Date of approval.
Date of revision.
Norfloxacin capsule instructions
Please read the instructions carefully and use under the guidance of a physician
WARNING: Serious adverse reactions, including tendonitis and tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis.
Concurrent disabling and potentially irreversible serious adverse reactions have been reported with the use of fluoroquinolones, including norfloxacin capsules (see [Precautions]), including
Tendonitis and tendon rupture (see [Precautions])
Peripheral neuropathy (see [Precautions])
Central nervous system effects (see [Precautions])
When these serious adverse reactions occur (see [Precautions]), norfloxacin capsules should be discontinued immediately and fluoroquinolone drugs should be avoided.
Fluoroquinolone drugs may exacerbate the symptoms of muscle weakness in patients with myasthenia gravis. Patients with a known history of myasthenia gravis should avoid norfloxacin capsules (see [Precautions]).
Because serious adverse reactions have been reported with fluoroquinolones (including norfloxacin capsules) (see [Precautions]), norfloxacin capsules should be used only in the absence of other drug therapy in patients with the following indications.
Simple urinary tract infection (see [Indications] and [Dosage]) [Drug Name
Generic name: Norfloxacin Capsules
English: Norfloxacin Capsules
Hanyu Pinyin: Nuofushaxing Jiaonang
Ingredients
The main ingredient of this product is Norfloxacin.
Chemical name: 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.
Chemical structure formula.
Molecular formula: C16H18FN3O3
Molecular weight: 319.24
Properties]: This product is a hard capsule, the contents of which are white to light yellow granules or powder.
Indications
It is indicated for urinary tract infection, gonorrhea, prostatitis, intestinal infection and typhoid and other Salmonella infections caused by sensitive bacteria.
Since serious adverse reactions have been reported with fluoroquinolones (including norfloxacin capsules), and for some patients, simple urinary tract infections are self-limiting, norfloxacin capsules should be used only when no other medication is available.
Specification】0.1g
Dosage]
It should be taken orally with 250ml of water, at least 1 hour before or at least 2 hours after eating a meal or consuming milk and/or other dairy products.
For acute simple lower urinary tract infection caused by Escherichia coli, Klebsiella pneumoniae and Acinetobacter chimaera, 400mg (4 capsules) once, twice a day for 3 days.
For simple urinary tract infections caused by other pathogens, the dose is the same as above for 7 to 10 days.
For complicated urinary tract infections, the dose is the same as above for 10 to 21 days.
Simple gonococcal urethritis single 800mg (8 capsules).
Acute and chronic prostatitis, 400mg (4 capsules) twice a day for 28 days.
For intestinal infection, 300~400mg (3~4 capsules) twice a day for 5~7 days.
For Salmonella typhi infection, 800~1200mg (8~12 capsules) once a day, divided into 2~3 times, the course of treatment is 14~21 days.
Adverse reactions]
Serious and other important adverse reactions
Disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathy, central nervous system effects
Tendinopathy and tendon rupture
Prolonged QT interval
Allergic reactions
Other serious and sometimes fatal reactions
Central nervous system effects
Clostridium difficile-associated diarrhea
Peripheral neuropathy
Interference with blood glucose
Photosensitivity/phototoxicity
The above adverse reactions are described in detail under [Precautions].
Cardiovascular system: QT interval prolongation, tip-twisting ventricular tachycardia, ventricular arrhythmias
Central nervous system: Convulsions, ataxia, toxic psychosis, tremor, agitation, anxiety, dizziness, headache, drowsiness, confusion, hallucinations, delusions, depression, nightmares, insomnia, seizures, and in rare cases, suicidal thoughts or actions.
