Active ingredients: Daptomycin
Cubicin 350 mg powder for solution for injection or infusion
Cubicin package inserts are available for pack sizes:- Cubicin 350 mg powder for solution for injection or infusion
- Cubicin 500 mg powder for solution for injection or infusion
Indications Why is Cubicin used? What is it for?
The active substance in Cubicin powder for solution for injection or infusion is daptomycin. Daptomycin is an antibacterial that can stop the growth of some bacteria. Cubicin is used in adults and children and adolescents (aged 1 to 17 years) to treat infections of the skin and subcutaneous (under the skin) tissues. It is also used in adults to treat infections of the tissues lining the inside of the heart (including heart valves) caused by a bacterium called Staphyloccocus aureus and to treat blood infections caused by the same bacterium when they are associated with infections. of the skin and subcutaneous tissues.
Depending on the type of infection (s) you have, your doctor may also prescribe other antibacterials while you are being treated with Cubicin.
Contraindications When Cubicin should not be used
You must not be given Cubicin
If you are allergic to daptomycin or sodium hydroxide or any of the other ingredients of this medicine (listed in section 6). If this applies to you, please tell your doctor or nurse.
If you think you may be allergic, consult your doctor or nurse.
Precautions for use What you need to know before taking Cubicin
Talk to your doctor or nurse before you are given Cubicin.
- If you have or have previously had kidney problems. Your doctor may need to adjust your Cubicin dose (see section 3 of this package leaflet).
- Patients treated with Cubicin sometimes present with muscle pain or pain or weakness (see section 4 of this leaflet for more information). In this case, please inform your doctor. Your doctor will make sure that you have a blood test and will advise you whether or not to continue taking Cubicin. Symptoms, as a rule, disappear within a few days after Cubicin is discontinued.
- If you are overweight. It is possible that your blood levels of Cubicin are higher than those seen in people of average weight, so you may need to be monitored more carefully for side effects.
If any of these apply to you, please tell your doctor or nurse before you are given Cubicin.
Tell your doctor right away if any of the following symptoms appear:
- Severe, acute allergic reactions have been observed in patients treated with almost all antibacterial medicinal products, including Cubicin. Tell your doctor or nurse immediately if you experience symptoms that may suggest an allergic reaction such as wheezing, difficulty in breathing, swelling of the face, neck and throat, skin rash and hives, fever (see section 4 of this leaflet. illustrative for more information).
- Unusual tingling or numbness in the hands or feet, loss of sensation or difficulty moving. If this happens, tell your doctor who will decide whether to continue the treatment.
- Diarrhea, especially if you notice blood or mucus or if the diarrhea becomes severe or persistent.
- New or worsening fever, cough, difficulty in breathing. These may be signs of a rare but serious lung disease called eosinophilic pneumonia. Your doctor will check the condition of your lungs and decide whether or not you should continue treatment with Cubicin.
Cubicin can interfere with laboratory tests performed to measure blood clotting. The results may suggest a blood clotting difficulty, although there is actually no problem at all. It is therefore important that your doctor bears in mind that you are taking Cubicin. Tell your doctor that you are being treated with Cubicin.
Your doctor will carry out blood tests to check the condition of your muscles both before starting treatment and frequently during treatment with Cubicin.
Children and adolescents
Cubicin should not be given to children under one year of age as animal studies have indicated that serious side effects may occur in this age group.
Use in the elderly
People over the age of 65 can take the same dose as adults, provided they have normal kidney function.
Interactions Which drugs or foods may change the effect of Cubicin
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines.
It is especially important that you communicate if you are hiring:
- Medicines called statins or fibrates (to lower cholesterol) or cyclosporine (a medicine used in transplants to prevent organ rejection or in other conditions such as rheumatoid arthritis or atopic dermatitis). If you take these medicines (and others that may affect the muscles) while taking Cubicin, the risk of side effects on the muscles may be higher. Your doctor may decide not to prescribe Cubicin or to stop using the other medicines for a certain period of time.
- Analgesics called non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors (eg celecoxib). These could interfere with the effects of Cubicin in the kidney.
- Oral anticoagulants (e.g. warfarin) which are medicines that prevent blood from clotting. Your doctor may need to check your bleeding time.
Warnings It is important to know that:
Pregnancy and breastfeeding
Cubicin is generally not given to pregnant women. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before being given this medicine.
Do not breast-feed if you are taking Cubicin, as Cubicin can pass into breast milk and consequently could affect the baby.
Driving and using machines
Cubicin has no known effects on the ability to drive and use machines.
Dosage and method of use How to use Cubicin: Dosage
Cubicin is usually given by your doctor or nurse. The dose given depends on your weight and the type of infection being treated. In adults, the normal dose is 4 mg for each kilogram (kg) of body weight given once a day. day for skin infections or 6 mg for every kg of body weight given once daily for a "heart infection or" blood infection associated with skin or heart infection. In adult patients, this dose is injected directly into the bloodstream (into the vein) or as an infusion lasting approximately 30 minutes or as an injection lasting approximately 2 minutes.The same dose is recommended for people over the age of 65, provided they have normal kidney function.
