20170308.
Note: Based on the latest version (15th edition, issued in 2011) of the original research unit approved instructions for dry syrup, including data for children.
20171225: [Pharmacology and Toxicology] Based on the approved version of the pharmacology and toxicology professional to determine
Date of approval.
Date of revision.
Paediatric Faropenem Sodium Granules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Pediatric Faropenem Sodium Granules
Trade name: Feropem
English name: Pediatric Faropenem Sodium Granules
Hanyu Pinyin：Xiao’er Faluopeinanna Keli
Ingredients
The main ingredient of this product is Faropenem Sodium. Its chemical name: (5R,6S)-6-[(R)-1-hydroxyethyl]-7-oxo-3-[(R)-2-tetrahydrofuranyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt dibasic hemihydrate.
Chemical structure formula.
Molecular formula: C12H14NNaO5S-2.5H2O
Molecular weight: 352.34
【Properties】This product is orange granules.
Indications]
This product is a granule, mainly used for the treatment of the following infectious diseases in children caused by bacteria sensitive to Faropenem.
Pediatric patients
This product is indicated for the treatment of the following infectious diseases in children caused by Staphylococcus spp., Streptococcus spp., Streptococcus pneumoniae, Enterococcus spp., Catamorax spp., Escherichia coli, Citrobacter spp., Klebsiella spp., Haemophilus influenzae, and Pertussis spp. that are sensitive to Faropenem.
Superficial skin and skin tissue infection, deep skin and skin tissue infection, lymphangitis, lymphadenitis, chronic skin suppurative disease, pharyngitis, tonsillitis, acute bronchitis, pneumonia, cystitis, pyelonephritis, otitis media, sinusitis, periodontal tissue infection, scarlet fever, pertussis.
Specification】0.05g（According to C12H15NO5S）.
Dosage and Administration
Usage
Dissolve the product in appropriate amount of water and take orally.
This product needs to be prepared for immediate use, and it should not be left for a long time after preparation. It should be used quickly after dissolving with water, and if necessary, it can be stored in the refrigerator, but it should also be used as soon as possible.
2.Dosage
The dosage should be increased or decreased by the doctor according to the type and severity of the infection and the specific situation of the patient.
In order to prevent the emergence of drug-resistant strains, bacterial susceptibility testing should be done in principle, and the shortest course of treatment should be used under the premise of ensuring efficacy.
Recommended dosage for children.
Usually, children are given 5mg/kg per dose, 3 times daily. The dosage can be increased or decreased according to age, weight and symptoms. For older children, the dose should not exceed the upper limit of the adult dose, i.e. 300mg per dose, 900mg per day.
Adverse reactions]
There is no detailed information on the adverse reactions of this product for domestic clinical use. Information on the adverse reactions of foreign marketed faropenem sodium dry syrup and faropenem sodium tablets are as follows.
1.Faropenem sodium dry syrup
In the clinical trial at the time of approval, 48 cases (8.2%) out of a total of 587 cases showed adverse reactions, the main adverse reactions were 35 cases (6.0%) of diarrhea and 9 cases (1.5%) of loose stools.
In addition, the clinical examination values were abnormal in 22 (6.8%) cases of eosinophilia, 15 (4.9%) cases of elevated ALT (GPT), and 11 (3.6%) cases of elevated AST (GOT).
The results of the post-marketing use survey: 367 cases (10.2%) of a total of 3613 cases experienced adverse reactions, with the main adverse reactions being diarrhea and loose stools in 349 cases (9.7%), rash in 10 cases (0.3%), vomiting in 4 cases (0.1%), and urticaria in 3 cases (0.1%) (by the end of the 2005 re-examination).
(1) Serious adverse reactions
(1) Shock (less than 0.1%), allergy-like symptoms (incidence unknown): Sometimes shock and allergy-like symptoms may be caused, so close observation is necessary. In case of discomfort, abnormalities in the mouth, wheezing, dyspnea, dizziness, dysgeusia, tinnitus, sweating, general flushing, vascular swelling, hypotension, etc., the drug should be stopped and appropriate treatment should be given.