Peripheral neuropathy: sensory confusion, dullness, pain to touch, pain, burning, tingling, numbness, weakness, or abnormalities in light touch, pain, temperature, position, and vibration, polyneuritis
Skeletal muscle system: arthralgia, myalgia, muscle weakness, hypertonic tendonitis, tendon rupture, worsening of myasthenia gravis, elevated creatine kinase (CK), muscle spasms
Hypersensitivity reactions: urticaria, pruritus and other severe skin reactions (e.g., toxic epidermolysis bullosa [Lyell syndrome], cutaneous mucocutaneous eye syndrome [Stevens-Jonhnson syndrome], erythema multiforme, exfoliative dermatitis, drug reactions with eosinophilia and systemic symptoms [DRESS syndrome]), respiratory distress, angioneurotic edema ( including edema/swelling of the tongue, throat, pharynx, or face), cardiovascular collapse, hypotension, loss of consciousness, airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), allergic pneumonia, anaphylaxis
Digestive tract: pseudomembranous colitis, abdominal discomfort or pain, diarrhea, nausea, vomiting, loss of appetite, indigestion, bloating, constipation, stomatitis, labyrinthitis, stomatitis, pancreatitis
Hepatobiliary system: hepatitis, jaundice, acute liver necrosis or liver failure
Urological system: acute renal insufficiency or renal failure, interstitial nephritis, crystalluria (mostly seen with high dose application)
Hematologic system: anemia, including hemolytic anemia and aplastic anemia, thrombocytopenia, including thrombotic thrombocytopenic purpura, leukopenia, granulocytopenia, eosinophilia, holocytopenia, and/or other hematologic disorders
Other: fatigue, chills, fever, vasculitis, serum sickness, Clostridium difficile-associated diarrhea, dysglycemia, photosensitivity/phototoxicity, palpitations, chest pain, hearing loss, tinnitus, diplopia, taste disturbance
Contraindications
Contraindicated in patients with hypersensitivity to this product and fluoroquinolones.
Contraindicated in patients who have had tendonitis or tendon rupture caused by the use of this product or fluoroquinolones.
Precautions]
1. Disabling and potentially irreversible serious adverse reactions, including tendonitis and tendon rupture, peripheral neuropathy, central nervous system effects
Disabling and potentially irreversible serious adverse reactions have been reported with the use of fluoroquinolones in different organ systems of the body in the same patient, usually including: tendonitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy and central nervous system reactions (hallucinations, anxiety, depression, insomnia, severe headache and confusion). These adverse reactions can occur from hours to weeks after the use of norfloxacin capsules. These adverse reactions have been reported in patients of any age with no prior associated risk factors.
2. Tendinopathy and tendon rupture
Fluoroquinolones, increase the risk of tendinopathy and tendon rupture in patients of all ages. This adverse reaction occurs most often in the Achilles tendon, which may require surgical repair for rupture. Tendonitis and tendon rupture have also been reported in the shoulder, hand, biceps, thumb, and other tendon points. Tendonitis and tendon rupture can occur hours or days after starting norfloxacin capsules, or months after finishing treatment. Tendonitis and tendon rupture can occur bilaterally. This risk is further increased in elderly patients over 60 years of age, in patients taking corticosteroid drugs and in patients who have had kidney, heart or lung transplants. In addition to age and corticosteroid use, other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disease such as rheumatoid arthritis. Tendonitis and tendon rupture also occur in patients using fluoroquinolones without these risk factors. Tendon ruptures can occur during or after the end of treatment; they have also been reported several months after the end of treatment. This product should be discontinued after a patient experiences tendon pain, swelling, inflammation, or rupture. After signs of tendonitis or tendon rupture, patients should be advised to rest and contact their physician to switch to a non-quinolone drug. Patients with a history of tendon disease or who have experienced tendonitis and tendon rupture should avoid fluoroquinolone drugs.
3. Exacerbation of myasthenia gravis
Fluoroquinolones, which have neuromuscular blocking activity, may exacerbate the symptoms of muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse events, including death and the need for ventilatory support, and patients with myasthenia gravis have been associated with the use of fluoroquinolone drugs. Norfloxacin capsules should be avoided in patients with myasthenia gravis.