Children and adolescents (1 to 17 years)
The dose for children and adolescents (1 to 17 years) to be used for the treatment of skin infections depends on the age of the patient. The recommended doses according to age are shown in the table below:
If you have impaired kidney function, you may take Cubicin less frequently, for example every other day. If you are on dialysis and the next dose of Cubicin is to be given on the day of dialysis, you will usually be given Cubicin after the end of dialysis.
As a rule, a course of treatment lasts from 1 to 2 weeks for skin infections. For blood or heart infections and skin infections your doctor will decide how long it will need to be treated.
Detailed instructions for use and handling can be found at the end of this package leaflet.
Side Effects What are the side effects of Cubicin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
The most serious side effects are described below:
Very rare serious side effects (may affect less than 1 in 10,000 patients)
In some cases, a hypersensitivity reaction (severe allergic reaction including anaphylaxis, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS)) has been reported during administration of Cubicin. This severe allergic reaction requires immediate medical attention. Tell your doctor or nurse immediately if any of the following symptoms appear:
- Chest pain or tightness
- Rash (skin) with blistering that sometimes affects the mouth and genitals,
- Swelling around the throat
- Fast or weak heartbeat,
- Wheezing,
- Fever,
- Chills or tremors
- Flushes,
- Dizziness
- Fainting,
- Metallic taste in the mouth.
If you notice any unexplained muscle pain, tenderness or weakness, tell your doctor immediately. In very rare cases (reported in less than 1 in 10,000 patients) muscle problems can be serious, including muscle breakdown (rhabdomyolysis) which can cause kidney damage.
Serious side effects with frequency not known (frequency cannot be estimated from the available data)
A rare but potentially serious lung disease, called eosinophilic pneumonia, has been reported in patients given Cubicin, in most cases after more than 2 weeks of treatment. Symptoms may include difficulty breathing, new or worsening cough, or new or worsening fever. If you experience these symptoms, tell your doctor or nurse immediately.
The most frequently reported side effects are described below:
Common side effects (may affect up to 1 in 10 people)
- Fungal infections such as oral candidiasis,
- Urinary tract infections,
- Reduction in the number of red blood cells (anemia),
- Dizziness, anxiety, difficulty sleeping,
- Headache,
- Fever, weakness (asthenia),
- High or low blood pressure,
- Constipation, abdominal pain,
- Diarrhea, feeling nauseous or vomiting,
- Flatulence,
- Bloating or abdominal tension,
- Rash (skin) or itching,
- Pain, itching or redness at the infusion site,
- Pain in the arms or legs,
- Increased levels of liver enzymes (liver) or creatinine phosphokinase (CPK) shown in blood tests.
Other side effects that may occur following treatment with Cubicin are described below:
Uncommon side effects (may affect up to 1 in 100 people)
- Blood disorders (such as an increase in the number of small particles called platelets, which could increase the tendency of the blood to clot or increase in the levels of certain types of white blood cells),
- Decreased appetite,
- Tingling or numbness in the hands or feet, change in taste,
- Tremor,
- Heart rhythm changes, flushing,
- Indigestion (dyspepsia), inflammation of the tongue,
- Rash (skin) associated with itching,
- Muscle pain or weakness, inflammation of the muscles (myositis), joint pain,
- Kidney problems
- Vaginal inflammation and irritation,
- General pain or weakness, tiredness (fatigue),
- Blood tests showing increased levels of blood sugar, serum creatinine, myoglobin or lactate dehydrogenase (LDH), prolonged bleeding time or salt imbalance.
Rare side effects (may affect up to 1 in 1,000 people)
- Yellowing of the skin and eyes,
- Prolongation of prothrombin time.
Frequency not known (frequency cannot be estimated from the available data)
Colitis associated with the use of antibacterials, including pseudomembranous colitis (severe and persistent diarrhea containing blood and / or mucus, associated with abdominal pain or fever).
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the carton and label after EXP / EXP. The expiry date refers to the last day of that month.
- Store in a refrigerator (2 ° C - 8 ° C)
What Cubicin contains
- The active ingredient is daptomycin. One vial of powder contains 350 mg of daptomycin.
- The other component is sodium hydroxide.
Description of what Cubicin looks like and contents of the pack
Cubicin powder for solution for injection or infusion is supplied as a light yellow to light brown lyophilisate or powder in a glass vial. Before administration it is mixed with a solvent to form a liquid.
Cubicin is available in packs containing 1 vial or 5 vials.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CUBICIN 350 MG POWDER FOR SOLUTION FOR INJECTION OR FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 350 mg daptomycin.
After reconstitution with 7 ml of sodium chloride 9 mg / ml (0.9%) solution, 1 ml contains 50 mg of daptomycin.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for injection or infusion.
Pale yellow to light brown lyophilisate or powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Cubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).
- Complicated skin and soft tissue infections (cSSTI).
- Infective endocarditis of the right heart (RIE) from Staphylococcus aureus. It is recommended that the decision to use daptomycin be made considering the antibacterial susceptibility of the organism and based on expert opinion. See sections 4.4 and 5.1.
- Bacteremia from Staphylococcus aureus (SAB) when associated with RIE or cSSTI.
Daptomycin is only active against Gram positive bacteria (see section 5.1). In mixed infections, where the presence of Gram-negative bacteria and / or certain types of anaerobes is suspected, Cubicin should be administered concomitantly with one or more appropriate antibacterial agents.