(2) Acute renal insufficiency (incidence unknown): Serious renal dysfunction, including acute renal insufficiency, may sometimes occur, and when such abnormalities are confirmed, the drug should be discontinued and appropriate treatment should be given.
(3) Severe colitis such as pseudomembranous colitis with bloody stools (incidence unknown): Severe colitis such as pseudomembranous colitis with bloody stools may occur in some cases, so close observation is necessary, and when symptoms such as abdominal pain or frequent diarrhea occur, the drug should be discontinued immediately and appropriate treatment should be given.
(4) Skin-mucous membrane eye syndrome (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome) (incidence unknown): Since symptoms such as skin-mucous membrane eye syndrome (Stevens-Johnson syndrome) and toxic epidermal necrolysis (Lyell syndrome) may occur sometimes, close observation is necessary, and when such symptoms occur, the drug should be discontinued and appropriate treatment should be given. When such symptoms appear, the drug should be discontinued and appropriate treatment should be done.
(5) Interstitial pneumonia (incidence unknown): Interstitial pneumonia with symptoms such as fever, cough, dyspnea, and abnormal chest x-ray may occur.
(6) Liver dysfunction and jaundice (less than 0.1%): sometimes elevated glutamic oxaloacetic transaminase (AST (GOT)), glutamic alanine transaminase (ALT (GPT)), alkaline phosphatase (Al-P) and jaundice may occur, liver function should be checked regularly, and the drug should be discontinued and appropriate treatment should be given if abnormalities are confirmed.
(7) Granulocyte deficiency (incidence unknown): Granulocyte deficiency may sometimes occur, and should be closely observed, and once the abnormality is confirmed, the drug should be discontinued and appropriate treatment should be given.
(8) Rhabdomyolysis (incidence unknown): sometimes rhabdomyolysis characterized by myalgia, weakness, elevated creatine phosphokinase (CK (CPK)), elevated myoglobin in blood and urine, etc. may occur, and may be accompanied by acute renal insufficiency and other serious renal dysfunction, and the drug should be discontinued and appropriate treatment should be given when the above symptoms occur.
(2) Serious adverse reactions (similar drugs)
Eosinophilic pulmonary infiltration syndrome (PIE syndrome): It has been reported that similar compounds (cephalosporins, carbapenems) can cause fever, cough, dyspnea, abnormal chest X-ray, eosinophilia and other PIE syndrome, and if the above symptoms occur, the drug should be discontinued and appropriate therapeutic measures such as giving adrenocorticosteroids should be taken.
3) Other adverse reactionsNote 1)
Incidence unknown incidence 0.1-<5% incidence<0.1% allergyNote 2) Itchy rash, urticariaNote 4), fever, erythema, erythema and other blood EosinophiliaNote 3), abnormal white blood cell classification, etc. Abnormal granulocyte count, abnormal platelet count Liver Elevated glutamic aminotransferase (AST), glutamic aminotransferase (ALT), gamma-glutamyl aminotransferase (gamma-GTP), etc. Elevated alkaline phosphatase (Al-P), bilirubin, lactate dehydrogenase (LDH), etc. Kidney Elevated urea nitrogen (BUN), creatinine Digestive
System Nausea, diarrheaNote 4), loose stoolsNote 4), abdominal pain and vomitingNote 4), loss of appetite, abdominal distention, stomatitis, stomatitis, gastrointestinal dysfunction, dyspepsia, gastritis, constipation Bacterial flora
Dysbiosis Candida infectionNote 5), stomatitis Vitamin deficiency Vitamin K deficiency (hypoprothrombinemia, bleeding tendency, etc.), vitamin B deficiency (tongue inflammation, stomatitis, loss of appetite, neuritis, etc.) Other numbness Hot flashes, headache, dizziness, drowsiness, edema, dry mouth and lips, eye pain, nail discoloration, lethargy. (Note 1) Based on the results of the survey on the use of tablets and dry syrup for children at the time of approval and during the reexamination (20,916 total cases, special
investigation 63 cases, post-marketing clinical trial 17 cases) to count the incidence of adverse reactions.