4. Prolonged QT interval
Certain fluoroquinolone drugs can prolong the QT interval of the ECG and a few patients can develop arrhythmias. Spontaneous reports of tip-twist ventricular tachycardia in patients treated with fluoroquinolones during postmarketing surveillance are rare. Norfloxacin capsules should be avoided in patients with known QT interval prolongation, in patients with uncorrected hypokalemia, and in patients using antiarrhythmic drugs of classes IA (quinidine, procainamide) and III (amiodarone, sotalol). Elderly patients are more likely to be affected by drug-related QT interval.
5. Allergic reactions
Serious allergic reactions have been reported with the use of fluoroquinolones. Some reactions occur in some patients after the first dose, and some reactions may be accompanied by cardiovascular system failure, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and pruritus. Severe allergic reactions require emergency treatment with epinephrine. Norfloxacin capsules should be discontinued at the first sign of rash or any other signs of allergy. Oxygen administration, intravenous steroids, airway management, including intubation, may be administered if necessary.
6. Other serious and potentially fatal reactions
Other serious and potentially fatal events have been reported with the use of fluoroquinolones. Some of these events are due to allergy and others are of unknown etiology. These events may be severe and usually occur after multi-dose administration. Clinical manifestations may include one or more of the following: fever, rash, severe skin reactions (e.g., toxic epidermolysis bullosa, Stevens-Johnson syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonia; interstitial nephritis; acute renal insufficiency or renal failure; hepatitis, jaundice, acute hepatic necrosis, or hepatic failure; anemia, including hemolytic anemia and aplastic anemia; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; granulocyte deficiency; holocytopenia and/or other hematologic abnormalities. The drug should be discontinued and action taken immediately at the first appearance of rash, jaundice, or any other manifestation of allergy.
7. Central nervous system effects
The use of fluoroquinolones, including norfloxacin capsules, has been reported to increase the risk of CNS adverse reactions, including convulsions and increased intracranial pressure (including pseudotumor cerebri) and psychosis due to toxicity. Use of fluoroquinolones may cause CNS reactions including agitation, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or behaviors. These reactions may occur after the first dose of the drug. If these reactions occur while the patient is using norfloxacin capsules, dosing should be discontinued and appropriate measures taken. As with all fluoroquinolones, norfloxacin capsules should be administered when the benefits outweigh the risks in patients with known or suspected CNS disease (e.g., severe cerebral atherosclerosis, epilepsy) or in the presence of other risk factors (e.g., propensity for seizures or reduced seizure threshold).
8. Peripheral neuropathy
Rare sensory or sensorimotor axonal neuropathy affecting small and/or large axons, resulting in abnormal skin sensation, sensory dullness, painful sensation to touch, and debilitation, has been reported in patients using fluoroquinolones. In some patients, symptoms may occur soon after norfloxacin capsules are administered and may be irreversible. If patients develop peripheral neuropathy symptoms, including pain, burning, tingling, numbness and/or weakness, or other sensory changes, including light touch, pain, temperature, position and vibration, the drug should be discontinued immediately. Patients with a history of peripheral neuropathy should avoid the use of fluoroquinolone antibiotics.
9. Clostridium difficile-associated diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with almost all antimicrobial drugs, including norfloxacin capsules, ranging in severity from mild diarrhea to severe colitis. Antimicrobial drug therapy alters the normal flora of the colon, leading to C. difficile overgrowth.
Toxins A and B, produced by C. difficile, are responsible for C. difficile-associated diarrhea. Highly virulent Clostridium difficile causes increased morbidity and mortality, and these infections are ineffective with antimicrobial therapy and may require colectomy. The possibility of CDAD should be considered in all cases of diarrhea after antibiotic therapy. Because CDAD may occur up to two months after treatment with antimicrobial drugs, a careful history is necessary.
If C. difficile-associated diarrhea is suspected or confirmed, current antibiotics that do not target C. difficile may need to be discontinued. Appropriate fluid and electrolyte replacement, protein supplementation, treatment with C. difficile-specific antibiotics, and surgical evaluation should be performed when clinical indications arise.
