Hycamtin
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HICAMTIN® (HYCAMTIN®)
Composition:
Active substance: topotecan;
1 vial contains 4 mg of topotecan (as topotecan hydrochloride);
Excipients: tartaric acid, mannitol (E 421), hydrochloric acid diluted, sodium hydroxide.
Pharmaceutical form. Lyophilisate for solution for infusion.
Main physicochemical properties: a cake of light yellow to greenish color.
Pharmacotherapeutic group. Antineoplastic agents. Plant alkaloids and other natural products.
ATC code L01C E01.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
The antitumor activity of topotecan is due to inhibition of topoisomerase I—an enzyme that plays a direct role in DNA replication. Topotecan inhibits topoisomerase I by stabilizing the covalent complex between the enzyme and the cleaved DNA strand, which is an intermediate step in the catalytic mechanism. The cellular consequences of topoisomerase I inhibition by topotecan include induction of protein-associated single-strand DNA breaks.
Children
Topotecan has also been studied in children; however, data on safety and efficacy are currently limited.
In an open-label study involving children (n = 108, age range: up to 16 years) with recurrent or progressive solid tumors, topotecan was administered at an initial dose of 2.0 mg/m² as a 30-minute intravenous infusion for 5 consecutive days, with a 3-week interval between cycles, for up to one year depending on treatment response. Tumors included Ewing's sarcoma/primitive neuroectodermal tumor, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Antitumor activity was primarily demonstrated in patients with neuroblastoma. The toxic effects of topotecan in children with recurrent and refractory solid tumors were similar to those observed in adult patients. In this study, 44 (43%) patients received G-CSF (granulocyte colony-stimulating factor) during more than 192 (42.1%) treatment courses; 65 patients (60%) received red blood cell transfusions and 50 (46%) patients received platelet transfusions during more than 139 and 159 courses (30.5% and 34.9%), respectively. Considering the dose-limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at 2.0 mg/m²/day with G-CSF and 1.4 mg/m²/day without G-CSF in a pharmacokinetic study involving children with refractory solid tumors (see section "Pharmacological Properties. Pharmacokinetics").
Pharmacokinetics
Distribution
After intravenous administration of topotecan as a 30-minute infusion at doses ranging from 0.5 to 1.5 mg/m² for 5 days, the drug exhibits high clearance (62 L/h), approximately two-thirds of hepatic blood flow. Topotecan also has a large volume of distribution—approximately 132 L, about three times the total body water—and a relatively short elimination half-life of 2–3 hours. Based on pharmacokinetic parameters, no significant changes in drug pharmacokinetics occur over the 5-day treatment period. The area under the concentration-time curve (AUC) increased proportionally with dose escalation. Data on pharmacokinetic changes after multiple dosing are limited. Plasma protein binding of topotecan is low (35%), with nearly equal distribution between blood cells and plasma.
Metabolism
The elimination of topotecan in humans has been only partially characterized. The primary route of clearance is hydrolysis of the lactone ring, forming an open-ring hydroxyacid metabolite.
Metabolism accounts for less than 10% of topotecan elimination. The N-desmethyl metabolite, which has similar or lower activity than the parent compound in cellular assays, is detectable in urine, plasma, and feces. The AUC ratio of intermediate metabolite to parent compound was <10% for both total topotecan and the lactone form. O-glucuronide and N-desmethyltopotecan are detectable in urine.
Excretion
Overall elimination of the drug after administration of five daily doses of topotecan accounts for 71–76% of the intravenously administered dose.
Approximately 51% of the drug is excreted in urine as topotecan and 3% as N-desmethyltopotecan. Fecal excretion of topotecan accounts for 18%, while fecal elimination of N-desmethyltopotecan is approximately 1.7%. Overall, the N-desmethyl metabolite constitutes on average less than 7% (range 4–9%) of the total topotecan recovered in urine and feces. Topotecan-O-glucuronide and N-desmethyltopotecan-O-glucuronide in urine account for less than 2.0% of the administered dose.
In vitro studies using human liver microsomes indicate minimal formation of N-demethylated topotecan. In vitro, topotecan does not inhibit human cytochrome P450 enzymes—CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A—nor does it inhibit human cytosolic enzymes—dihydropyrimidine dehydrogenase or xanthine oxidase.