(Note 2) Adequate observation must be made, and the drug should be discontinued and appropriate measures taken in the event of these symptoms.
(Note 3) Based on the results of the trial when the dry syrup for children was approved, eosinophilia was changed in 22 cases (6.8%).
(Note 4) Based on the results of the approval and post-marketing use of dry syrup for children, 393 cases (9.5%) of diarrhea and loose stools, 5 cases of urticaria
(0.1%), and vomiting in 4 cases (0.1%). Discontinue the drug and take appropriate measures when these symptoms occur.
(Note 5) This product may cause superficial cutaneous Candida infection on the buttocks in children.
Take appropriate measures.
2. Faropenem Sodium Tablets
In clinical trials at the time of approval, adverse reactions occurred in 127 cases (5.8%) out of a total of 2207 cases. The main adverse reactions were diarrhea in 55 cases (2.5%), abdominal pain in 19 cases (0.9%), loose stools in 15 cases (0.7%), rash in 13 cases (0.6%), and nausea in 12 cases (0.5%).
In addition, the clinical examination values were abnormal in 56 cases (3.4%) of elevated glutamic transaminase (ALT (GPT)), 36 cases (2.2%) of elevated glutamic oxalacetic transaminase (AST (GOT)), and 27 cases (1.8%) of eosinophilia.
The post-marketing findings showed that adverse reactions occurred in 528 cases (3.0%) out of a total of 17,383 cases, and the main adverse reactions were diarrhea and loose stools in 365 cases (2.1%), abdominal pain in 26 cases (0.2%), and skin rash in 25 cases (0.1%) .
Serious adverse reactions, serious adverse reactions (similar drugs) and other adverse reactions are the same as those described above under the same item of Faropenem sodium dry syrup adverse reactions.
Contraindications] Contraindicated in patients with a history of shock to the ingredients of this product.
In principle, it is contraindicated in patients with a history of hypersensitivity to the ingredients of this product.
Precautions]
1, the following patients should be used with caution
(1) Patients with a history of hypersensitivity to penicillins, cephalosporins or carbapenems.
(2) Patients who are prone to bronchial asthma, rash, urticaria and other allergic symptoms, such as parents or siblings.
(3) Patients who have poor oral intake or are receiving non-oral nutritional therapy, or patients with poor systemic status (sometimes vitamin K deficiency may occur and should be closely monitored).
(4) Patients with diarrhea (may lead to worsening of diarrheal symptoms and require close observation)
(5) Patients with severe renal dysfunction (the product is mainly excreted through the kidneys, and renal impairment may lead to prolonged drug half-life and prolonged sustained high blood concentration, so the dose should be reduced or the interval should be extended appropriately).
2. Attention when using
(1) Shock may occur when taking this product, so it should be fully investigated.
(2) The most common adverse effects of this product are diarrhea and loose stools, so when the following symptoms occur, control the dose and observe the condition of the stools. If symptoms such as diarrhea or loose stools occur, take appropriate measures (including discontinuation of the drug) according to the symptoms, extent and history.
In addition, when diarrhea or loose stools are observed, the patient or guardian should be instructed by the physician (see [Adverse Reactions] for details).
The incidence of side effects such as diarrhea and loose stools: children under 3 years of age (13.5%) is higher than children over 3 years of age (4.0%)
The incidence of side effects such as diarrhea and loose stools is higher in children under 3 years of age (13.5%) than in children over 3 years of age (4.0%).
(2) Symptoms such as diarrhea and loose stools are most likely to occur within 3 days after administration, so careful observation is particularly important during the initial period of administration.