10. Interference with blood glucose
Fluoroquinolone antibiotics have been reported to cause dysglycemia (e.g. symptomatic hyperglycemia and hypoglycemia), which mostly occurs in diabetic patients who are also taking oral hypoglycemic agents (e.g. euglycemia/glibenclamide) or using insulin. Therefore, for such patients, it is recommended that they should be closely monitored for changes in blood glucose. If a patient develops hypoglycemic reactions while receiving norfloxacin capsules, the drug should be discontinued immediately and appropriate therapeutic measures should be taken.
11. Photosensitivity/phototoxicity
Moderate to severe photosensitivity/phototoxicity can occur after exposure to sunlight or ultraviolet radiation following the use of fluoroquinolone antibiotics. The latter may manifest as excessive sunburn reactions (e.g., burning sensation, erythema, blistering, oozing, edema), often in areas exposed to light (usually the “V” area of the neck, the surface of the forearm extensors, the back of the hand). Therefore, overexposure to light sources should be avoided. The drug should be discontinued in case of phototoxic reactions.
12. Safety for children, adolescents, nursing mothers, and during pregnancy
The safety and efficacy of oral norfloxacin in children, adolescents (under 18 years of age), pregnant women, and nursing mothers has not been established.
13. Syphilis treatment
Norfloxacin has not been shown to be effective in the treatment of syphilis. Treatment of gonorrhea with high doses of antimicrobial agents over a short period of time may mask or delay the symptoms of latent syphilis. All patients with gonorrhea should be tested for syphilis serology at the time of diagnosis. Patients treated with norfloxacin should undergo follow-up serologic testing for syphilis after three months.
14. Crystalluria can occur when this product is applied in large doses or when the urine pH is above 7. To avoid the occurrence of crystalluria, it is advisable to drink more water and keep the 24-hour urine output above 1200ml.
15. In case of reduced renal function, the dose should be adjusted according to the renal function.
16. In patients with glucose-6-phosphate dehydrogenase deficiency, hemolytic reactions may occur in rare cases.
17. Since Escherichia coli are often resistant to flunofloxacin, urine specimens should be taken for culture before administration, and the dose should be adjusted with reference to the bacterial drug sensitivity results. In the case of undiagnosed or not highly suspected bacterial infection, or no indication for prophylaxis, the use of this product may not be beneficial to the patient, and may increase the risk of drug-resistant bacteria.
18. In case of hepatic decompensation, such as severe (cirrhotic ascites), drug clearance may be reduced and blood concentration may be increased, especially in those with hepatic and renal decompensation, which should be applied after weighing the advantages and disadvantages and dose adjustment.
19. During long-term treatment, the function of organ systems, including kidney, liver and hematopoietic function, should be evaluated regularly.
20. Use in food and feed processing is strictly prohibited.
Pregnant women and nursing mothers
Norfloxacin was found to cause abortion when given to monkeys at 10 times the maximum daily human dose (based on mg/kg). At this dose, the peak plasma concentration (Cmax) in monkeys was about twice as high as that in humans. No teratogenic effects were demonstrated in test animals (rats, rabbits, mice, monkeys) at doses 6-50 times the maximum daily human dose (based on mg/kg). However, adequate, well-controlled studies have not been conducted in pregnant women, and therefore this product should not be used in pregnant women.
There is a lack of information on whether this product is secreted through breast milk. However, due to the small doses studied and the secretion of other species of this drug through breast milk, as well as the potential adverse effects on newborns and infants, pregnant women should avoid using this product or stop breastfeeding when applying it.
Children’s medication
The safety and efficacy of oral norfloxacin in children and adolescents under 18 years of age have not been established. Norfloxacin can cause joint lesions when used in several species of young animals. It should not be used in children and adolescents under 18 years of age.
