Pharmacological properties of the drug Kubitsin
Pharmacodynamics . Daptomycin is an antibacterial drug of a new class of antibiotics - cyclic lipopeptides. Daptomycin is a naturally occurring antibiotic used to treat infections caused by gram-positive bacteria. Daptomycin is active against antibiotic-resistant gram-positive bacteria, including microorganisms resistant to methicillin, vancomycin and linezolid. Mechanism of action. The mechanism of action of daptomycin differs from that of all antibiotics known today. Daptomycin binds to bacterial cell membranes and causes rapid depolarization of the cell membrane potential, both in the growth phase and in the stationary phase. The loss of membrane potential causes inhibition of DNA protein and RNA synthesis, resulting in the death of the bacterial cell with its minor lysis. Pharmacokinetics . General characteristics. The pharmacokinetics of daptomycin is usually linear and dose-dependent in the dose range of 4–12 mg/kg body weight once a day for 14 days. The equilibrium therapeutic concentration of the drug is achieved by the 3rd day of treatment. Distribution. The volume of distribution of daptomycin is approximately 0.1 L/kg in healthy adult volunteers, with distribution primarily interstitial. Daptomycin is predominantly distributed in highly vascularized tissues and to a small extent penetrates the BBB and the placental barrier with single and repeated use. Daptomycin is reversibly bound to plasma proteins (on average 90–93% regardless of concentration) in healthy volunteers. This rate decreases slightly (83.5–87.6%) in severe renal failure (creatinine clearance ≤30 ml/min or in patients on dialysis). Biotransformation. in vitro study demonstrated that hepatic microsomal metabolism of daptomycin is limited or absent, and the involvement of CYP 450 in the metabolism of daptomycin is minimal. in vitro study determined that daptomycin does not affect the activity of clinically significant human CYP isoforms (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). No metabolites were detected in the blood plasma of patients receiving daptomycin at a dose of 6 mg/kg, which confirms that the metabolism of daptomycin is insignificant and non-systemic. Excretion. Daptomycin is excreted primarily by the kidneys. The plasma clearance of daptomycin is 7–9 ml/h/kg, and the renal clearance is 4–7 ml/h/kg. When using a radioactive label, 78% of the drug was excreted in the urine, while approximately 52% of the substance was excreted unchanged, and 5% of daptomycin was excreted in the feces. Special patient groups. Elderly patients . For this category of patients there is no need for dose adjustment. Renal function should be monitored and the dose reduced accordingly in severe renal failure. Children and adolescents under 18 years of age . The pharmacokinetics of daptomycin have not been studied. Overweight patients . Systemic exposure to daptomycin increased by 28% in patients with overweight and obesity degrees I and II (body mass index 25–40 kg/m2) and by 42% in patients with obesity degree III (body mass index 40 kg/m2). But there is no need to adjust the dose taking into account excess body weight. Floor . There were no significant differences in the pharmacokinetics of daptomycin depending on the gender of the patient. Kidney failure . With a daptomycin dosage regimen of 4 mg/kg or 6 mg/kg in patients with varying degrees of renal impairment, daptomycin clearance decreased and systemic exposure (AUC) increased. In patients with severe renal failure (creatinine clearance ≤30 ml/min and in the terminal stage), AUC and T1/2 increased 2-3 times compared to healthy volunteers. Liver failure . The pharmacokinetics of daptomycin when using a single dose of 4 mg/kg in patients with moderate to moderate hepatic impairment (class B on the Child-Pugh scale) is not different. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Cubicin lyophilisate for injection 350 mg No. 1
Dosage forms lyophilisate for injection 350 mg lyophilized powder for the preparation of injection solution 500 mg International nonproprietary name? Daptomycin Composition Cubicin lyophilisate for injection 350 mg Active ingredient - daptomycin. Group? Antibiotics - cyclic lipopeptides Manufacturers Novartis Pharma GmbH (Germany), OCO Biopharmaceuticals Manufacturing LLC, packaged Novartis Pharmaceuticals UK Ltd (United States of America), OSO Biopharmaceuticals Manufacturing LLC/Novartis Pharma GmbH (United States of America) Indications for use Cubitin lyophilisate for injection 350 mg Complicated infections of the skin and soft tissues in adults; bacteremia caused by Staphylococcus aureus, including known or suspected infective endocarditis in adults. Directions for use and dosage Cubicin lyophilisate for injection 350 mg Intravenous infusion over at least 30 minutes. For complicated infections of the skin and soft tissues, the recommended dose for adults is 4 mg/kg once a day for 7-14 days or until the infection disappears. With the