Official guidelines on the appropriate use of antibacterial agents should be considered.
04.2 Posology and method of administration
Clinical studies in patients were conducted by administering daptomycin as a 30 minute infusion. There is no clinical experience in patients for the administration of daptomycin as a 2-minute injection. This method of administration has only been studied in healthy volunteers. However, when compared to the same doses administered by intravenous infusion over 30 minutes, there were no clinically significant differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).
Dosage
- cSSTI without concomitant bacteremia due to Staphylococcus aureus: Cubicin 4 mg / kg is administered once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
- cSSTI with concomitant bacteremia due to Staphylococcus aureus: Cubicin 6 mg / kg is administered once every 24 hours. For dose adjustment in patients with renal impairment see below. The duration of therapy may need to be extended to more than 14 days depending on the possible risk of complications in the individual patient.
- Known or suspected infective endocarditis of the right heart from Staphylococcus aureus. Cubicin 6 mg / kg is administered once every 24 hours. For dose adjustment in patients with renal impairment see below. Duration of therapy should be in accordance with available official recommendations.
Cubicin is administered intravenously in 0.9% sodium chloride solution (see section 6.6). The frequency of administration should not be more than once a day.
Impaired renal function
Daptomycin is eliminated primarily by the kidney.
In light of limited clinical experience (see table and annotations below) Cubicin should be used in patients with any degree of renal impairment (Cr Cl creatine phosphokinase (CPK) should be closely monitored in all patients with any degree of renal impairment. renal function (see also sections 4.4 and 5.2).
Dose adjustments in patients with renal impairment based on indication and creatinine clearance
The safety and efficacy of dose interval adjustment have not been evaluated in controlled clinical trials and the recommendations are derived from pharmacokinetic studies and pharmacokinetic modeling results (see sections 4.4 and 5.2).
The same dose adjustments from volunteer pharmacokinetic data and pharmacokinetic modeling are recommended for patients on hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered at the end of dialysis on the day of dialysis (see section 5.2).
Impaired liver function
No dose adjustment is required when Cubicin is administered to patients with mild or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). Since no data are available for patients with severe hepatic impairment (Child-Pugh Class C), caution is required when administering Cubicin to this patient population.
Elderly patients
The recommended doses should be administered to elderly patients, except those with severe renal impairment (see above and section 4.4).
Pediatric population
The safety and efficacy of Cubicin in children and adolescents aged below 18 years have not been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.
Method of administration
Cubicin is administered by intravenous infusion (see section 6.6) over 30 minutes or by intravenous injection (see section 6.6) over 2 minutes.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
General
If an outbreak of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy, the institution of alternative antibacterial therapy that has been shown to be effective in treating the specific type of infection (s) present should be considered. (the).
Anaphylactic and hypersensitivity reactions
Anaphylactic and hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, use should be discontinued and appropriate therapy instituted.
Pneumonia
Clinical studies have shown that Cubicin is not effective in the treatment of pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.
RIE from Staphylococcus aureus
Clinical data on the use of Cubicin in the treatment of RIE from Staphylococcus aureus are limited to 19 patients (see "Data from clinical trials" in section 5.1).
The efficacy of Cubicin in patients with prosthetic valve infections or left heart infective endocarditis has not been demonstrated.Staphylococcus aureus.
Deep infections
Patients with deep infections should undergo any necessary surgical interventions (such as debridement, removal of prosthetic devices, valve replacement surgery) without delay.
Enterococcal infections
There is insufficient evidence to allow conclusions to be drawn on the possible clinical efficacy of Cubicin against enterococcal infections, including Enterococcus faecalis And Enterococcus faecium.
Furthermore, the doses of daptomycin that might be adequate for the treatment of enterococcal infections, with or without bacteraemia, have not been determined. Failures of daptomycin therapy in the treatment of enterococcal infections, in the majority of cases associated with bacteraemia, have been reported. In some cases, therapeutic failure has been related to the selection of organisms with reduced sensitivity or overt resistance to daptomycin (see section 5.1).
Non-sensitive microorganisms
The use of antibacterials can promote the overproliferation of non-sensitive microorganisms. If superinfection occurs during therapy, appropriate measures should be taken for its treatment.
Diarrhea associated with Clostridium difficile
Diarrhea associated with Cubicin has been reported Clostridium difficile (CDAD) (see section 4.8).
In the event of suspected or confirmed CDAD, it may be necessary to discontinue use of Cubicin and initiate appropriate treatment, as clinically indicated.
Interactions with diagnostic tests
False prolongation of prothrombin time (PT) and elevation of the international normalized ratio (INR) were observed when certain recombinant thromboplastin reagents were used for testing (see also section 4.5).
Creatine phosphokinase and myopathy
Increases in plasma creatine phosphokinase (CPK, MM isoenzyme) levels associated with muscle pain and / or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during Cubicin therapy (see also sections 4.5, 4.8 and 5.3). In clinical trials, marked increase in plasma CPK to> 5 times the maximum limit of normal (ULN) without muscle symptoms was observed more frequently in patients treated with Cubicin (1.9%) than in those treated with drugs. comparison (0.5%). In light of these observations, it is recommended:
• to measure plasma CPK at baseline and, thereafter, at regular intervals (at least once a week) during therapy in all patients.