When administered in combination with cisplatin (cisplatin on day 1, topotecan for 5 consecutive days), the clearance of topotecan on day 5 was reduced compared to day 1 (19.1 L/h/m² vs. 21.3 L/h/m², respectively).
Special Patient Populations
Hepatic Impairment
In patients with hepatic impairment (serum bilirubin levels of 1.5–10 mg/dL), plasma clearance is reduced by approximately 67% compared to the control group. The elimination half-life of topotecan increases by about 30%, although no clear changes in volume of distribution were observed. Total plasma clearance of total topotecan (active and inactive forms) in patients with hepatic impairment is reduced by only 10% compared to the control group.
Renal Impairment
Plasma clearance in patients with renal impairment (creatinine clearance 41–60 mL/min) is reduced by approximately 67% compared to the control group. The volume of distribution is slightly reduced, resulting in a 14% increase in elimination half-life. In patients with moderate renal impairment, plasma clearance of topotecan is reduced by up to 34% compared to the control group. The volume of distribution is also reduced by approximately 25%, leading to an increase in elimination half-life from 1.9 hours to 4.9 hours.
Age/Body Weight
In a demographic study, several factors—including age, body weight, and ascites—were found to have no significant effect on the clearance of total topotecan (active and inactive forms).
Children
The pharmacokinetics of topotecan administered as a 30-minute intravenous infusion for 5 days were evaluated in two clinical studies. One study included dose ranges from 1.4 to 2.4 mg/m² in children (aged 2–12 years, n = 18), adolescents (aged 12–16 years, n = 9), and young adults (aged 16–21 years, n = 9) with refractory solid tumors. The second study included dose ranges from 2.0 to 5.2 mg/m² in children (n = 8), adolescents (n = 3), and young adults (n = 3) with leukemia. These studies did not reveal clear differences in topotecan pharmacokinetics among children, adolescents, and young adults with solid tumors or leukemia; however, the limited data do not allow definitive conclusions.
Nonclinical Safety Data
Like other cytotoxic agents, due to its mechanism of action, topotecan exhibits genotoxic effects on mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and on bone marrow cells in mice in vivo. It has also been shown that administration of topotecan to rats and rabbits causes embryofetal lethality.
In reproductive toxicity studies in rats, no effects on fertility in males or females were observed; however, supranumerary ovulation and a slight increase in preimplantation loss were observed in females.
The potential carcinogenicity of topotecan has not been studied.
Clinical characteristics.
Indications.
Monotherapy with topotecan is indicated:
- for patients with metastatic ovarian cancer after first-line chemotherapy or subsequent therapy if no positive effect has been achieved;
- for patients with recurrent small cell lung cancer in whom retreatment with first-line chemotherapy is not recommended.
Topotecan in combination with cisplatin is indicated for patients with recurrent cervical cancer after radiation therapy, as well as for patients with stage IV-B. To confirm treatment with this combination, the treatment-free interval from prior cisplatin therapy should be evaluated in patients previously treated with cisplatin.
Contraindications.
Severe hypersensitivity reactions to topotecan and/or any of its components in medical history.
Pregnancy or breastfeeding.
Severe bone marrow suppression prior to initiation of the first treatment cycle (baseline neutrophil count before administration <1.5 × 109/L, platelet count <100 × 109/L).
Interaction with other medicinal products and other forms of interaction.
Topotecan does not inhibit human cytochrome P450 enzymes (see section "Pharmacokinetic properties"). No significant effect on the pharmacokinetics of topotecan has been observed when administered concomitantly with granisetron, ondansetron, morphine, or corticosteroids. When topotecan is used in combination with other chemotherapeutic agents, dose reduction of each drug may be necessary to improve tolerability. However, interactions between these drugs when used with platinum-based agents depend on the sequence of administration and on whether the platinum agents are administered on day 1 or day 5 of the treatment cycle. If cisplatin or carboplatin is administered on day 1 of the topotecan treatment cycle, the dose of the drug should be reduced compared to doses administered on day 5 of the treatment cycle.
In 13 patients with ovarian cancer receiving topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1), the mean plasma clearance of topotecan on day 5 slightly decreased compared to day 1. As a result, systemic exposure to total topotecan, measured by AUC and Cmax, increased by 12% and 23%, respectively, on day 5. Pharmacokinetic data are not available for the co-administration of topotecan (0.75 mg/m2/day for 3 consecutive days) and cisplatin (60 mg/m2/day on day 1) in the treatment of ovarian cancer patients.
