Alburex 5

Alburex 5

Human Albumin

Solution for infusions

Traumatic and surgical shock, burns accompanied by dehydration, hypoproteinemia and hypoalbuminemia, cirrhosis of the liver, gastrointestinal lesions (peptic ulcer disease, tumors, impaired patency of gastrointestinal anastomosis), acute pancreatitis, brain edema, prolonged suppurative processes, dystrophy, nephropathic syndrome.

In/in, drip, at a rate of 3 ml (50-60 drops) per minute-100-500 ml.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the infusion. In case of shock, standard medical treatment for shock should be implemented.

Albumin should be used with caution in conditions where hypervolaemia and its consequences or haemodilution could represent a special risk for the patient. Examples of such conditions are:

- decompensated cardiac insufficiency

- hypertension

- oesophageal varices

- pulmonary oedema

- haemorrhagic diathesis

- severe anaemia

- renal and post-renal anuria

200-250 g/l human albumin solutions are relatively low in electrolytes compared to the 40-50 g/l human albumin solutions. When albumin is given, the electrolyte status of the patient should be monitored and appropriate steps taken to restore or maintain the electrolyte balance.

If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes).

Hypervolaemia may occur if the dosage and infusion rate are not adjusted to the patient's circulatory situation. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised venous pressure and pulmonary oedema, the infusion is to be stopped immediately.

Alburex 5 contains approximately 3.2 mg sodium per ml of solution (140 mmol/l).

That should be taken into consideration for patients on a controlled sodium diet.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

It is strongly recommended that every time that Alburex 5 is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

No specific interactions of human albumin with other medicinal products are known.

There are only limited data on the use of paclitaxel in pregnant women.

It is assumed that when prescribed during pregnancy, paclitaxel causes severe birth defects. In animal studies, the reproductive toxicity of the drug is shown. The use of the drug Abraxan during pregnancy is contraindicated. Women of childbearing age should use reliable methods of contraception.

It is not known whether paclitaxel penetrates into breast milk. Given the possible serious adverse reactions in breastfed children, Abraxane is contraindicated in lactating women. Women who are indicated for treatment with Abraxane should stop breastfeeding.

Fertility. In research in vivo It was found that paclitaxel has genotoxic, teratogenic, embryonic and fetotoxic effects, as well as reduces reproductive function in both males (testicular atrophy/degeneration) and females (a decrease in the number of pregnancy cases and an increase in the number of embryo deaths).

Abraxane causes infertility in male rats. Therefore, men should be advised to consider preserving their own sperm samples before starting treatment, given the risk of developing irreversible infertility during treatment with Abraxane.

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

The most frequent and clinically significant adverse drug reactions (NLR) that develop against the background of the use of the drug Abraxan were neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders. The following are the NLRs registered during treatment with Abraxane - as monotherapy and in combination with gemcitabine — for all possible indications.

The following terms are used in this description to assess the incidence of NLR of the drug: very often (≥1/10), often (<1/10–≥1/100), infrequently (<1/100–≥1/1000), rarely (<1/1000–≥1/10000), very rarely (<1/10000).

Breast cancer (monotherapy with Abraxane)

Infectious and parasitic diseases: common-infections, urinary tract infections, folliculitis, upper respiratory tract infections, candidiasis, sinusitis, infrequently-oral candidiasis, nasopharyngitis, phlegmon, herpes simplex, viral infections, pneumonia, catheter-associated infections, fungal infections, shingles infectious complications at the injection site, sepsis², neutropenic sepsis².

Benign, malignant, and unspecified neoplasms (including cysts and polyps): infrequently-metastatic pain, tumor necrosis.

From the blood and lymphatic system: very often — neutropenia, anemia, leukopenia, thrombocytopenia, lymphopenia, suppression of bone marrow hematopoiesis, often-febrile neutropenia, rarely-pancytopenia.

On the part of the immune system: infrequently¹ - hypersensitivity reactions, rarely-severe hypersensitivity reactions.

From the side of metabolism and nutrition: very often-anorexia, often-dehydration, decreased appetite, hypokalemia, infrequently-hypophosphatemia, fluid retention, hypoalbuminemia, polydipsia, hyperglycemia, hypokalemia, hypocalcemia, hypoglycemia, hyponatremia.

Mental disorders: often-insomnia, depression, anxiety, infrequently-anxiety.