• to measure CPK more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in patients who have a higher risk of developing myopathy, e.g. in patients with any degree of renal impairment (clearance of creatinine HMG-CoA reductase, fibrates and cyclosporine).
• to consider, at the start of daptomycin therapy, the possibility that patients with CPK values that exceed 5 times the upper limit of normal at baseline are at increased risk of further increases during therapy with daptomycin , since this possibility cannot be ruled out; if daptomycin is administered, this type of patient should be monitored more frequently than once a week.
• not to give Cubicin to patients taking other medicines associated with myopathy, unless the benefit to the patient is considered to outweigh the risk.
• to submit patients to regular examinations during therapy, to ascertain the presence of any signs and symptoms that may be suggestive of myopathy.
• to monitor CPK levels every 2 days in patients with unexplained pain, tenderness, weakness and muscle cramps; if the CPK level exceeds 5 times the upper limit of normal, Cubicin should be discontinued in the presence of unexplained muscle symptoms.
Peripheral neuropathy
Patients who exhibit signs and symptoms suggestive of peripheral neuropathy during Cubicin therapy should be investigated and consideration should be given to discontinuing treatment with daptomycin (see sections 4.8 and 5.3).
Eosinophilic pneumonia
Cases of eosinophilic pneumonia have been reported in patients administered Cubicin (see section 4.8). In the majority of reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory failure and diffuse pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with Cubicin and improved after discontinuation of Cubicin and initiation of steroid therapy. Relapses of eosinophilic pneumonia have been reported after re-exposure Patients who develop these signs and symptoms during treatment with Cubicin should undergo prompt medical examination, including bronchoalveolar lavage where appropriate to rule out other causes (e.g. infections) bacterial, fungal infections, parasites, other medicines). Cubicin treatment should be discontinued immediately and systemic steroid treatment initiated if appropriate.
Impaired renal function
Cases of renal impairment have been reported during treatment with Cubicin.The presence of severe renal impairment can, in itself, predispose the patient to increased levels of daptomycin, which, in turn, can increase the risk of developing myopathy (see previous points).
In patients with creatinine clearance
Before initiating therapy with Cubicin, caution is required when administering Cubicin to patients who already have some degree of renal impairment (creatinine clearance
Monitoring of renal function is also recommended for concomitant administration of potentially nephrotoxic agents, regardless of pre-existing renal function status (see also section 4.5).
Obesity
In obese subjects with a body mass index (BMI)> 40 kg / m2 but with a creatinine clearance> 70 ml / min, the AUC0-∞ of daptomycin was significantly higher (mean greater than 42%) compared to "identical control group of non-obese. In light of the fact that data on the safety and efficacy of daptomycin in very obese patients are limited, caution in its use is recommended. However, to the present state of knowledge, there is no evidence of the need for dose reduction (see section 5.2).
04.5 Interactions with other medicinal products and other forms of interaction
The metabolism of daptomycin is not mediated, or to a slight extent, by cytochrome P450 (CYP450). Daptomycin is unlikely to inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
Cubicin interaction studies were conducted with aztreonam, tobramycin, warfarin and probenecid. Daptomycin has no effect on the pharmacokinetics of warfarin or probenecid, nor do these drugs alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin are not significantly altered by aztreonam.
Although small changes in the pharmacokimetics of daptomycin and tobramycin were observed when administered simultaneously by intravenous infusion lasting 30 minutes using a 2 mg / kg dose of Cubicin, these changes were not statistically significant.
At approved doses of Cubicin, the interaction between daptomycin and tobramycin is unknown. Caution is recommended when Cubicin is co-administered with tobramycin.
Experience with the concomitant administration of Cubicin and warfarin is limited. No studies of Cubicin have been conducted with anticoagulants other than warfarin. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored from onset for several days after it is Cubicin therapy was instituted.
Experience with concomitant administration of daptomycin and other medicinal products that can trigger myopathy (eg HGM-CoA reductase inhibitors) is limited. However, some cases of marked elevation in CPK levels and rhabdomyolysis have been observed in patients taking either of these medicines concomitantly with Cubicin. It is therefore recommended that the use of other medicinal products associated with myopathy be temporarily discontinued, if possible, during treatment with Cubicin, unless the benefits of concomitant administration outweigh the risk. CPK should be measured more frequently than once a week, and patients should also be carefully monitored for signs or symptoms suggestive of myopathy. See sections 4.4, 4.8 and 5.3.
As daptomycin is eliminated primarily by renal filtration, plasma levels may be increased during co-administration of medicinal products that reduce renal filtration (eg NSAIDs and COX-2 inhibitors). A pharmacodynamic interaction may also occur during co-administration, caused by overlapping renal effects. Therefore, caution is required when co-administering daptomycin and any other medicinal product known to reduce renal filtration.
During post-marketing observation, there have been reports of interference between daptomycin and particular reagents used in some assays to determine the prothrombin time / international normalization ratio (TP / INR). This interference resulted in a false prolongation of the TP and an increase in the INR. If unexplained abnormalities in PT / INR are observed in patients receiving daptomycin, a possible interaction should be considered. in vitro with the laboratory test. The possibility of erroneous results can be minimized by postponing specimen collection for TP and INR tests for as long as possible until the plasma daptomycin concentration is at the lowest levels (see section 4.4).