Topotecan is a substrate for both ABCG2 (BCRP) and ABCB1 (P-glycoprotein) transporter proteins, as well as for breast cancer resistance protein. Inhibitors of ABCG2 and ABCB1 (e.g., elacridar) increase the exposure to topotecan when co-administered with oral topotecan. The effect of elacridar on the pharmacokinetics of intravenous topotecan is considerably less pronounced than on oral topotecan.
Special precautions for use.
Haematological toxicity is dose-dependent; therefore, blood parameters, including platelet count, should be monitored regularly (see section "Dosage and administration").
Like other cytotoxic agents, topotecan may cause severe myelosuppression. Cases of myelosuppression leading to sepsis and fatal outcomes due to sepsis have been reported in patients treated with topotecan (see section "Adverse reactions").
Topotecan-induced neutropenia may lead to neutropenic colitis. Fatal cases associated with neutropenic colitis have been reported during clinical trials with topotecan. In patients presenting with fever, neutropenia, and concomitant abdominal pain, neutropenic colitis should be considered.
Cases of interstitial lung disease, sometimes fatal, have been reported with the use of topotecan (see section "Adverse reactions"). Risk factors include a history of interstitial lung disease, pulmonary fibrosis, lung cancer, radiation to the lungs, and the use of pneumotoxic substances and/or colony-stimulating factors. Patients should be closely monitored for symptoms that may indicate interstitial lung disease (such as cough, fever, dyspnea, and/or hypoxia). If interstitial lung disease is diagnosed, topotecan should be discontinued.
Monotherapy with topotecan and topotecan in combination with cisplatin are frequently associated with clinically significant thrombocytopenia. This should be considered when prescribing Hycamtin® to patients at increased risk of tumour-related bleeding.
As expected, patients with poor performance status respond less favourably to treatment and have a higher incidence of complications such as fever, infections, and sepsis (see section "Adverse reactions"). Therefore, accurate assessment of the patient's performance status during therapy is essential to prevent clinical deterioration.
There is insufficient data on the use of topotecan in patients with severe renal impairment (creatinine clearance < 20 ml/min) or severe hepatic impairment (serum bilirubin ≥ 10 mg/dl) associated with liver cirrhosis. The use of topotecan in these patient groups is not recommended (see section "Dosage and administration").
In a small group of patients with hepatic impairment (serum bilirubin levels of 1.5–10 mg/dl) treated with intravenous topotecan at a dose of 1.5 mg/m²/day administered over 5 days every 3 weeks, a reduced topotecan clearance was observed. However, data are insufficient to provide dosing recommendations for this patient group (see section "Dosage and administration").
WARNING: In case of contact with skin, wash thoroughly with soap and water; mucous membranes should be rinsed thoroughly with water.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., it is practically "sodium-free". However, if a saline solution (0.9% sodium chloride solution) is used for dilution prior to administration, the resulting dose of sodium will be higher.
Use during pregnancy or breastfeeding.
Women of childbearing potential / Contraception in men and women
Preclinical studies have shown that topotecan causes embryofetal lethality and developmental abnormalities (see section "Preclinical safety data"). Like other cytotoxic agents, topotecan may be harmful to the fetus, and its use during pregnancy is contraindicated. Women should be advised to avoid pregnancy during treatment with topotecan.
As with other cytotoxic chemotherapeutic agents, effective contraception should be used if either partner is undergoing treatment with topotecan.
Pregnancy
If topotecan is used during pregnancy or if a woman becomes pregnant while receiving topotecan therapy, the patient should be informed of the potential risk to the fetus (see section "Contraindications").
Breastfeeding
Topotecan is contraindicated during breastfeeding (see section "Contraindications"). Although it is not known whether topotecan is excreted in breast milk, breastfeeding should be discontinued at the start of therapy.
Fertility
No effects on fertility in males or females were observed in reproductive toxicity studies in rats (see section "Preclinical safety data"). However, as with other cytotoxic agents, topotecan is genotoxic, and effects on fertility, including male fertility, cannot be excluded.
Ability to influence the ability to drive and use machines.
No studies on the effect on the ability to drive or operate machinery have been conducted. However, if patients experience prolonged fatigue or asthenia, caution should be exercised when driving or operating machinery.