From the nervous system: very often-peripheral neuropathy, neuropathy, hypesthesia, paresthesia, often-peripheral sensory neuropathy, headache, dysgeusia, dizziness, peripheral motor neuropathy, ataxia, sensory disorders, increased drowsiness, infrequently-polyneuropathy, decreased reflexes/areflexia, dyskinesia, neuralgia, loss of sensitivity, fainting, postural dizziness, neurogenic pain, tremor.

On the part of the visual organ: often-increased lacrimation, blurred vision, dry eye syndrome, dry keratoconjunctivitis, madarosis, infrequently-eye irritation, eye pain, visual impairment, decreased visual acuity, conjunctivitis, visual perception disorders, itching in the eyes, keratitis, rarely - cystic macular edema².

On the part of the organ of hearing and labyrinth disorders: often-vertigo, infrequently-ear pain, tinnitus.

From the heart: often-tachycardia, arrhythmia, supraventricular tachycardia, rarely-bradycardia, cardiac arrest, left ventricular dysfunction, congestive heart failure, AV block².

From the side of the vessels: often-hot flushes, increased blood pressure, lymphatic edema, infrequently decreased blood pressure, cold extremities, orthostatic hypotension, very rarely — thrombosis.

From the respiratory system, chest and mediastinal organs: often-interstitial pneumonitis³, shortness of breath, nasal bleeding, pharyngolaryngeal pain, cough, rhinitis, rhinorrhea, infrequently — cough with sputum, shortness of breath during exercise, swelling of the sinus mucosa, weakened breathing, pleural effusion, allergic rhinitis, hoarseness, dry/stuffy nose, wheezing, thromboembolism/embolism of the pulmonary artery.

From the gastrointestinal tract: very often — nausea, diarrhea, vomiting, constipation, stomatitis, often — abdominal pain, bloating, epigastric pain, dyspepsia, gastroesophageal reflux, hypesthesia of the oral mucosa, infrequently — dysphagia, flatulence, glossalgia, dry mouth, gum pain, loose stools, esophagitis, lower abdominal pain, ulcerative lesions of the oral mucosa, mouth pain, rectal bleeding.

From the liver and biliary tract: infrequently — hepatomegaly.

From the skin and subcutaneous tissues:², toxic epidermal necrolysis³.

Musculoskeletal and connective tissue disorders: very often — arthralgia, myalgia, often-pain in the extremities, bone pain, back pain, muscle cramps, pain in the distal extremities, infrequently-chest pain, muscle weakness, neck pain, groin pain, muscle spasms, musculoskeletal pain, side pain, feeling of discomfort in the extremities.

From the kidneys and urinary tract: infrequently-dysuria, pollakiuria, hematuria, nycturia, polyuria, urinary incontinence.

From the genitals and breast: infrequently-pain in the mammary gland.

General disorders and disorders at the injection site: very often-fatigue, asthenia, fever, often-peripheral edema, inflammation of the mucous membrane, pain, chills, swelling, weakness, decreased performance, chest pain, flu-like syndrome, malaise, drowsiness, hyperthermia, infrequently-a feeling of discomfort in the chest, gait disorders, swelling, reactions at the injection site, rarely-extravasation.

Laboratory and instrumental data: often-weight loss, increased ALT, ACT, ALP, GTT, decreased red blood cell count, decreased hematocrit, increased body temperature, infrequently-increased blood pressure, increased body weight, hyperbilirubinemia, increased serum creatinine concentration, hyperphosphatemia, hyperglycemia, hyponatremia, increased LDH activity.

Injuries, intoxication and complications of manipulation: infrequently-bruises, rarely-anamnestic radiation phenomenon, radiation pneumonitis³

¹ The frequency of hypersensitivity reactions was determined on the basis of one definitely associated with the drug Abraxane case in a population of 789 patients.

² According to the post-registration report on the drug Abraxane.

³ The frequency of pneumonitis was calculated based on the generalized data of 1310 patients who participated in clinical trials of the drug Abraxane, which was prescribed as monotherapy for breast cancer and other indications (see "Special instructions").

Pancreatic adenocarcinoma (drug Abraxane in combination with gemcitabine)

Infectious and parasitic diseases: often-sepsis, pneumonia, candidiasis of the oral cavity.

