Ciprolet А

Uses

Ciprofloxacin is used for the treatment of the following infections caused by sensitive bacteria:

Severe systemic infections: e.g; septicemia, bacteremia, peritonitis, infections in immunosuppressed patients with haematological or solid tumors and in patients in intensive care unit with specific problems such as infected burns.

Respiratory tract infections: Lobar and broncho pneumonia, acute and chronic bronchitis and empyema.

Urinary tract infections: Uncomplicated and complicated urethritis, cystitis, pyelonephritis, prostatitis and epididymitis.

Skin and soft tissue infections: Infected ulcers, wound infections, abscesses, cellulitis, otitis externa, erysipelas and infected burns.

Gastrointestinal infections: Enteric fever, infective diarrhea.

Infections of the biliary tract: Cholangitis, cholecystitis, empyema of the gall bladder.

Intra-abdominal infections: Peritonitis, intra abdominal abscesses.

Bone and joint infections: Osteomyelitis, septic arthritis.

Pelvic infections: Salpingitis, endometritis, pelvic inflammatory diseases.

Eye, ear, nose and throat infections: Otitis media, sinusitis, mastoiditis, tonsillitis.

Gonorrhoea: Urethral, rectal and pharyngeal gonorrhoea caused by beta-lactamase producing organism or organisms moderately sensitive to penicillin.

Ciprofloxacin (Eye/Ear) Solution is used for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

Eye

Corneal Ulcers:

• Pseudomonas aeruginosa

• Serratia marcescens

• Staphylococcus aureus

• Staphylococcus epidermidis

• Streptococcus pneumonia

• Streptococcus (Viridans Group)

Conjunctivitis:

• Haemophilus influenza

• Staphylococcus aureus

• Staphylococcus epidermidis

• Streptococcus pneumoniae

Ear

Otitis externa, acute otitis media, cronic suppurative otitis media. Prophylaxis in otic surgeries such as mastoid surgery.

Trichomoniasis: Tinidazole is used for the treatment of trichomoniasis caused by Trichomonas vaginalis. The organism should be identified by appropriate diagnostic procedures. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, partners of infected patients should be treated simultaneously in order to prevent re-infection.

Giardiasis: Tinidazole is used for the treatment of giardiasis caused by Giardia duodenalis in both adults and pediatric patients older than three years of age. Sections or subsections omitted from the full prescribing information are not listed.

Amebiasis: Tinidazole is used for the treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica in both adults and pediatric patients older than three years of age. It is not used for the treatment of asymptomatic cystpassage.

Bacterial Vaginosis: Tinidazole is used for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in non-pregnant women.

Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tinidazole and other antibacterialdrugs, Tinidazole should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Ciprolet А is also used to associated treatment for these conditions: Acute Otitis Externa, Acute Otitis Externa caused by Pseudomonas Aeruginosa, Acute Otitis Media, Acute Sinusitis, Acute Uncomplicated Pyelonephritis, Acute exacerbation of chronic bronchitis caused by Moraxella catarrhalis, Bone and Joint Infections, Chronic Otitis Media, Complicated Intra-Abdominal Infections, Complicated Urinary Tract Infection, Conjunctivitis caused by Haemophilus influenzae, Conjunctivitis caused by Staphylococcus epidermidis, Corneal Ulcers caused by Serratia marcescens, Corneal Ulcers caused by Staphylococcus aureus, Corneal Ulcers caused by Staphylococcus epidermidis, Corneal Ulcers caused by Streptococcus Pneumoniae, Corneal Ulcers caused by Streptococcus Viridans Group, Corneal Ulcers caused by pseudomonas aeruginosa, Escherichia urinary tract infection, External ear infection NOS, Febrile Neutropenia, Infection of the outer ear caused by susceptible bacteria, Infectious diarrhea, Lower respiratory tract infection caused by Enterobacter cloacae, Lower respiratory tract infection caused by Escherichia coli, Lower respiratory tract infection caused by Haemophilus influenzae, Lower respiratory tract infection caused by Haemophilus parainfluenzae, Lower respiratory tract infection caused by Klebsiella pneumoniae, Lower respiratory tract infection caused by Proteus mirabilis, Lower respiratory tract infection caused by penicillin-susceptible Streptococcus pneumoniae, Nosocomial Pneumonia, Otitis Media (OM), Otitis Media, Purulent, Plague caused by Yersinia pestis, Skin Infections, Typhoid fever caused by Salmonella typhi, UTI caused by Citrobacter diversus, UTI caused by Citrobacter frendii, UTI caused by Entercococcus faecalis, UTI caused by Enterobacter cloacae, UTI caused by Klebsiella pneumoniae, UTI caused by Morganella morganii, UTI caused by Proteus mirabilis, UTI caused by Providencia rettgeri, UTI caused by Pseudomonas aeruginosa, UTI caused by Serratia marcescens, UTI caused by methicillin-susceptible Staphylococcus epidermidis, Uncomplicated Urinary Tract Infections, Acute otitis externa caused by Staphylococcus aureus, Acute, uncomplicated Cystitis caused by Escherichia coli, Acute, uncomplicated Cystitis caused by Staphylococcus saprophyticus, Chronic Prostatitis caused by Escherichia coli, Chronic Prostatitis caused by Proteus mirabilis, Complicated Pyelonephritis caused by Escherichia coli, Complicated Urinary Tract Infection caused by Escherichia Coli, Inhaled anthrax caused by Bacillus anthracis, Uncomplicated Gonorrhea caused by Neisseria gonorrhoeaeAmebiasis, Bacterial Vaginosis (BV), Candidal Vulvovaginitis, Giardiasis, Mixed Vaginal Infections, Nongonococcal urethritis, Sexually Transmitted Disease (STD), Trichomonas Vaginalis Infection, Trichomoniasis

How Ciprolet А works

Ciprofloxacin acts on bacterial topoisomerase II (DNA gyrase) and topoisomerase IV. Ciprofloxacin's targeting of the alpha subunits of DNA gyrase prevents it from supercoiling the bacterial DNA which prevents DNA replication.

Tinidazole is a prodrug and antiprotozoal agent. The nitro group of tinidazole is reduced in Trichomonas by a ferredoxin-mediated electron transport system. The free nitro radical generated as a result of this reduction is believed to be responsible for the antiprotozoal activity. It is suggested that the toxic free radicals covalently bind to DNA, causing DNA damage and leading to cell death. The mechanism by which tinidazole exhibits activity against Giardia and Entamoeba species is not known, though it is probably similar.

Dosage

Ciprolet А dosage

Adult Dose:

For oral dosage &suspension:

Urinary Tract infection: Acute uncomplicated: 250 mg twice daily for 3 days; Mild/Moderate: 250 mg twice daily for 7 to 14 days; Severe/Complicated: 500 mg twice daily for 7 to 14 days; Chronic Bacterial Prostitis : 500 mg twice daily for 28 days; Lower Respiratory Tract infection: Mild/Moderate: 500 mg twice daily for 7 to 14 days, Severe/Complicated : 750 mg twice daily for 7 to 14 days; Acute Sinusitis : 500 mg twice daily for 10 days; Skin and Skin Structure infection: Mild/Moderate : 500 mg twice daily for 7 to 14 days, Severe/Complicated : 750 mg twice daily for 7 to 14 days, Bone and joint infection: Mild/Moderate 500 mg twice daily for 4 to 6 weeks, Severe/Complicated : 750 mg twice daily for 4 to 6 weeks, Intra Abdominal Infection: 500 mg twice daily for 7 to 14 days, Infectious Diarrhea: Mild/Moderate/Severe: 500 mg twice daily for 5 to 7 days, Typhoid Fever : 500 mg twice daily for 10 days, Urethral & Cervical Gonococcal Infections: Uncomplicated: 250 mg Single dose.