development of bacteremia caused by Staphylococcus aureus, 6 mg/kg of the drug is prescribed 1 time per day. For bacteremia caused by Staphylococcus aureus, including established or suspected infective endocarditis, the recommended dose for adults is 6 mg/kg 1 time per day for 2-6 weeks at the discretion of the attending physician. Contraindications Cubicin lyophilisate for injection 350 mg Hypersensitivity to daptomycin or excipients. Prescribe with caution to patients with impaired renal function (QC 9 points on the Child-Pugh scale), patients over 65 years of age. Patients with severe renal impairment (QC Pharmacological action Daptomycin is a cyclic lipopeptide of natural origin, active only against gram-positive bacteria. Daptomycin, in the presence of calcium ions, binds to the cell membrane (both in the growth phase of the bacterial cell and in the resting state), causing it depolarization, which leads to rapid inhibition of protein, DNA and RNA synthesis and cell death with minor lysis. In vitro, daptomycin quickly exhibits bactericidal activity (concentration dependent) against sensitive gram-positive microorganisms. In vivo with a single dose (at a dose equivalent to 4 mg/ kg and 6 mg/kg once daily in humans), the AUC/MIC and Cmax/MIC ratios correlated with the efficacy and predicted bactericidal effect.In the group of highly sensitive microorganisms for which the MIC (according to the European Committee on Antibiotic Susceptibility Testing, EUCAST) of daptomycin is 1 mg/l includes: Staphylococcus aureus*, Staphylococcus haemolyticus, coagulase-negative staphylococci, Streptococcus agalactiae*, Streptococcus dysgalactiae subsp equisimilis*, Streptococcus pyogenes*, group G streptococci, Clostridium perfringens, Peptostreptococcus spp. (*species are marked for which the activity of the drug against which, demonstrated in clinical studies, was considered to be satisfactory). The group of resistant microorganisms for which the MIC (according to EUCAST) of daptomycin is > 1 mg/l includes naturally resistant gram-negative microorganisms. Daptomycin is effective in patients with complicated infections of the skin and soft tissues (wound infections, subcutaneous abscesses), with bacteremia caused by Staphylococcus aureus, incl. methicillin-resistant strains (infective endocarditis, including early postoperative endocarditis) Side effect Cubitin lyophilisate for injection 350 mg The most common adverse reactions: headache, nausea, vomiting, diarrhea, fungal infections, rash, reactions at the injection site, increased activity of creatine phosphokinase (CPK) and liver function enzymes: ALT, AST and alkaline phosphatase. During clinical studies, the following adverse events were noted: Infectious diseases: often - fungal infections; sometimes - urinary tract infections. From the blood system and hematopoietic organs: sometimes - thrombocytosis, anemia, eosinophilia. Metabolic and nutritional disorders: sometimes - anorexia, hyperglycemia. Mental disorders: sometimes - anxiety, insomnia. From the nervous system and sensory organs: often - headache; sometimes - dizziness, paresthesia, taste disturbance. From the cardiovascular system: sometimes - supraventricular tachycardia, extrasystole, hot flashes, increase or decrease in blood pressure. From the digestive system: often - nausea, vomiting, diarrhea; sometimes - constipation, abdominal pain, dyspepsia, glossitis. From the liver and biliary tract: sometimes - jaundice. From the skin and subcutaneous tissue: often - rash; sometimes - itching, urticaria. From the musculoskeletal system: sometimes - myositis, muscle weakness, myalgia, arthralgia. From the urinary system: sometimes - renal dysfunction. From the reproductive system: sometimes - vaginitis. On the part of the body as a whole and reactions at the site of drug administration: often - reactions at the site of drug administration; sometimes - fever, weakness, fatigue, pain. Changes in laboratory parameters: often - disturbances in laboratory parameters of liver function (increased activity of AST, ALT and alkaline phosphatase), increased activity of CPK; sometimes - electrolyte imbalance, increased plasma creatinine levels, increased myoglobin levels, increased LDH activity. When using the drug in clinical practice, the following adverse events were observed. From the immune system: very rarely - hypersensitivity (isolated spontaneous messages), including eosinophilic infiltrates in the lungs, vesiculobullous rash on the skin and mucous membranes, a feeling of swelling in the oropharynx; anaphylaxis; post-infusion reactions (tachycardia, wheezing, fever, chills, systemic hyperemia, dizziness, fainting, metallic taste in the mouth). From the musculoskeletal system: very rarely - rhabdomyolysis. In approximately 50% of cases, rhabdomyolysis was observed in patients with pre-existing renal failure or when the drug was used concomitantly with drugs that cause rhabdomyolysis. Changes in laboratory parameters: in some cases, myopathy, manifested