 hours. The excretion rates of idarubicin and idarubicinol from blood plasma and cells are almost identical: the terminal T1/2 of idarubicin from cells is about 15 h, and that of idarubicinol about 72 h. It is excreted mainly in the bile as idarubicinol and in the urine (1-2% unchanged and 4.6% as idarubicinol).

Contraindications

Side effects

Cardiovascular system disorders: phlebitis, thrombophlebitis, thromboembolism (including pulmonary embolism). Manifestation of early (acute) cardiotoxicity of Rubid is mainly sinus tachycardia and/or abnormalities on ECG (nonspecific changes of ST-T waves). Tachyarrhythmias (including ventricular extrasystole, ventricular tachycardia), bradycardia, AV-blockade, Gis bundle branch block may also be observed. These phenomena are rarely clinically significant, do not require cancellation of therapy with Rubida and are not always a prognostic factor for later delayed cardiotoxicity. Late (delayed) cardiotoxicity usually develops during the last courses of therapy or several months/years after completion of therapy.

Late cardiomyopathy is manifested by decreased left ventricular ejection fraction and/or symptoms of congestive heart failure: dyspnea, pulmonary edema, hypostatic edema, cardiomegaly, hepatomegaly, oliguria, ascites, exudative pleurisy, galloping rhythm. Subacute phenomena (pericarditis/myocarditis) may also be noted. The most severe form of anthracycline-induced cardiomyopathy is life-threatening congestive heart failure, which is a toxicity that limits the total dose of the drug.

Hematopoietic system: leukopenia, neutropenia, thrombocytopenia, anemia. Number of neutrophils and platelets usually reaches the lowest values by 10-14 days after drug administration; recovery of blood picture is observed during the 3rd week. Suppression of bone marrow function (dosolimiting toxicity) is dose-dependent and usually reversible. Clinical manifestations of severe myelosuppression may include chills, infections, sepsis/septicemia, septic shock, hemorrhages, tissue hypoxia.

Digestive system disorders: nausea, vomiting, anorexia, dehydration, stomatitis, esophagitis, abdominal pain, heartburn, erosions/ ulcers, diarrhea, colitis (including neutropenic enterocolitis with perforation), increased liver enzyme activity, increased serum bilirubin levels.

Urinary system disorders: nephropathy due to increased uric acid formation, red coloration of urine for 1-2 days after drug administration.

Dermatological reactions: alopecia, rash, itching, hyperpigmentation of skin and nails, hypersensitivity of irradiated skin (“radiation response”), urticaria, peripheral erythema.

Allergic reactions: hot flashes to the face, anaphylaxis.

Local reactions: if the drug gets under the skin – blistering, severe cellulitis, necrosis of the surrounding soft tissues.

Others: immunosuppression, hyperuricemia due to rapid lysis of tumor cells (“tumor lysis syndrome”), secondary leukemia with/without preleukemic phase (most often seen with anthracyclines in combination with DNA-damaging anticancer agents) with a latency period of 1 to 3 years.

Overdose