(3) The incidence of diarrhea and loose stools tends to increase with increasing single dose (5.4% for 5mg/kg, 9.2% for 7.5mg/kg, 10.9% for 10mg/kg), so the dose should be observed.
(3) This product may cause superficial cutaneous Candida infection on the buttocks in children, which should be adequately observed and discontinued and appropriate measures taken when the above symptoms appear.
(4) Effects on clinical examination
(1) In addition to urine sugar test tape (Tes tape) reaction, Benedict’s reagent (Benedict’s reagent), Fehling’s reagent (Fehling’s reagent), copper sulfate containing tablet reagent (Clinitest) urine sugar test shows false positive reaction.
2) May lead to a positive result in the direct Coombs test.
[Pregnant and lactating women use].
For pregnant women or women who may become pregnant, do not take this product unless you can determine that the benefits of treatment outweigh the potential risks (the safety of use in pregnant women has not been established).
Since this product can be distributed into breast milk, avoid breast-feeding when using this product.
For Children]
The safety of this product has not been established for low birth weight infants and neonates (no experience with this product).
For Elderly]
This product is a granule, mainly used for the treatment of infectious diseases in children caused by bacteria sensitive to Faropenem. This product can also be used for the treatment of infectious diseases in adults caused by bacteria sensitive to faropenem.
Elderly patients need to be used with caution and special attention should be paid to the following matters, starting from 150mg per dose, paying attention to the patient’s status and careful administration (because the elderly generally have lower physiological functions and are prone to adverse reactions).
1, human pharmacokinetic tests on elderly patients show that compared with healthy adults, the blood half-life of elderly patients is prolonged and the blood concentration remains high for a long time, which may be related to increased age and low renal function.
2.Symptoms such as diarrhea and soft stools in elderly patients are likely to lead to worsening of systemic symptoms; therefore, adequate observation is required, and the drug should be discontinued and appropriate measures taken when these symptoms occur.
3. Bleeding tendency due to vitamin K deficiency may occur in elderly patients.
Drug Interaction]
Note when this product is used in combination with the following drugs.
Combined drug name clinical symptoms mechanism, risk factors imipenem-
Cilastatin sodium animal studies (rats) reported: can lead to increased blood concentration cilastatin inhibits the metabolizing enzyme activity of this product. Furosemide animal studies (dog) report: enhanced nephrotoxicity of this product. It is not clear that the combination of sodium valproate and carbapenems (meropenem, panipenem betamilon, imipenem cistatin sodium) can reduce the concentration of valproic acid in the blood, resulting in seizure recurrence. Unclear [Drug overdose] Unclear.
Pharmacology and Toxicology
Pharmacological effects
Faropenem sodium is a penicillin-based oral antibiotic with a basic penicillin backbone. It exerts antibacterial and bactericidal effects by preventing bacterial cell wall synthesis. It has high affinity for various penicillin binding proteins (PBPs), especially for PBPs, which are essential for bacterial proliferation.
In vitro test shows that faropenem sodium has a wide antibacterial spectrum against aerobic Gram-positive bacteria, aerobic Gram-negative bacteria and anaerobic bacteria; especially it shows strong bactericidal effect on Staphylococcus, Streptococcus, Pneumococcus and Enterococcus among aerobic Gram-positive bacteria, Citrobacter, Enterobacter and Pertussis among aerobic Gram-negative bacteria and Streptococcus digestiveis, Bacillus and Prevotella among anaerobic bacteria. It is also stable to various bacteria producing β-lactamase, and has strong antibacterial activity against bacteria producing β-lactamase.
Toxicological studies
Genotoxicity Ames test, cultured cell mutation test and chromosome abnormality test, and mouse micronucleus test did not find that faropenem sodium is mutagenic.