From the blood and lymphatic system: very often-neutropenia, anemia, thrombocytopenia, often-pancytopenia, infrequently-thrombotic thrombocytopenic purpura.

From the side of metabolism and nutrition: very often — dehydration, decreased appetite, hypokalemia.

Mental disorders: very often — insomnia, depression, infrequently-anxiety.

From the nervous system: very often — peripheral neuropathy, dysgeusia, headache, dizziness, infrequently-facial nerve paralysis.

On the part of the visual organ: often-increased lacrimation, infrequently - cystic edema of the macula.

From the heart: often-congestive heart failure, tachycardia.

From the side of the vessels: often-a decrease and increase in blood pressure.

From the respiratory system, chest and mediastinal organs: very often-shortness of breath, nosebleeds, cough, often-pneumonitis, nasal congestion, infrequently - dry throat/nose.

From the gastrointestinal tract: very often-nausea, diarrhea, vomiting, constipation, abdominal pain, pain in the epigastric region, often-stomatitis, intestinal obstruction, colitis, dryness of the oral mucosa.

From the liver and biliary tract: often-cholangitis.

From the skin and subcutaneous tissues: very often-alopecia, skin rash, often-itching, dry skin, nail diseases, hot flashes.

Musculoskeletal and connective tissue disorders: very often-pain in the extremities, arthralgia, myalgia, often-muscle weakness, pain in the bones.

From the kidneys and urinary tract: often-acute renal failure, infrequently-hemolytic-uremic syndrome.

General disorders and disorders at the injection site: very often — fatigue, peripheral edema, fever, asthenia, chills, often-reactions at the injection site.

Laboratory and instrumental data: very often-weight loss, increased ALT activity, often-increased ACT activity, hyperbilirubinemia, increased creatinine concentration in blood plasma.

Description of individual adverse reactions

From the blood and lymphatic system: Table 4 provides information on the frequency and severity of changes in the indicators of hematological tests in patients receiving the drug Abraxan in combination with gemcitabine or gemcitabine alone.

Table 4

Pathological changes in the parameters of hematological tests in patients with pancreatic adenocarcinoma

¹ The data of 405 patients treated with the combination of Abraxane/gemcitabine were evaluated.

² The data of 388 patients treated with gemcitabine were evaluated.

³ The data of 404 patients treated with the combination of Abraxane/gemcitabine were evaluated.

Post-registration application experience

During the post-registration study of the drug Abraxan, cases of cranial nerve paralysis, paresis of the vocal cords, and rare cases of severe hypersensitivity reactions were described.

Rare cases of decreased visual acuity due to cystic retinal macular edema have also been reported during therapy with Abraxan. It is necessary to cancel Abraxan when making a diagnosis of cystic edema of the retinal macula. In some patients who received pre-capecitabine, cases of palmar-plantar erythrodysesthesia were noted. Due to the fact that such complications were reported spontaneously during clinical use of the drug, their true frequency and causal relationship cannot be determined.

The specific antidote of paclitaxel is unknown. In the case of an overdose of the drug Abraxane, symptomatic treatment and careful monitoring of the patient are carried out. Treatment should be directed to the main predicted complications (myelosuppression, mucositis, and peripheral neuropathy).

Mechanism of action

The mechanism of action of paclitaxel is based on its ability to stimulate the assembly of mitotic spindle microtubules from dimeric tubulin molecules and to stabilize the microtubules by suppressing their depolymerization. This leads to the suppression of the normal dynamic reorganization of the microtubular network in the mitotic interphase, and also causes the formation of abnormal clusters of microtubules throughout the cell cycle and the appearance of multiple star-shaped clusters (asteroids) in the mitotic phase.

Abraxane contains nanodisperse paclitaxel, stabilized by albumin, with a nanoparticle size of approximately 130 nm, in which paclitaxel is in a non-crystalline (amorphous) state.

After intravenous administration, the nanoparticles rapidly dissociate to form soluble complexes of paclitaxel bound to albumin, with an approximate size of 10 nm. It is known that albumin regulates the processes of transendothelial transfer of plasma components, and in studies in vitro It has been demonstrated that the presence of albumin in the drug Abraxane stimulates the transport of paclitaxel through the endothelial cell layer. It was hypothesized that transendothelial transport is mediated by the gp-60 albumin transporter and there is an increase in the accumulation of paclitaxel in the tumor due to the presence of albumin-binding protein-an acidic secreted protein rich in cysteine (SPARC).