04.6 Pregnancy and lactation
Pregnancy
No clinical data on pregnancy are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3).
Cubicin should not be used during pregnancy unless absolutely necessary, i.e. only if the expected benefit outweighs the possible risk.
Feeding time
In a single human case study, Cubicin was administered intravenously every day for 28 days to a nursing mother at a dose of 500 mg / day and on day 27 samples of the patient's milk were collected in the day. The highest concentration of daptomycin measured in breast milk was found to be 0.045 mcg / ml, which corresponds to a low concentration. Therefore, until more experience is gained, breastfeeding should be discontinued when Cubicin is given to women who are breastfeeding.
Fertility
No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
Based on reports of adverse drug reactions, it is considered unlikely that Cubicin will induce effects on the ability to drive and use machines.
04.8 Undesirable effects
Summary of the safety profile
In clinical trials, Cubicin was administered to 2,011 subjects. As part of these studies, 1,221 subjects received a daily dose of 4 mg / kg, of which 1,108 were patients and 113 healthy volunteers; 460 subjects received a daily dose of 6 mg / kg, of these 304 were patients and 156 healthy volunteers Adverse reactions (ie those which, according to the investigator, are possibly, probably or definitively related to the medicinal product) have been reported with similar frequencies for Cubicin and the comparator dose schedules.
The most frequently reported adverse reactions (with common frequency (≥ 1/100, urinary tract, candida infection, anemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhea, flatulence, abdominal bloating and tension, abnormal liver function test (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, pain in extremities, increased serum creatine phosphokinase (CPK) , administration site reactions, pyrexia, asthenia.
Less frequently reported but more serious adverse reactions include hypersensitivity reactions, eosinophilic pneumonia, drug eruption with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.
Table of adverse reactions
The following adverse reactions were reported during therapy and follow-up, with a frequency corresponding to very common (≥ 1/10); common (≥ 1/100,
Within each frequency class, undesirable effects are reported in descending order of severity.
Table 1 Adverse reactions from clinical trials and post-marketing reports
* Based on post-marketing reports. As these reactions are reported spontaneously from a population of uncertain size, it is not possible to reliably define their frequency, which is therefore classified as unknown.
** See section 4.4.
1 Although the exact incidence of daptomycin-associated eosinophilic pneumonia is not known, the number of spontaneous reports is currently very low (
2 In some cases of myopathy accompanied by elevated CPK and muscle symptoms, patients also had elevated transaminases, possibly related to musculoskeletal effects. In the majority of cases, the transaminase elevation was Grade 1-3 and resolved after discontinuation of treatment.
3 Where clinical data from patients were available it was found that approximately 50% of cases occurred in the presence of pre-existing renal impairment or in the presence of concomitant therapy with medicinal products known to induce rhabdomyolysis.
Data on the safety of administration of daptomycin by 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on the results of these studies, both methods of administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had similar safety and tolerability profiles. There were no relevant differences in local tolerability or in the nature and frequency of adverse reactions.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
In the event of an overdose, supportive therapy is recommended. Daptomycin is slowly eliminated from the body by hemodialysis (approximately 15% of the administered dose is eliminated over 4 hours) or peritoneal dialysis (approximately 11% of the administered dose is eliminated over 48 hours).
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials.
ATC code: J01XX09.
Mechanism of action
Daptomycin is a natural cyclic lipopeptide product, active only against Gram-positive bacteria.
The mechanism of action is given by the ability of daptomycin to bind (in the presence of calcium ions) to the bacterial membranes of cells in both the proliferative and stationary phases, inducing depolarization and rapid inhibition of protein, DNA and protein synthesis. RNA. This action leads to the cell death of bacteria with negligible cell lysis.
PK / PD relationship
In vitro And in vivo in animal models, daptomycin exhibits rapid, concentration-dependent bactericidal action against Gram-positive organisms. In animal models, AUC / MIC and Cmax / MIC correlate with efficacy and expected killing of bacteria in vivo at single doses equivalent to doses of 4 mg / kg / day and 6 mg / kg / day in humans.
Mechanisms of resistance
Strains with decreased sensitivity to daptomycin have been reported, especially during the treatment of patients with difficult-to-treat infections and / or after administration for prolonged periods. In particular, in patients with Staphylococcus aureus, Enterococcus faecalisAnd Enterococcus faecium, including patients with bacteraemia, cases of treatment failure have been reported that have been related to selection of organisms with reduced susceptibility or overt resistance to daptomycin.
The mechanism (s) of resistance to daptomycin is not yet fully known.
Breakpoint
The minimum inhibitory concentration (MIC) breakpoint established by EUCAST (European Committee on Antimicrobial Susceptibility Testing) for staphylococci and streptococci (except S. pneumoniae) are Sensitive ≤ 1 mg / l and Resistant> 1 mg / l.
Sensitivity
For selected species, the prevalence of resistance may vary geographically and over time, so data on resistance is desirable, particularly in the treatment of severe infections. As appropriate, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent, at least for some types of infections, is questionable.
* denotes the species against which it is believed that activity has been satisfactorily demonstrated in clinical studies.
Clinical efficacy and safety
In two clinical trials of complicated skin and soft tissue infections, 36% of patients treated with Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound infection (38% of patients), while 21% had major abscesses. When deciding whether to use Cubicin, these limitations of the treated patient population should be considered.