Reproductive toxicity
Oral administration of 320, 800 and 2000 mg/kg during organogenesis, 80, 360 and 1620 mg/kg during pre-pregnancy and early gestation, perinatal and lactation periods in rats showed no change in overall status and body weight, except for a slight change in food intake. The results showed that faropenem sodium had no effect on the reproductive function of mothers, fetuses and newborn rats, and no teratogenicity was observed.
In rabbits, intravenous administration of 50, 100 and 200 mg/kg during the organogenesis phase resulted in soft stools, diarrhea and abortion in the group administered above 100 mg/kg, and maternal mortality, increased fetal mortality and mild growth retardation in the group administered at 200 mg/kg, but no teratogenicity of faropenem sodium was observed.
Toxicity of repeated dosing
In rats and dogs given 100, 450 and 2000 mg/kg orally for 26 weeks, the rats showed decreased β-globin levels in the 450 mg/kg and above group, and the 2000 mg/kg group showed a transient decrease in food intake and decreased γ-GTP values. However, no mortality was observed in the 2000 mg/kg group. A decrease in erythrocyte levels occurred in the group administered above 450 mg/kg in dogs. The non-toxic dose of faropenem sodium for both rats and dogs was 100mg/kg.
Pharmacokinetics]
The pharmacokinetic studies in children presented in the literature are as follows.
Pharmacokinetics in children
(1) Blood concentration
In pediatric patients, 5 and 10 mg/kg were administered orally after meals, and the blood concentration peaked after about 1 hour, at 1.3 and 2.1 μg/ml, respectively, with a half-life of about 1 hour.
Blood concentration-time curve of oral administration in pediatric patients
Pharmacokinetic parameters of oral administration after meals in pediatric patients (mean ± standard deviation)
Dose (mg/kg) Number of cases Peak concentration (Cmax)
(mg/ml) Time to peak (Tmax) (h) Half-life (T1/2) (h) Area under the curve (AUC) (mg×h/ml) 5121.32±0.721.17±0.391.66±1.124.10±2.3210112.08±1.281.27±0.651.14±0.535.89±3.76
(2) Tissue distribution (Faropenem sodium tablets, for adults)
It was distributed in patients’ sputum, wound exudate after tooth extraction, skin tissue, tonsils, mucosal tissue of maxillary sinus and prostate tissue.
(3) Metabolism (Faropenem Sodium Tablets, for adults)
The product is absorbed in its original form, partially excreted in urine as a prototype drug, and the rest is eliminated from urine after metabolism by dehydrogenase-1 (DHP-1) in the kidney. No metabolites of faropenem sodium with antibacterial activity have been found in human plasma and urine.
(4) Excretion
Mainly excreted by the kidneys. In children (after meal), urinary excretion rate (0~6 hours) is 3.7% and 3.1% for 5 and 10 mg/kg orally, respectively. Urinary drug peak (27μg/ml) is reached 2~4 hours after administration in 5mg/kg group, and urinary drug peak (41μg/ml) is reached 0~2 hours after administration in 10mg/kg group.
Storage
Keep away from light, sealed, not more than 30℃.
Package】
Laminated film bag; 120 bags/box.
Expiration date
24 months
【Execution standard
Imported drug registration standard JX20170294
【Imported drug registration certificate number
Licensee
Company Name: Maruhiro Co.
Address: 1-5-22 Nakatsu,kita-ku,Osaka,Japan
Postal Code: 531-0071
Phone number: +81-(0)120-12-2834
【Manufacturer
Company name: Takayama Plant, Teva Takada Pharma Ltd.
Production address: 1040-22, Matsunoki-machi,Takayama,Gifu,Japan
Postal Code: 506-0802
Phone number：+81-(0)577-33-0811
Domestic Contact]
Company Name: Beijing Guoren Tang Pharmaceutical Technology Development Co.
Address: Room 917, Building 2, No. 66 Jiaoda East Road, Haidian District, Beijing
Postal Code: 100044
Telephone number: 010-84032957
Fax number: 010-84017022