Method of Administration and Dosage
The medicinal product should be administered in specialized oncology departments. Topotecan should only be administered under the supervision of a physician experienced in the use of chemotherapeutic agents.
If topotecan is used in combination with cisplatin, the package leaflet for cisplatin should be carefully read.
Before initiating the first treatment cycle with topotecan, patients must have baseline neutrophil levels ≥ 1.5 × 109/L, platelet counts ≥ 100 × 109/L, and hemoglobin levels ≥ 9 g/dL (after blood transfusion, if necessary).
Ovarian Cancer and Small Cell Lung Cancer
Initial Treatment Cycle
The recommended dose of topotecan is 1.5 mg/m2 body surface area administered as a 30-minute intravenous infusion once daily for 5 consecutive days, with a 3-week interval between the start of each cycle. If the treatment is well tolerated, it should be continued until disease progression occurs (see section "Adverse Reactions" and "Pharmacological Properties").
Subsequent Treatment Cycles
For subsequent cycles, the drug must not be administered until neutrophil levels have recovered to ≥ 1 × 109/L, platelet counts to ≥ 100 × 109/L, and hemoglobin levels to ≥ 9 g/dL (after blood transfusion, if necessary).
To manage neutropenia in oncology patients and maintain adequate neutrophil counts, other medicinal products (e.g., colony-stimulating factor) are usually co-administered with topotecan, or the dose of topotecan is reduced.
If dose reduction of topotecan is required due to severe neutropenia (neutrophil count ≤ 0.5 × 109/L) lasting 7 or more days, or severe neutropenia accompanied by fever or signs of infection, or if treatment was delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to 1.25 mg/m2/day (or further reduced sequentially as needed to 1.0 mg/m2/day).
If platelet counts fall below 25 × 109/L during treatment, the dose of topotecan should be reduced similarly.
If further dose reduction below 1.0 mg/m2/day is required to prevent adverse reactions, administration of topotecan should be discontinued (based on clinical trial data).
Cervical Cancer
Initial Treatment Cycle
The recommended dose of topotecan is 0.75 mg/m2/day administered as a 30-minute intravenous infusion on days 1, 2, and 3. On day 1, after administration of topotecan, cisplatin is administered as a daily intravenous infusion at a dose of 50 mg/m2 body surface area. This treatment regimen is repeated every 21 days for up to 6 cycles or until disease progression.
Subsequent Treatment Cycles
For subsequent cycles, the drug must not be administered until neutrophil levels have recovered to ≥ 1.5 × 109/L, platelet counts to ≥ 100 × 109/L, and hemoglobin levels to ≥ 9 g/dL (after blood transfusion, if necessary).
To manage neutropenia in oncology patients and maintain adequate neutrophil counts, other medicinal products (e.g., colony-stimulating factor) are usually co-administered with topotecan, or the dose of topotecan is reduced.
If dose reduction of topotecan is required for patients who develop severe neutropenia (neutrophil count < 0.5 × 109/L) lasting 7 or more days, or for patients with severe neutropenia accompanied by fever or signs of infection, or if treatment was delayed due to neutropenia, the dose should be reduced by 20% to 0.60 mg/m2 body surface area/day for subsequent cycles (or further to 0.45 mg/m2 body surface area/day, if necessary).
For patients whose platelet counts fall below 25 × 109/L during treatment, a similar dose reduction of topotecan is recommended.
Special Patient Populations
Dosage in Renal Impairment
Monotherapy (Ovarian Cancer and Small Cell Lung Cancer)
There are insufficient data to recommend dosing for patients with creatinine clearance < 20 mL/min. Topotecan is not recommended in these patient groups (see section "Special Warnings and Precautions for Use").
Limited data suggest that dose reduction may be necessary in patients with moderate renal impairment.
The recommended dose of topotecan as monotherapy in patients with ovarian cancer or small cell lung cancer and creatinine clearance between 20 and 39 mL/min is 0.75 mg/m2/day for 5 consecutive days.
Combination Therapy (Cervical Cancer)
Treatment with topotecan in combination with cisplatin for cervical cancer should only be initiated if serum creatinine levels are ≤ 1.5 mg/dL. If serum creatinine exceeds 1.5 mg/dL during combination therapy (topotecan/cisplatin), careful consideration should be given to dose reduction or continuation of cisplatin treatment. There is insufficient data regarding continuation of topotecan monotherapy in cervical cancer patients if cisplatin treatment is discontinued.