In an open-label, randomized controlled clinical trial in 235 patients with Staphylococcus aureus (i.e. at least one positive blood culture for Staphylococcus aureus before receiving the first dose) 19 out of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected with Staphylococcus aureus sensitive to methicillin and 8 from Staphylococcus aureus resistant to methicillin. Success rates in patients with RIE are described in the table below.
Failure to respond to treatment due to infections was observed Staphylococcus aureus persistent or relapsing in 19/120 (15.8%) patients treated with Cubicin; in 9/53 (16.7%) patients treated with vancomycin and in 2/62 (3.2%) patients treated with anti-staphylococcal semi-synthetic penicillin. As part of these non-responses, six patients treated with Cubicin and one patient treated with vancomycin were infected withStaphylococcus aureus and had developed increased MICs of daptomycin during or following therapy (see "Mechanisms of Resistance" above). Most of the patients who have not responded to therapy, due to infection with Staphylococcus aureus persistent or relapsing, had deep infection and had not undergone the necessary surgery.
05.2 "Pharmacokinetic properties
The pharmacokinetics of daptomycin are usually linear and independent of time at doses ranging from 4 to 12 mg / kg administered as a single daily dose by 30 minute intravenous infusion for up to 14 days in healthy volunteers. Steady state concentrations are achieved at the third daily dose.
In the range of approved therapeutic doses (4 to 6 mg / kg), daptomycin administered by 2 minute intravenous injection also exhibits dose proportional pharmacokinetics.
In healthy volunteers, comparable exposure (AUC and Cmax) was found after administration of daptomycin by 2 minute intravenous injection or 30 minute intravenous infusion.
Animal studies have shown that daptomycin is not significantly absorbed with oral administration.
Distribution
In healthy adult volunteers, the steady-state volume of distribution of daptomycin was approximately 0.1 L / kg and was dose independent. Tissue distribution studies in rats showed that daptomycin appears to cross the blood brain and placental barrier only minimally after single or multiple dose administration.
Daptomycin reversibly binds human plasma proteins in a concentration independent manner. In healthy volunteers and patients treated with daptomycin, protein binding was on average 90%, including subjects with renal impairment.
Biotransformation
In the studies in vitro, daptomycin was not metabolised by human liver microsomal enzymes.
Studies in vitro with human hepatocytes indicate that daptomycin does not inhibit or induce the activity of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. Daptomycin is unlikely to inhibit or induce the metabolism of metabolised medicinal products from the P450 system.
After infusion with daptomycin-14C in healthy adults, plasma radioactivity was similar to the concentration determined by microbiological titration. Inactive metabolites were detected in urine as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In another study, no metabolites were observed in plasma, while negligible amounts of three oxidative metabolites and one unidentified compound were found in urine. The site of metabolism was not identified.
Elimination
Daptomycin is mainly excreted via the kidney. In humans, co-administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics; this observation suggests low or no active tubular secretion of daptomycin.
Following intravenous administration, the plasma clearance of daptomycin is approximately 7-9 ml / h / kg, while the renal clearance is 4-7 ml / h / kg.
In a mass balance study using radiolabelled material, 78% of the administered dose was detected from the urine based on total radioactivity, while urinary detection of unchanged daptomycin was approximately 50% of the dose. Approximately 5% of the dose. The radiolabeller administered was excreted in the faeces.
Special populations
Senior citizens
Following administration of a single 4 mg / kg intravenous dose of Cubicin as a 30-minute infusion, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ higher by approximately 58% in subjects. elderly (age ≥ 75 years) compared to those in healthy young subjects (ages 18 to 30 years). There were no differences in Cmax. Most likely the differences found are due to the normal reduction in renal function observed in the population. elderly.
No dose adjustment is required based on age alone. However, renal function should be assessed and the dose should be reduced in the presence of severe renal impairment.
Children and adolescents (age
The pharmacokinetics of daptomycin following a single 4 mg / kg dose of Cubicin were evaluated in three groups of pediatric patients with proven or suspected Gram positive infection (2-6 years, 7-11 years and 12-17 years). The pharmacokinetics of daptomycin following a single 4mg / ml dose in adolescents aged 12-17 years are generally similar to that seen in healthy adult subjects with normal renal function with a trend towards lower AUC and Cmax in adolescents. In the younger groups (2-6 years and 7-11 years) total clearance was higher than in adolescents, resulting in lower exposure (Cmax and AUC) and shorter elimination half-lives. Efficacy was not evaluated in this study.
Another study was conducted to evaluate the pharmacokinetics of daptomycin following a single dose of 8 mg / kg or 10 mg / kg of Cubicin as a 1 or 2 hour infusion in pediatric subjects aged 2 to 6 years, with proven or suspected Gram positive infection who were already receiving standard antibacterial therapy.
After administration of single doses of 8 and 10 mg / kg, the mean exposure (AUC0-∞) was approximately 429 and 550 mcg * hr / ml, respectively, similar to the exposure observed in adults for the 4 mg / kg dose. kg at steady state (495 mcg * hour / ml). The pharmacoconetics of daptomycin appear to be linear over the dose range studied. The half-life, clearance and volume of distribution were similar for both doses.