Geriatric Use]
Elderly patients are at increased risk of serious tendon disease (including tendon rupture) when treated with fluoroquinolones such as norfloxacin. This risk is further increased if concomitant corticosteroid therapy is received. Tendonitis or tendon rupture may occur in the Achilles tendon, hand, shoulder, or other tendon sites and can occur during or after treatment is completed. Cases have been reported that occurred several months after fluoroquinolone therapy. This product should be used with caution in elderly patients (especially those who are taking corticosteroids). Patients should be informed of this adverse effect and advised to discontinue use of the product and seek prompt medical attention if they develop any symptoms of tendonitis or tendon rupture.
In a large foreign clinical study of norfloxacin for the treatment of urinary tract infections involving 340 subjects, 103 patients were 65 years of age and older and 77 patients were 70 years of age and older, and there were no significant differences in safety and efficacy between these subjects and younger subjects. In clinical practice, there were no differences in the types of adverse reactions reported by older and younger patients, except that older patients treated with concomitant corticosteroids may have an increased risk of tendon rupture. In addition, an increased risk of other adverse reactions in some older adults cannot be excluded.
The product is primarily excreted by the kidneys and the risk of toxic reactions may be greater in patients with impaired renal function. As elderly patients often have reduced renal function and require reduced dose application, renal function monitoring may be required.
In general, elderly patients are more susceptible to drug-related QT intervals. Therefore, precautions should be taken when taking this product with concomitant medications that can cause prolongation of the QTc interval (e.g., class IA and class III antiarrhythmics) or in patients with risk factors for tip-twist ventricular tachycardia (e.g., patients with known QT interval prolongation, uncorrected hypokalemia).
[Drug Interactions].
Quinolones, including norfloxacin, have been shown to inhibit CYP1A2 in in vitro tests, and concomitant use with CYP1A2 metabolizing drugs (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) at normal doses may result in increased drug concentrations.
Urinary alkalinizing agents can reduce the solubility of this product in the urine, leading to crystalluria and nephrotoxicity.
When this product is combined with theophylline, the competitive inhibition with cytochrome P450 binding site may lead to a significant decrease in hepatic clearance of theophylline, prolongation of blood clearance half-life (t1/2β), increase in blood concentration and symptoms of theophylline toxicity, such as nausea, vomiting, tremor, restlessness, agitation, convulsions, palpitations, etc. Therefore, theophylline blood concentration should be measured and dose adjusted when combined.
The combination of cyclosporine and this product can increase the blood concentration of the former, so the blood concentration of cyclosporine must be monitored and the dose adjusted.
The anticoagulant effect of the latter can be enhanced when this product is used together with the anticoagulant warfarin, and the prothrombin time of patients should be closely monitored when combined.
Propofol may reduce the secretion of this product from the renal tubules by about 50%, and the combination may cause toxicity due to the increase of blood concentration of this product.
This product is antagonistic to furantoin and is not recommended for combination use.
Multivitamins, or other preparations containing iron or zinc ions, and acid-control drugs containing aluminum or magnesium may reduce the absorption of this product, and it is recommended to avoid combining them.
Dehydroxylinosine can reduce the oral absorption of this product, because its preparation contains aluminum and magnesium, which can chelate with fluoroquinolones, so it should not be combined.
This product interferes with the metabolism of caffeine, resulting in reduced clearance of caffeine, prolonged blood elimination half-life (t1/2β), and possible central nervous system toxicity.
Concomitant administration of nonsteroidal anti-inflammatory drugs (NSAIDs) with quinolones, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures.
The combination of quinolones, including norfloxacin, with glibenclamide (a sulfonylurea) has, in rare cases, resulted in severe hypoglycemia.
[Drug overdose].
No lethal effects were found in mice and rats at single oral doses of up to 4g/kg of this drug. Acute overdose requires emetic or gastric lavage to promote gastric emptying, careful observation of changes in condition, symptomatic treatment and supportive therapy. Proper rehydration must be maintained.