Patients with Hepatic Impairment
A small group of patients with hepatic impairment (serum bilirubin 1.5–10 mg/dL) received intravenous topotecan at a dose of 1.5 mg/m2/day for 5 days every 3 weeks. A reduction in topotecan clearance was observed. However, there are insufficient data to provide dosing recommendations for this patient group (see section "Special Warnings and Precautions for Use").
There are insufficient data on the use of topotecan in patients with severe hepatic impairment (serum bilirubin ≥ 10 mg/dL) due to cirrhosis. Topotecan is not recommended in these patients (see section "Special Warnings and Precautions for Use").
Dosing Regimen in Combination with Other Medicinal Products
The dose of topotecan may be altered when used in combination with other cytotoxic agents (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). If topotecan is used in combination with cisplatin, the package leaflet for cisplatin should be carefully read.
Preparation of the Solution
To dissolve 4 mg of topotecan, add 4 mL of sterile water for injection to the vial. A solution containing 1 mg of topotecan per 1 mL will be obtained. Further dilution to achieve a final concentration between 25 and 50 µg/mL should be performed using appropriate volumes of 0.9% sodium chloride solution for intravenous infusion or 5% dextrose solution for intravenous infusion.
Children
There is insufficient experience with the use of the medicinal product in children. Available data are presented in the section "Pharmacological Properties".
Overdose
Overdose (at a dose 10 times higher than recommended) has been reported in patients treated with intravenous topotecan. Symptoms observed after overdose are similar to known adverse reactions associated with topotecan use (see section "Adverse Reactions"). Primary complications of overdose include bone marrow suppression and mucositis. Additionally, elevated liver enzyme levels have been reported following intravenous topotecan overdose.
There is no known antidote for overdose. Further management should be based on clinical indications or in accordance with recommendations from the national toxicology center, if available.
Adverse Reactions
Based on clinical studies involving 523 patients with recurrent ovarian cancer and 631 patients with recurrent small cell lung cancer, hematological toxicity was dose-dependent, predictable, and reversible. There was no evidence of cumulative hematological or non-hematological toxicity.
The safety profile of topotecan in combination with cisplatin in cervical cancer clinical trials was similar to that observed with topotecan monotherapy. Overall hematological toxicity was lower in patients receiving topotecan in combination with cisplatin compared to topotecan monotherapy, but higher than in patients receiving cisplatin alone.
Additional adverse reactions were observed with the use of topotecan in combination with cisplatin; however, these events were also reported with cisplatin monotherapy and were not related to topotecan. The package leaflet for cisplatin should be carefully reviewed for a complete list of adverse reactions associated with cisplatin use.
Integrated safety data from topotecan monotherapy are presented below.
Adverse reactions observed during administration of the medicinal product are classified by organ systems and frequency of occurrence. Frequency categories are defined as follows: very common ≥1/10, common ≥1/100 and <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000, or unknown (cannot be estimated based on available data).
Within each group, adverse reactions are listed in order of decreasing severity of manifestations.
| Infections and infestations |
|
| Very common |
Infections |
| Common |
Sepsis1 |
| Blood and lymphatic system disorders |
|
| Very common |
Febrile neutropenia, neutropenia (see "Gastrointestinal disorders"), thrombocytopenia, anaemia, leukopenia |
| Common |
Pancytopenia |
| Unknown |
Severe bleeding (associated with thrombocytopenia) |
| Immune system disorders |
|
| Common |
Hypersensitivity reactions, including rash |
| Rare |
Anaphylactic reactions, angioedema, urticaria |
| Metabolism and nutrition disorders |
|
| Very common |
Anorexia (which may be severe) |
| Respiratory, thoracic and mediastinal disorders |
|
| Rare |
Interstitial lung disease (in some cases resulting in death) |
| Gastrointestinal disorders |
|
| Very common |
Nausea, vomiting and diarrhoea (which may be severe), constipation, abdominal pain2, mucositis |
| Unknown |
Gastrointestinal perforation |
| Hepatobiliary disorders |
|
| Common |
Hyperbilirubinemia |
| Skin and subcutaneous tissue disorders |
|
| Very common |
Alopecia |
| Common |
Pruritus |
| General disorders and administration site reactions |
|
| Very common |
Pyrexia, asthenia, fatigue |
| Common |
Malaise |
| Very rare |
Capillary leak3 |
| Unknown |
Mucosal inflammation |
| 1 Fatal outcomes due to sepsis have been reported in patients receiving topotecan (see section "Special warnings and precautions for use"). 2 Neutropenic colitis, including fatal neutropenic colitis, has been reported as a complication of topotecan-induced neutropenia (see section "Special warnings and precautions for use"). 3 Reactions were mild and generally did not require specific therapy. |
|
The frequency of the adverse reactions listed above is more typical for patients with severe somatic status (see section "Special precautions").