For IV infusion :

Urinary Tract Infection: Mild to Moderate: 200 mg 12 hourly for 7-14 days;Severe or Complicated: 400 mg 12 hourly for 7-14 days; Lower Respiratory Tract infection: Mild to Moderate: 400 mg 12 hourly for 7-14 days; Severe or Complicated: 400 mg 8 hourly for 7-14 days; Nosocomial Pneumonia: Mild/Moderate/Severe: 400 mg 8 hourly for 10-14 days; Skin and Skin Structure: Mild to Moderate: 400 mg 12 hourly for 7-14 days; Severe or Complicated: 400 mg 8 hourly for 7-14 days; Bone and Joint Infection: Mild to Moderate: 400 mg 12 hourly for more than 4-6 weeks; Severe/Comlicated: 400 mg 8 hourly for more than 4-6weeks; Intra abdominal (Acute abdomen): Complicated: 400 mg 12 hourly for 7-14 days; Acute Sinusitis: Mild/Moderate: 400 mg 12 hourly for10 days: Chronic Bacterial Prostatitis: Mild/Moderate: 400 mg 12 hourly for 28 Days.

Children and adolescents:

RTI & GI infections: Neonate-15mg/kg twice daily, Child (1 month -18 years)-20mg/kg (max 750 mg) twice daily; UTI: Neonate-10 mg/kg twice daily, Child (1 month -18 years)-10mg/kg (max 750 mg) twice daily; Pseudomonal lower respiratory tract infection in cystic fibrosis: Child (1 month -18 years) - 20mg/kg (max 750 mg) twice daily; Anthrax (treatment & post exposure prophylaxis): Child (1 month -18 years) - 20mg/kg (max 750 mg) twice daily.

Use in Pregnancy and Lactation

Reproduction studies performed in rats and rabbits using parenteral and oral administration did not reveal any evidence of teratogenicity, impairment of fertility or impairment of pre or postnatal development. However, as with other quinolones, Ciprofloxacin has been shown to cause arthropathy in immature animals and therefore, its use during pregnancy is not recommended. Studies in rats have indicated that Ciprofloxacin is secreted in milk, administration to nursing mothers is thus not recommended.

Eye

Corneal Ulcers: The recommended dosage regimen for the treatment of corneal ulcers is 2 drops into the affected eye every 15 minutes for the first 6 hours and then 2 drops into the affected eye every 30 minutes for the remainder of the first day. On the second day, instill 2 drops in the affected eye hourly. On the third through the fourteenth day, place 2 drops in the affected eye every four hours. Treatment may be continued after 14 days if corneal re-epithelialization has not occurred.

Conjunctivitis: The recommended dosage regimen for the treatment of bacterial conjunctivitis is 1 or 2 drops instilled into the conjunctival sac(s) every 2 hours while awake for 2 days and one or 2 drops every 4 hours while awake for the next 5 days.

Ear

For all infections, 2-3 drops every 2-3 hours initially, reducing the frequency of the instillation with control of infection. Treatment should be continued at least 7 days.

Prevention of Postoperative Infections :

• Adult: A single oral dose of 2g approximately 12 hours before surgery.
• Children less than 12 years: Data are not available to allow dosage recommendations for children below the age of 12 years in the prophylaxis of anaerobic infections.

Trichomoniasis: a single 2 g oral dose taken with food. Treat sexual partners with the same dose and at the same time Giardiasis:

• Adults: a single 2 g dose taken with food.
• Pediatric patients older than three years of age: a single dose of 50 mg/kg (up to 2 g) with food

Amebiasis, Intestinal:

• Adults: 2 g per day for 3 days with food.
• Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3 days with food

Amebic liver abscess:

• Adults: 2 g per day for 3-5 days with food.
• Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3-5 days with food

Bacterial vaginosis: Non-pregnant, adult women: 2 g once daily for 2 days taken with food, or 1 g once daily for 5 days taken with food.

Information for patients: Should be swallowed whole with an adequate amount of liquid, it may be taken with or without meals. The preferred time of dosing is two hours after a meal and patients should not take antacid within two hours of dosing.

Directions for use of granules for suspension

Whole contents of the packet should be taken into a small glass containing 2-3 teaspoonful of water. Other liquids or foods should not be used. The mixer should be stirred well and drink immediately. The glass should be refilled with water and drink.

Direction for reconstitution of suspension (60 ml)

Shake the bottle well to loosen the granules. Add 50 ml (with the help of supplied measuring cup) of boiled cool water to the dry granules in the bottle. Shake the bottle vigorously until all the granules is in suspension.

Should be taken with food. Take during or immediately after meals.