by muscle symptoms and increased CPK activity, was accompanied by an increase in transaminase levels. The increase in transaminase activity was likely due to the drug's effect on skeletal muscle. In most cases, there was an increase in transaminase activity of grade 1-3, which disappeared after cessation of therapy. Overdose Treatment: Medical observation and symptomatic therapy are recommended. Daptomycin is slowly eliminated from the body by hemodialysis (about 15% of the administered dose is eliminated after 4 hours) or by peritoneal dialysis (about 11% of the administered dose is eliminated after 48 hours). Interaction Cubicin lyophilisate for injection 350 mg Daptomycin is not metabolized or is slightly metabolized with the participation of the cytochrome P450 isoenzyme system (CYP450). Since in in vitro studies the drug does not have a clinically significant inducing or inhibitory effect on the CYP isoenzyme system (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4), the development of CYP-dependent interactions in humans is unlikely. Experience with the simultaneous use of daptomycin with drugs whose use may be accompanied by myopathy is limited. However, there have been several cases of increased CPK activity and the development of rhabdomyolysis in patients taking the drug together with drugs that cause myopathy. The drug should be prescribed together with drugs that cause myopathy only in cases where the benefits of therapy outweigh the possible risks. When using daptomycin together with drugs that cause myopathy, it is necessary to monitor CPK activity more than once a week and monitor patients in order to promptly identify any symptoms indicating the development of myopathy. Since daptomycin is eliminated primarily by renal filtration, its plasma concentration may increase when used concomitantly with drugs that reduce renal filtration (including NSAIDs, including selective COX-2 inhibitors). In addition, when daptomycin is used with these drugs, pharmacodynamic interactions may develop due to a cumulative effect on renal function. Cubicin should be used with caution in combination with potentially nephrotoxic drugs, ensuring additional regular monitoring of renal function in all patients (regardless of the initial state of renal function). In clinical practice, there have been cases of interaction of daptomycin with a specific reagent used in determining prothrombin time/International Normalized Ratio (PT/INR). This interaction led to a pronounced prolongation of PT and an increase in INR. When detecting deviations in PT/INR in patients receiving treatment with Cubicin, the possibility of interaction of daptomycin in vitro with a laboratory reagent should be taken into account. The likelihood of error in determining PT or INR can be minimized if blood is collected at the lowest possible concentration of daptomycin in the blood plasma. If necessary, the drug can be used (administered intravenously) simultaneously with aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine. Pharmaceutical incompatibility: Cubitsin should not be mixed with glucose-containing solutions, as well as with other agents, except for those mentioned above. Special instructions If the development of a mixed infection (including gram-negative and/or anaerobic microorganisms) is suspected, Cubitsin must be combined with appropriate antibiotics. Limited experience with the use of daptomycin in complicated skin and soft tissue infections caused by Enterococcus faecalis and Enterococcus faecium does not allow us to draw conclusions about the clinical effectiveness of Cubicin. There is no experience with the use of the drug in patients after valve replacement. According to clinical studies, Kubitsin is ineffective in patients with pneumonia and bacteremia in patients with severe left-sided endocarditis caused by Staphylococcus aureus. Treatment failure due to persistent or recurrent infection caused by Staphylococcus aureus was observed in 19/20 (15.8%) patients receiving Cubicin, 9/53 (16.7%) - vancomycin and 2/62 (3.2%) - semisynthetic penicillins. These patients, including 6 in the Cubicin group and 1 in the vancomycin group, experienced an increase in MIC during or after therapy. Most patients with persistent or recurrent infections had deeply localized infections and did not receive surgical treatment. For deeply localized infections, appropriate surgical intervention (including wound debridement, removal of prostheses, valve replacement) should be immediately performed to achieve a clinical effect. Since the development of antibiotic-associated colitis and pseudomembranous colitis from moderate to severe degrees (life-threatening conditions) has been observed with the use of almost all antibacterial drugs, the possibility of the development of these adverse events should also be taken into account when using Cubicin and the condition of patients with diarrhea should be monitored during treatment or shortly after its ending. The mechanism for the