Pharmacology and Toxicology
It is a fluoroquinolone antibacterial drug with broad-spectrum antibacterial effect, especially high antibacterial activity against gram-negative bacilli, and has good antibacterial effect on the following bacteria in vitro: most of the bacteria of Enterobacteriaceae, including Enterobacter citri, Enterobacter gutterus, Enterobacter aerogenes, Escherichia coli, Klebsiella, Aspergillus, Salmonella, Shigella, Vibrio, Yersinia, etc. Norfloxacin also has antibacterial effect on a variety of drug-resistant bacteria in vitro. Norfloxacin is a bactericidal agent that acts on the A-subunit of bacterial DNA helicase to inhibit the synthesis and replication of DNA and cause bacterial death.
Pharmacokinetics
Blood concentration
The blood concentration and pharmacokinetic parameters of norfloxacin 200mg in a single oral dose in healthy adults are as follows.
Figure: Blood concentration (healthy adult)
Pharmacokinetic parameters
Dose (mg) Tmax (hr) Cmax (μg/ml) T1/2 (hr) AUC (μg.hr/ml) 2001.31.152.744.29
2. Distribution: The concentrations in tissues of adult patients who received a single oral dose of norfloxacin 200 mg were as follows.
Number of cases Time concentration after administration Sputum 2 about 4 hours 0.77μg/ml Tonsils 62 hours 1.87μg/ml Maxillary sinus mucosa 42 hours 0.72~2.03μg/ml Ear leakage 12 hours 1.93μg/ml Bile sac 91~4.5 hours 1.39μg/ml Bile 61~4.5 hours 10.4μg/ml Prostate fluid 61 hours 0.16 μg/ml urethral secretion 51 hours 0.51 μg/ml 3. Metabolism
A single oral dose of norfloxacin 200 mg was administered to healthy adult subjects, and approximately 80% was excreted in the urine as the prototype, and five other metabolites were observed.
4. Excretion
In a single oral dose of 200 mg of norfloxacin in healthy adult subjects, the concentration in urine peaked at 348 μg/mL in 0-2 hours, and the drug recovery in urine at 8 hours was 42.6%.
In addition, excretion in urine was significantly reduced in patients with severe renal insufficiency with creatinine clearance ≤29 ml/min.
Food and/or dairy products may reduce absorption.
In healthy elderly volunteers (age 65-75 years, normal renal function), norfloxacin was eliminated more slowly due to a slight decrease in renal function. After a single dose of 400 mg norfloxacin, mean (±SD) AUC and Cmax of 9.8 (2.83) μg-hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. systemic exposure was slightly higher than in younger individuals (AUC 6.4 μg-hr/mL and Cmax 1.5 μg/ml). Drug absorption was not affected. However, the half-life of norfloxacin in these elderly subjects was 4 hours.
There was no accumulation of multiple doses of norfloxacin in elderly patients. Therefore, no separate dose adjustment according to age is required. For elderly patients with diminished renal function, the dose should be adjusted according to other patients with renal insufficiency.
Storage】Store under shade and seal.
Package】Packaged in aluminum foil and polyvinyl chloride solid pharmaceutical rigid tablets (plus composite film bag packaging and desiccant). 10 capsules/plate, 3 plates/box; 12 capsules/plate, 2 plates/box; 12 capsules/plate, 3 plates/box.
【Validity】18 months
【Execution standard
【Approval Number】State Drug Certificate H20153262
【Manufacturing enterprise】.
Company Name: Yantai Valiant Pharmaceutical Co.
Address: No. 60 Taiyuan Road, Dajijia Industrial Park, Yantai Development Zone
Postal Code: 264006
Telephone number: 0535-6977293
Fax number: 0535-6977292
Registered Address: No. 60 Taiyuan Road, Dajijia Industrial Park, Yantai Development Zone
Web
Address: www.wanrunyaoye.com
If you have any questions, please contact with the manufacturer directly