Side Effects

Ciprofloxacin is generally well tolerated. Frequent adverse reactions are- Gastrointestinal disturbance: e.g. nausea diarrhea, vomiting, dyspepsia, abdominal pain. Disturbance of the CNS: e.g. dizziness, headache, tiredness, confusion, convulsions. Hypersensitivity reactions: e.g. skin rashes, pruritus, and possible systemic reactions. Other possible side effects are - joint pain, light sensitivity, transient increase in liver enzyme (especially in patients with history of liver damage), serum bilirubin, urea or serum creatinine. Arthralgia and myalgia may also occur.

The most frequently reported drug related adverse reaction is local burning or discomfort. In corneal ulcer studies with frequent administration of the drug, white crystalline precipitates were seen in approximately 17% of patients. Other reactions occurring in less than 10% of patients included lid margin crusting, crystals/scales, foreign body sensation, itching, conjunctival hyperemia and a bad taste following instillation. Additional events occurring in less than 1% of patients included corneal staining, keratopathy/keratitis, allergic reactions, lid edema, tearing, photophobia, corneal infiltrates, nausea and decreased vision.

Reported side effects have generally been infrequent, mild and self-limiting. Side effects from the gastrointestinal tract include nausea, vomiting, anorexia, diarrhoea and metallic taste. Hypersensitivity reactions, occasionally severe, may occur in rare cases in the form of skin rash, pruritis, urticaria and angioneurotic oedema. As with related compounds, tinidazole may produce transient leukopenia. Other rarely reported side-effects are headache, tiredness, furry tongue and dark urine.

Toxicity

Patients experiencing an overdose may present with nausea, vomiting, abdominal pain, crystalluria, nephrotoxicity, and oliguria. Ciprofloxacin overdose typically leads to acute renal failure. An overdose may progress over the next 6 days with rising serum creatinine and BUN, as well as anuria. Patients may require prednisone therapy, urgent hemodialysis, or supportive therapy. Depending on the degree of overdose, patients may recover normal kidney function or progress to chronic kidney failure.

The oral LD50 in rats is >2000mg/kg.

Ciprofloxacin for intratympanic injection or otic use has low systemic absorption and so it unlikely to be a risk in pregnancy or lactation. There is generally no harm to the fetus in animal studies, however high doses may lead to gastrointestinal disturbances in the mother which may increase the incidence of abortion. In human studies there was no increase in fetal malformations above background rates. The risk and benefit of ciprofloxacin should be weighed in pregnancy and breast feeding.

2/8 in vitro tests and 0/3 in vivo tests of mutagenicity of ciprofloxacin have yielded a positive result.

Oral doses of 200 and 300 times the maximum recommended clinical dose in rats and mice have shown no carcinogenicity or tumorigenicity.

Oral doses above the maximum recommended clinical dose have shown no effects on fertility in rats.

There are no reported overdoses with tinidazole in humans. In acute studies with mice and rats, the LD 50 for mice was generally > 3,600 mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD 50 was > 2,000 mg/kg for both oral and intraperitoneal administration.

Precaution

Ciprofloxacin should be used with caution in patients with a history of convulsive disorders. Crystalluria related to the use of Ciprofloxacin has been observed only rarely. Patients receiving Ciprofloxacin should be well hydrated to avoid excessive alkalinity of the urine.

Beuflox Injection should only be administered by slow intravenous infusion over a period of 60 minutes. Local IV site reactions have been reported with the intravenous administration of Ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less or if small vein of the hand are used.

Compounds of similar chemical structure have produced various neurological disturbances such as dizziness, vertigo, uncoordination, and ataxia. If, during therapy with tinidazole, abnormal neurological signs develop, therapy should be discontinued. Use in Pregnancy & Lactation: Tinidazole is contraindicated during the first trimester of pregnancy. While there is no evidence that tinidazole is harmful during the late stages of pregnancy, its use during the last two trimesters requires that the potential benefits outweigh the possible risk to mother and foetus. Tinidazole is excreted in breast milk in concentrations similar to those seen in serum. Tinidazole can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose.

Interaction

Increased plasma levels of theophylline have been observed following concurrent administration with Ciprofloxacin. Ciprofloxacin suspension should not be administered within 4 hours of medications containing magnesium, aluminium, calcium or iron salts as interference with absorption may occur.