The pharmacokinetics (FC) of paclitaxel was studied in clinical studies with 30-and 180-minute infusions of the drug Abraxane at doses from 80 to 375 mg / m². The AUC values for paclitaxel increased linearly, from 2653 to 16736 ng * h / ml in the dose range from 80 to 300 mg / m².

In a study involving patients with advanced solid tumors, the parameters (FC) of paclitaxel after intravenous administration of the drug Abraxan at a dose of 260 mg / m² for 30 minutes, the parameters of FC were compared with those of the solvent-based paclitaxel at a dose of 175 mg/m.² for 3 hours. Based on the results of the analysis without taking into account compartments, the clearance of paclitaxel (43%) and V_d its (53%) was higher with the administration of the drug Abraxane than with the solvent-based paclitaxel.

Differences of the terminal T_1/2 it was not registered. During the study of multiple intravenous administration of the drug Abraxane at a dose of 260 mg / m² In 12 patients, the intra-individual variability of the values of the systemic exposure of paclitaxel (AUC) was 19% (the spread of values = 3.21–27.7%). There were no signs of accumulation of paclitaxel during several courses of therapy.

Distribution. After administration of the drug Abraxan to patients with solid tumors, paclitaxel was evenly distributed in blood cells, plasma and bound to plasma proteins by 94% . The binding of paclitaxel to proteins was evaluated by ultrafiltration in a comparison study in the same patient. The proportion of free paclitaxel was significantly higher with the use of Abraxane (6.2%) than with the introduction of solvent-based paclitaxel (2.3%). This provided significantly higher exposure values for the unbound paclitaxel fraction when administered with Abraxane than for solvent-based paclitaxel, even with comparable total exposure values.

This phenomenon is probably due to the lack of binding of paclitaxel to micelles Cremophor EL what is observed when using solvent-based paclitaxel. According to published studies in which in vitro The association of paclitaxel (in concentrations from 0.1 to 50 mcg/ml) with human plasma proteins was evaluated, the presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect the association of paclitaxel with plasma proteins.

Taking into account the results of the population analysis of FC data, the overall V_d is approximately 1741 l, large V_d indicates intensive extravascular distribution and / or binding of paclitaxel to tissue proteins.

Metabolism and excretion. In research in vitro Using liver microsomes and human tissue sections, it was shown that paclitaxel is metabolized primarily to form 6α-hydroxypaclitaxel, as well as two additional metabolites present in smaller amounts (3'-n-hydroxypaclitaxel and 6α-3'-n-dihydroxypaclitaxel). The formation of these hydroxylated metabolites is catalyzed by the cytochrome P450 isoenzymes CYP2C8, CYP3A4, and both CYP2C8 and CYP3A4, respectively.

In patients with metastatic breast cancer after intravenous drip administration of the drug Abraxan for 30 minutes at a dose of 260 mg / m² the average cumulative urinary excretion of the unchanged active substance corresponded to 4% of the total administered dose of the drug, less than 1% of the administered dose was accounted for by the urinary metabolites 6α-hydroxypaclitaxel and 3'-n-hydroxypaclitaxel, which indicates a significant extrarenal clearance of the drug. Paclitaxel is mainly eliminated by hepatic metabolism and excretion with bile. When the drug is administered at a therapeutic dose of 80 to 300 mg / m² the average plasma clearance of paclitaxel varies from 13 to 30 l / h / m², and the middle terminal T_1/2 it ranges from 13 to 27 hours.

Special patient groups

Impaired liver function. The results of the conducted clinical studies demonstrated that mild hepatic insufficiency (total bilirubin >1 to < 1.5×ULN) did not have a clinically significant effect on the parameters of paclitaxel FC. In patients with moderate hepatic insufficiency (total bilirubin >1.5 to ≤3×ULN) and severe (total bilirubin >3 to ≤5×ULN), there was a decrease in the maximum elimination rate of paclitaxel by 22-26% and an increase in the average AUC of paclitaxel by about 20%.

Hepatic insufficiency did not affect the mean value of C_max paclitaxel. In addition, the elimination of paclitaxel was inversely correlated with the total bilirubin and directly proportional to the albumin concentration in the blood plasma.