Obesity
Compared to non-obese subjects, systemic exposure to daptomycin, as measured by AUC, was approximately 28% higher in moderately obese subjects (BMI 25-40 kg / m2) and 42% in those extremely obese (Body mass index> 40 kg / m2). It is not believed, however, that dose adjustment is necessary solely on the basis of obesity.
Sex
No clinically significant sex-related differences were observed in daptomycin pharmacokinetics.
Impaired renal function
After administration of a single 4 mg / kg or 6 mg / kg intravenous dose of daptomycin as a 30-minute infusion to patients with varying degrees of renal impairment, with decreasing renal function (creatinine clearance) total clearance (CL) of daptomycin decreased, while systemic exposure (AUC) increased.
Based on pharmacokinetic data and modeling, daptomycin AUC on the first day after administration of a 6 mg / kg dose to patients on hemodialysis or continuous ambulatory peritoneal dialysis was 2-fold higher than that observed in patients with normal renal function who received the same dose. On the second day of administration of a dose of 6 mg / kg to patients on hemodialysis or continuous ambulatory peritoneal dialysis, the AUC of daptomycin was approximately 1.3 times higher than that observed after a second dose of 6 mg / kg in patients with normal renal function. Based on the foregoing, it is recommended that daptomycin be administered to patients on hemodialysis or continuous ambulatory peritoneal dialysis every 48 hours, at the recommended dose for the type of infection being treated (see section 4.2).
Impaired liver function
In subjects with moderate hepatic impairment (Child-Pugh hepatic impairment classification B), the pharmacokinetics of daptomycin were not altered compared to gender, age and weight identical healthy volunteers following administration of a single dose of 4 mg / kg. No dose adjustment is required when daptomycin is administered to patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh classification C) have not been evaluated.
05.3 Preclinical safety data
In clinically relevant studies (14-28 days), administration of daptomycin was associated with mild degenerative / regenerative musculoskeletal changes in rats and dogs.
Microscopic changes in skeletal muscle were minimal (affecting approximately 0.05% of myofibers) and were accompanied by elevations in CPK at higher doses. No fibrosis or rhabdomyolysis was observed. Depending on the duration of the study, all effects on muscle, including microscopic changes, were fully reversible within 1-3 months after dosing was stopped. No functional or pathological changes in smooth or cardiac muscle were observed.
In rats and dogs the lowest dose (LOEL) at which myopathy is observed corresponds to exposure levels of 0.8 to 2.3 times the therapeutic levels in humans at a dose of 6 mg / kg (by intravenous infusion of 30 minutes. ) for patients with normal renal function Since the pharmacokonetic properties (see section 5.2) are comparable, the safety margins of both methods of administration are very similar.
A dog study showed that skeletal myopathy was reduced after once daily dosing compared to the same total daily dose given in a fractional manner, suggesting that myopathic effects in animals are mainly related to the interval between doses.
Neuroperipheral effects were observed at doses higher than those associated with musculoskeletal effects in adult rats and dogs, and were mainly related to plasma Cmax. The neuroperiferic changes were characterized by minimal or mild axonal degeneration and were frequently associated with functional alterations. The microscopic and functional effects were fully reversible within 6 months post-dosing. The safety margins for neuroperipheral effects in rats and dogs are 8- and 6-fold, respectively, based on comparison of Cmax values at the NOAEL, with a Cmax achieved at a single daily dose of 6 mg / kg via a 30-minute intravenous infusion. in patients with normal renal function.
The results of the studies in vitro and some studies in vivo designed to elucidate the mechanism of daptomycin myotoxicity indicate that the target of toxicity is the plasma membrane of spontaneously contracting differentiated muscle cells. It has not been identified which specific cell surface component is the direct target of daptomycin. Mitochondrial damage / loss was also observed; however, the role and significance of this evidence on the overall pathology remain to be established. This evidence was not associated with an effect on muscle contraction.
Unlike adult dogs, juvenile dogs appeared to be more sensitive to neuroperipheral lesions than skeletal myopathy. Juvenile dogs developed neuroperipheral and neurospinal lesions at lower doses than those associated with musculoskeletal toxicity.
Reproductive toxicity tests showed no evidence of effects on fertility, embryo-fetal or postnatal development. However, daptomycin can cross the placental barrier in pregnant rats (see section 5.2). The excretion of daptomycin in the milk of lactating animals has not been studied.
Long-term carcinogenicity studies in rodents have not been conducted. Daptomycin was shown to be non-mutagenic and non-clastogenic in a series of genotoxicity tests in vivo And in vitro.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium hydroxide
06.2 Incompatibility
Cubicin is physically or chemically incompatible with solutions containing glucose. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity
3 years
After reconstitution: Chemical-physical stability in use of the reconstituted solution in the vial has been demonstrated for 12 hours at 25 ° C and up to 48 hours at 2 ° C - 8 ° C. Chemical stability has been established. physics of the diluted solution in infusion bags is 12 hours at 25 ° C or 24 hours at 2 ° C - 8 ° C.
For the 30 minute intravenous infusion, the total storage period (reconstituted solution in the vial and diluted solution in the infusion bag; see section 6.6) at 25 ° C should not exceed 12 hours (or 24 hours at 2 ° C - 8 ° C).