The following interactions were reported with metronidazole, which is chemically-related to tinidazole.

Alcohol, disulfiram: Avoid during tinidazole use and for 3 days afterward because cramps, nausea, vomiting, headaches, and flushing may occur.

Anticoagulants, oral (eg, warfarin): Anticoagulant effects may be increased. Anticoagulant dose may need to be adjusted during coadministration and for up to 8 days after discontinuation.

Cholestyramine: Bioavailability of tinidazole may be decreased. Cyclosporine, lithium, tacrolimus: Levels may be elevated by tinidazole, increasing the risk of toxicity.

Drugs that induce CYP3A4 (eg, fosphenytoin, phenobarbital, phenytoin, rifampin): May increase metabolism of tinidazole, decreasing plasma levels and therapeutic effect.

Drugs that inhibit CYP3A4 (eg, cimetidine, ketoconazole): May prolong t½ and decrease tinidazole Cl, increasing plasma levels and risk of adverse reactions.

Fluorouracil: Cl may be decreased by tinidazole, increasing the risk of adverse reactions

Fosphenytoin, phenytoin: The t½ may be prolonged and Cl reduced by tinidazole, increasing the risk of adverse reactions.

Oxytetracycline: Therapeutic effect of tinidazole may be decreased.

Volume of Distribution

Cirpofloxacin follws a 3 compartment distribution model with a central compartment volume of 0.161L/kg and a total volume of distribution of 2.00-3.04L/kg.

• 50 L

Elimination Route

A 250mg oral dose of ciprofloxacin reaches an average maximum concentration of 0.94mg/L in 0.81 hours with an average area under the curve of 1.013L/h*kg. The FDA reports an oral bioavailability of 70-80% while other studies report it to be approximately 60%. An early review of ciprofloxacin reported an oral bioavailability of 64-85% but recommends 70% for all practical uses.

Rapidly and completely absorbed under fasting conditions. Administration with food results in a delay in T_max of approximately 2 hours and a decline in C_max of approximately 10% and an AUC of 901.6 ± 126.5 mcg hr/mL.

Half Life

The average half life following a 250mg oral dose was 4.71 hours and 3.65 hours following a 100mg intravenous dose. Generally the half life is reported as 4 hours.

The elimination half-life is 13.2±1.4 hours and the plasma half-life is 12 to 14 hours.

Clearance

The average renal clearance after a 250mg oral dose is 5.08mL/min*kg. Following a 100mg intravenous dose, the average total clearance is 9.62mL/min*kg, average renal clearance is 4.42mL/min*kg, and average non renal clearance is 5.21mL/min*kg.

Elimination Route

27% of an oral dose was recovered unmetabolized in urine compared to 46% of an intravenous dose. Collection of radiolabelled ciprofloxacin resulted in 45% recovery in urine and 62% recovery in feces.

Tinidazole crosses the placental barrier and is secreted in breast milk. Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces.

Pregnancy & Breastfeeding use

Reproduction studies performed in rats and rabbits using parenteral and oral administration did not reveal any evidence of teratogenicity, impairment of fertility or impairment of pre or postnatal development. However, as with other quinolones, Ciprofloxacin has been shown to cause arthropathy in immature animals and therefore, its use during pregnancy is not recommended. Studies in rats have indicated that Ciprofloxacin is secreted in milk, administration to nursing mothers is thus not recommended.

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Ciprofloxacin is contra-indicated in patients who have shown hypersensitivity to Ciprofloxacin or other quinolones.

As with other compounds of similar structure, tinidazole, is contraindicated in patients having, or with a history of, blood dyscrasias although no persistent haematological abnormalities have been noted in clinical or animal studies. Tinidazole should be avoided in patients with organic neurological disorders. Tinidazole should not be administered to patients with known hypersensitivity to the compound.

Special Warning

Renal Impairment: Haemodialysis: Additional dose equal to half the usual dose at the end of haemodialysis.

Acute Overdose

In case of acute overdose, the patient should be carefully observed and given supporative treatment, including monitoring of renal function. Adequate hydration must be maintained.

Storage Condition

Store in a cool dry place protected from light. Keep out of reach of children.

Store at room temperature & protected from light.

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