Pharmacokinetic / pharmacodynamic modeling showed no correlation between liver function (based on baseline albumin or total bilirubin concentrations) and neutropenia, taking into account exposure to Abraxane. FC analysis was not performed in patients with total bilirubin >5×HCV or in patients with metastatic pancreatic adenocarcinoma (see "Dosage and administration").

Impaired renal function. Mild or moderate renal insufficiency (creatinine Cl from ≥30 to <90 ml / min) did not have a clinically significant effect on the maximum elimination rate and systemic exposure (AUC and C_max) paclitaxel. There are insufficient FC analysis data for patients with severe renal insufficiency, and there are no data for patients with end-stage renal insufficiency.

Elderly patients. The population FC analysis of the drug Abraxan included data from patients aged 24 to 85 years. The results showed that age does not significantly affect the maximum elimination rate and systemic exposure (AUC and C_max) paclitaxel.

Pharmacokinetic / pharmacodynamic modeling using data from 125 patients with advanced solid tumors showed that patients >65 years of age may be more likely to develop neutropenia during the first cycle of therapy, although age did not affect the plasma exposure of paclitaxel.

Other internal factors. Population FC analysis of the drug Abraxan demonstrated that gender, race (Mongoloid versus Caucasian), and type of solid tumors do not have a clinically significant effect on systemic exposure (AUC and C_max) paclitaxel. The AUC of paclitaxel in patients with a body weight of 50 kg is approximately 25% lower than in patients with a body weight of 75 kg. The clinical significance of these findings is unknown.

• Enteral and parenteral nutrition products
• Substitutes for plasma and other blood components

Human albumin is a normal constituent of human plasma and acts like physiological albumin.

In animals, single dose toxicity testing is of little relevance and does not permit the evaluation of toxic or lethal doses or of a dose-effect relationship. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models.

To date, human albumin has not been reported to be associated with embryo-foetal toxicity, oncogenic or mutagenic potential. No signs of acute toxicity have been described in animal models.

Sodium N-acetyltryptophanate 4 mmol/l

Sodium caprylate 4 mmol/l

Sodium chloride q.s.to a sodium content of 4 mmol/lWater for injections q.s.to 1 litre

Special studies of the interaction of paclitaxel with other drugs have not been conducted. Due to the fact that the metabolism of paclitaxel is partially mediated by the isoenzymes CYP2C8 and CYP3A4 of the cytochrome P450 system, the drug Abraxane should be used with caution together with inhibitors of these isoenzymes (including ketoconazole and other antifungal agents — imidazole derivatives, erythromycin, cimetidine, fluoxetine, gemfibrozil, ritonavir, saquinavir, indinavir, etc.). nelfinavir) or inducers of these isoenzymes (including rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine).

Paclitaxel and gemcitabine have different metabolic pathways. The clearance of paclitaxel is mainly due to metabolism catalyzed by the isoenzymes CYP2C8 and CYP3A4, followed by bile excretion, gemcitabine is inactivated by cytidine deaminase, followed by urinary excretion. Studies of the pharmacokinetic interaction of the drug Abraxane and gemcitabine in humans have not been conducted.

The drug Abraxane is indicated as a monotherapy for breast cancer or in combination with gemcitabine for the treatment of pancreatic adenocarcinoma (see "Indications"). The drug Abraxane should not be combined with other antitumor agents.

3 years.

In a place protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

lyophilizate for the preparation of suspension for infusions of 100 mg — 3 years. after preparation — 8 hours (bottle: in a place protected from light, at a temperature of 2-8 °C., infusion package: at a temperature not exceeding 25 °C)

lyophilizate for the preparation of suspension for infusions of 100 mg — 3 years.

Do not use after the expiration date indicated on the package.

Lyophilizate for the preparation of suspension for infusions, 100 mg. In clear glass bottles, capped with rubber stoppers with aluminum retainers, covered with removable plastic caps. Each bottle is packed in a cardboard box.

The solution can be directly administered by the intravenous route.

Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients.

If large volumes are administered, the product should be warmed to room or body temperature before use.

Do not use solutions which are cloudy or have deposits. This may indicate that the protein is unstable or that the solution has become contaminated.

Once the vial has been opened, the contents should be used immediately

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

UK: PL 15036/0031, IE: PA 800/8/1

UK: 07 January 2010, IE: 13 June 2014

19 December 2014

Thrombosis, hypertension, internal bleeding.