The frequency of the hematological and non-hematological adverse reactions listed below refers to adverse reactions associated or possibly associated with the use of topotecan.
Hematological.
Neutropenia: severe (neutrophil count < 0.5 × 10⁹/L) was observed during the first cycle in 55% of patients; lasting ≥ 7 days – in 20%; overall – in 77% of patients (39% of cycles).
In association with severe neutropenia, fever or infection occurred in 16% of patients during the first treatment cycle and overall in 23% of patients (6% of treatment cycles). On average, onset of severe neutropenia occurred on day 9 with a mean duration of 7 days. Severe neutropenia lasting more than 7 days occurred in 11% of cycles. Among all patients enrolled in clinical trials, including those who developed severe neutropenia and those who did not, fever developed in 11% (4% of cycles) and infectious complications occurred in 26% (9% of cycles). Additionally, sepsis developed in 5% of all treated patients (1% of cycles).
Thrombocytopenia: severe (platelet count < 25 × 10⁹/L) was observed in 25% of patients (8% of cycles), moderate (platelet count between 25.0 and 50.0 × 10⁹/L) – in 25% of patients (15% of cycles). On average, severe thrombocytopenia occurred on day 15 and lasted on average 5 days. Platelet transfusions were administered in 4% of cycles. There were isolated reports of severe complications associated with thrombocytopenia, including fatal hemorrhages from tumors.
Anemia: moderate to severe (Hb ≤ 8.0 g/dL) was observed in 37% of patients (14% of cycles). Red blood cell transfusions were administered to 52% of patients (21% of cycles).
Non-hematological.
Common non-hematological adverse reactions included gastrointestinal events such as nausea (52%), vomiting (32%), diarrhea (18%), constipation (9%), and mucositis (14%). The frequency of severe (grade 3–4) nausea, vomiting, diarrhea, and mucositis was 4%, 3%, 2%, and 1%, respectively.
Moderate abdominal pain was reported in 4% of patients.
Fatigue was observed in approximately 25%, and asthenia in 16% of patients treated with topotecan. Severe (grade 3–4) fatigue and asthenia occurred in 3% of cases.
Total or marked alopecia was observed in 30% of patients, partial alopecia – in 15% of patients.
Other adverse reactions reported as associated or possibly associated with topotecan use included anorexia (12%), malaise (3%), and hyperbilirubinemia (1%).
There were isolated reports of hypersensitivity reactions, including rash, urticaria, angioedema, and anaphylactic reactions. During clinical trials, rash occurred in 4% of patients, pruritus – in 1.5% of patients.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the National Reporting System (Automated Pharmacovigilance Information System).
Shelf life.
3 years.
Storage conditions.
Store at temperatures not exceeding 30 °C. Keep out of reach of children. Vials should be stored in the original cardboard package to protect from light. The reconstituted solution remains stable for 24 hours at temperatures between 5 and 30 °C. The solution diluted in 0.9% sodium chloride injection or 5% dextrose injection should be used immediately or stored in a refrigerator (2–8 °C) for no more than 24 hours.
Incompatibilities.
Unknown. The medicinal product is administered by intravenous infusion (method of solution preparation is specified in the section "Dosage and administration") through a separate infusion line.
Packaging. Glass vial stoppered with a rubber plug and sealed with an aluminum cap with a plastic cap, in a cardboard package.
Prescription status. Prescription only.
Manufacturer.
GlaxoSmithKline Manufacturing S.p.A. (Italy)/
GlaxoSmithKline Manufacturing S.p.A., (Italy).
Manufacturer's address.
GlaxoSmithKline Manufacturing S.p.A., Strada Provinciale Asolana 90, (loc. San Polo) – 43056 Torrile (Parma), Italy/
GlaxoSmithKline Manufacturing S.p.A., Strada Provinciale Asolana 90, (loc. San Polo) – 43056 Torrile (Parma), Italy.