development of resistance to daptomycin has not been established. Reduced sensitivity to daptomycin, as well as to other antibacterial drugs, has been observed when used in patients with severe, difficult-to-treat infections and/or for a long period of time. In a clinical study using Cubicin in 6 people with endocarditis and bacteremia, a decrease in sensitivity to daptomycin was observed, which may have been the reason for the ineffectiveness of antibiotic therapy. In clinical practice, isolated cases of decreased sensitivity to daptomycin have also been observed. Because data on antibiotic resistance patterns vary by geographic area and change over time, it is recommended that local resistance information be taken into account, especially when treating severe infections. If there is any doubt about the effectiveness of the drug, at least against some types of pathogens (taking into account local antibiotic resistance), it is recommended to consult with a qualified specialist. If antibiotic resistance (superinfection) to daptomycin develops, appropriate measures must be taken. Since during clinical studies in patients receiving Cubitsin, an increase in CPK activity (5 times higher than ULN) without the development of muscle symptoms was observed more often than with the use of the comparison drug (1.9% and 0.5%, respectively), the following recommendations must be followed: - plasma CPK activity blood levels are determined before the start of therapy and during treatment with Cubicin at regular intervals (once a week) in all patients; - since when using the drug in patients with high levels of CPK (5 ULN), a further increase in enzyme activity is possible, in this category of patients it is necessary to monitor the level of CPK more than once a week; - determination of CPK levels more often than once a week should be carried out in patients with an increased risk of developing myopathy: severe renal failure (CK 5 ULN), treatment with the drug should be discontinued. If symptoms of peripheral neuropathy develop, patients should be examined and discontinuation of treatment with Cubicin should be considered. administration of Cubicin, isolated cases of renal failure were observed, but the relationship of this adverse event with the drug has not been established. In patients with severe renal failure, the concentration of daptomycin in the blood plasma may increase, leading to an increased risk of developing myopathy. In clinical studies, renal dysfunction was more often observed in patients , who received a comparison drug than Kubitsin. The effect of the drug on the ability to drive vehicles and operate machinery has not been studied. However, given the safety profile of Kubitsin, a negative effect on the ability to perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions is unlikely. Storage conditions: Keep out of the reach of children, at a temperature of 2-8°C.
Use of the drug Cubitsin
Cubicin is administered as a slow intravenous infusion over 30 minutes. Bacteremia caused by Staphylococcus aureus, including right-sided endocarditis . The recommended dose for adults is 6 mg/kg once a day for 2–6 weeks, depending on the nosological form and characteristics of the course of the disease. Complicated skin and soft tissue infections . The recommended dose for adults is 4 mg/kg body weight once a day for 1–2 weeks. Patients with renal failure (creatinine clearance ≥ 30 ml/min) . Patients with creatinine clearance ≥ 30 ml/min do not require dose adjustment of Cubicin. Response to treatment and renal function should be carefully monitored in patients with renal insufficiency. Patients with renal failure (creatinine clearance ≤ 30 ml/min) . The intervals between individual doses should be increased to 48 hours in patients with creatinine clearance ≤ 30 ml/min. The clinical response to treatment and the status of renal function in such patients should be carefully monitored. The same dosage adjustment is recommended for patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Patients with severe renal failure. Cubitsin is not recommended for elderly patients with severe renal failure. Liver failure. Patients with moderate hepatic impairment will not require dose adjustment of Cubicin. There are no data for patients with severe hepatic impairment (Child-Pugh class C). Elderly patients. Elderly patients take the drug in recommended doses.
Release form, composition and packaging
Lyophilisate for the preparation of solution for infusion from light yellow to light brown.
One bottle contains:
active substance: Daptomycin - 350 mg;
excipients: sodium hydroxide solution 3N.
Colorless glass bottles with a capacity of 10 ml (1) with a yellow snap-on cap - cardboard packs.
Lyophilisate for the preparation of solution for infusion from light yellow to light brown.
One bottle contains:
active substance: Daptomycin - 500 mg;
excipients: sodium hydroxide solution 3N.
Colorless glass bottles with a capacity of 10 ml (1) with a blue snap-on cap - cardboard packs.