For the 2 minute intravenous injection, the storage period of the reconstituted solution in the vial (see section 6.6) should not exceed 12 hours at 25 ° C (or 48 hours at 2 ° C - 8 ° C).
However, from a microbiological point of view, the medicine should be used immediately.
This medicinal product does not contain preservatives or bacteriostatic agents. If not used immediately, the user is responsible for the in-use storage period which, as a rule, should not exceed 24 hours at 2 ° C - 8 ° C, unless reconstitution / dilution is done under conditions aseptic controlled and validated.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
For storage conditions after reconstitution and after reconstitution and dilution see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Single-use 10 ml type I clear glass vials with type I rubber stopper and aluminum cap with yellow plastic cap.
Available in packs containing 1 vial or 5 vials.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Daptomycin can be administered intravenously as a 30 minute infusion or as a 2 minute injection (see sections 4.2 and 5.2). Preparation of the infusion solution requires further dilution, as described below.
Administration of Cubicin by intravenous infusion over 30 minutes
A 50 mg / ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilisate with 7 ml of sodium chloride 9 mg / ml (0.9%) solution for injection.
It takes about 15 minutes for the lyophilisate to dissolve. The fully reconstituted medicine has a clear appearance and there may be some bubbles or foam around the edges of the vial.
For the preparation of Cubicin for intravenous infusion, the following instructions should be followed: Aseptic technique should be used throughout the reconstitution of lyophilized Cubicin.
1. Remove the polypropylene cap to expose the central part of the rubber stopper. Withdraw 7 ml of sodium chloride 9 mg / ml (0.9%) solution for injection into a syringe and slowly inject into the vial by inserting the needle into the center of the rubber stopper with the tip pointing towards the vial wall.
2. Shake the vial with a gentle twisting motion to ensure that the product is completely wetted by the liquid, then let it rest for 10 minutes.
3. Finally, shake the vial with a gentle rotating motion for a few minutes until a clear reconstituted solution is obtained. Vigorous shaking or shaking of the vial should be avoided to prevent foaming.
4. Before use, the reconstituted solution should be carefully checked to ensure that the product is completely dissolved and inspected with the naked eye for the absence of particulates. The color of the reconstituted Cubicin solution may vary from pale yellow to light brown.
5. The reconstituted solution must then be diluted with sodium chloride 9 mg / ml (0.9%) solution for intravenous infusion (typical volume 50 ml).
6. Invert the vial to allow the solution to flow down to the stopper. Using a new syringe insert the needle into the inverted vial. Keeping the inverted vial keep the needle tip at the bottom of the solution while drawing the solution into the syringe.
Before removing the needle from the vial, pull the plunger back to the end of the syringe barrel to withdraw all of the solution from the inverted vial.
7. Replace the needle with a new intravenous infusion needle.
8. Expel air, large bubbles and excess solution until the required dose is obtained.
9. The reconstituted and diluted solution should then be slowly injected intravenously over 30 minutes as described in section 4.2.
The following agents have been shown to be compatible when added to Cubicin-containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
Administration of Cubicin by intravenous injection for 2 minutes
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only be reconstituted with 9 mg / ml (0.9%) sodium chloride.
A 50 mg / ml concentration of Cubicin for injection is obtained by reconstituting the lyophilisate with 7 ml of sodium chloride 9 mg / ml (0.9%) solution for injection.
It takes about 15 minutes for the lyophilisate to dissolve. The fully reconstituted medicine is clear in appearance and may have some bubbles or foam around the edges of the vial.
To prepare Cubicin for intravenous injection, the following instructions should be followed: Aseptic technique should be used throughout the reconstitution of lyophilized Cubicin.
1. Remove the polypropylene cap to expose the central part of the rubber stopper. Withdraw 7 ml of sodium chloride 9 mg / ml (0.9%) solution for injection into a syringe and slowly inject into the vial by inserting the needle into the center of the rubber stopper with the tip pointing towards the vial wall.
2. Shake the vial with a gentle twisting motion to ensure that the product is completely wetted by the liquid, then let it rest for 10 minutes.
3. Finally, shake the vial with a gentle rotating motion for a few minutes until a clear reconstituted solution is obtained. Vigorous shaking or shaking of the vial should be avoided to prevent foaming.
4. Before use, the reconstituted solution should be carefully checked to ensure that the product is completely dissolved and inspected with the naked eye for the absence of particulates. The color of the reconstituted Cubicin solution may vary from pale yellow to light brown.
5. Invert the vial to allow the solution to flow down to the stopper. Using a new syringe insert the needle into the inverted vial. Keeping the inverted vial place the needle tip at the bottom of the solution while drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger back to the end of the syringe barrel to withdraw all of the solution from the inverted vial.
6. Replace the needle with a new needle for intravenous injection.
7. Expel air, large bubbles and excess solution until the required dose is obtained.
8. The reconstituted solution should be injected slowly intravenously over 2 minutes as described in section 4.2.
Cubicin vials are for single use only.
From a microbiological point of view, the medicinal product should be used immediately (see section 6.3).
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/05/328/001
037151014
EU / 1/05/328/003
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: January 19, 2006
Date of most recent renewal: January 19, 2011
10.0 DATE OF REVISION OF THE TEXT
D.CCE April 2015