Side effects of the drug Cubitsin
Infections and infestations : fungal infections, infections of the genitourinary system. From the blood and lymphatic system : anemia, eosinophilia, thrombocytosis. Metabolic: decreased appetite, hyperglycemia. Mental disorders : anxiety, dyssomnia. From the central nervous system: dizziness, headache, paresthesia, dysgeusia. From the organ of hearing and vestibular apparatus : vertigo. From the cardiovascular system : supraventricular arrhythmia, feeling of hot flashes, hypertension (arterial hypertension), hypotension. From the gastrointestinal tract : abdominal pain, constipation, diarrhea, nausea, vomiting. From the hepatobiliary system : jaundice. From the skin and subcutaneous tissues: rash, itching, urticaria. From the musculoskeletal system: arthralgia, myalgia, muscle weakness, rhabdomyolysis. From the urinary system : renal failure. From the reproductive system: vaginitis. General disorders and local reactions: increased fatigue, hyperthermia, chills, general weakness, reactions at the injection site. From the laboratory parameters : electrolyte imbalance, increased CPK, creatinine, AST, ALT, ALP, LDH in the blood plasma. From the immune system : hypersensitivity reactions, anaphylaxis, pulmonary eosinophilia.
Special instructions for the use of the drug Cubitsin
General instructions . When using antibiotics, microorganisms may develop resistance to the drug. If superinfection occurs during therapy, appropriate measures are taken. There are reports of moderate to severe cases of colitis and pseudomembranous colitis associated with the use of almost all groups of antibacterial agents, which should be considered in patients with established or probable diarrhea. For a deeply localized source of infection, complex treatment is necessary, including surgical care (surgical debridement, removal of prostheses, valve replacement). A clinical study of Kubicin showed that the drug is ineffective against pneumonia because it binds to surfactant and is inactivated. Creatine phosphokinase and myopathy . There are reports of increased plasma levels of CPK, which is associated with muscle pain, weakness and/or rhabdomyolysis during therapy with Cubicin. It is recommended to monitor the level of CPK in the blood plasma at the beginning of therapy and during treatment once every 7 days in all patients. In patients with an unclear reason for the increase in CPK in the blood plasma or with muscle pain, muscle soreness on palpation, weakness of unspecified origin, CPK levels should be monitored more often than once a week. CPK should be monitored more often than once a week in patients at high risk of developing myopathy. Taking Kubicin should be discontinued in patients with unspecified symptoms from the muscular system and an increase in the level of CPK in the blood plasma of 1000 units/l (more than 5 times higher than normal) or in the absence of symptoms of myopathy and an increase in the level of CPK in the blood plasma of 2000 units/l (10 times or more times the norm). Neuropathy . Patients should be closely monitored for signs or symptoms of neuropathy during therapy. Kidney failure. The condition of patients with renal failure, both dysfunction and increased CPK levels, needs to be monitored more often. During pregnancy and breastfeeding . During pregnancy, Cubitsin is used only if the expected benefit to the mother outweighs the potential risk to the fetus/child. There is no data on the penetration of daptomycin into breast milk. Stop breastfeeding while using the drug. Children . Studies have not been conducted in children under the age of 18 years, therefore Cubitin is not recommended for the treatment of this age group. The ability to influence reaction speed when driving vehicles or working with machinery . There are no specific recommendations.
Pregnancy and lactation
The use of Cubicin in pregnant women has not been studied. In experimental studies, daptomycin does not have a negative effect on the course of pregnancy, embryo, fetus, childbirth and postnatal development.
The drug should be prescribed during pregnancy only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.
It is not known whether daptomycin is excreted into breast milk in humans. If it is necessary to use the drug during lactation, breastfeeding must be stopped.
Drug interactions Cubitsin
Daptomycin does not affect cytochrome P450-mediated metabolism. Data regarding the combined use of HMG-CoA reductase inhibitors and Cubicin are limited, therefore, when using Cubicin, it is necessary to temporarily discontinue the use of HMG-CoA reductase inhibitors. The drug interactions of Cubicin with aztreonam, tobramycin, warfarin, simvastatin and probenecid were studied. Cubicin does not affect the bioavailability of aztreonam, warfarin and probenecid. A clinically significant interaction between Cubicin and tobramycin is unknown, so these drugs are used together with caution. Clinical data regarding the combined use of Cubicin with simvastatin (an HMG-CoA reductase inhibitor) are limited, therefore patients using Cubicin should temporarily discontinue use of HMG-CoA reductase inhibitors. Cubicin is incompatible with solvents containing glucose.
For liver dysfunction
Cubicin should be prescribed with caution to patients with severe liver dysfunction (>9 points on the Child-Pough scale).
Impact on the ability to drive vehicles and operate machinery
The effect of the drug on the ability to drive vehicles and operate machinery has not been studied. However, given the safety profile of Kubitsin, a negative effect on the ability to perform potentially hazardous activities that require increased concentration and speed of psychomotor reactions is unlikely.
