Cifran^® OD (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

J01MA02 (Ciprofloxacin)

Active Substance

Ciprofloxacin (Rec.INN registered by WHO)

Dosage Forms

	Cifran® OD	Extended-release film-coated tablets, 500 mg: 5 or 10 pcs.
		Extended-release film-coated tablets, 1000 mg: 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets from white to almost white, oval in shape, with “Cifran OD 500 MG” printed on one side of the tablet with food-grade ink; the appearance of the tablet on the break: a compressed mass from white to almost white.

Excipients: sodium alginate (Keltone LVCR) – 2.5 mg, hypromellose – 17.5 mg, sodium bicarbonate – 97.5 mg, crospovidone (CLM) – 89 mg, magnesium stearate – 13.5 mg, colloidal silicon dioxide (200) – 5 mg, talc – 2.5 mg.

Film coating composition: Opadry 31B58910 white (hypromellose, lactose monohydrate, titanium dioxide, macrogol 400), talc, hypromellose, black ink Opacode S-1-17823 black (shellac 45% (20% esterified) in ethanol, isopropanol, n-butanol, propylene glycol, 28% aqueous ammonia, iron oxide black dye).

5 pcs. – blisters (1) – cardboard packs.
5 pcs. – blisters (2) – cardboard packs.

Extended-release film-coated tablets from white to almost white, oval in shape, with “Cifran OD 1000 MG” printed on one side of the tablet with food-grade ink; the appearance of the tablet on the break: a compressed mass from white to almost white.

Excipients: sodium alginate (Keltone LVCR) – 5 mg, hypromellose – 35 mg, sodium bicarbonate – 195 mg, crospovidone (CLM) – 178 mg, magnesium stearate – 27 mg, colloidal silicon dioxide (200) – 10 mg, talc – 5 mg.

Film coating composition: Opadry 31B58910 white (hypromellose, lactose monohydrate, titanium dioxide, macrogol 400), talc, hypromellose, black ink Opacode S-1-17823 black (shellac 45% (20% esterified) in ethanol, isopropanol, n-butanol, propylene glycol, 28% aqueous ammonia, iron oxide black dye).

5 pcs. – blisters (1) – cardboard packs.
5 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Antibacterial drug of the fluoroquinolone group

Pharmacotherapeutic Group

Systemic antibacterial agents; quinolone derivatives; fluoroquinolones

Pharmacological Action

The bactericidal action of fluoroquinolones is due to the inhibition of the bacterial enzyme – topoisomerase II (DNA gyrase). Topoisomerase II is necessary for normal replication of bacterial DNA. This ATP-dependent process, in the absence of topoisomerase II, leads to uncontrolled replication of damaged DNA, and consequently, to disruption of the synthesis of normal proteins in the bacterial cell.

Antibacterial spectrum

Ciprofloxacin has pronounced in vitro activity against a wide range of gram-negative and gram-positive bacteria. Ciprofloxacin acts on both multiplying microorganisms and those in a resting state. As in vitro studies and clinical use have shown, Ciprofloxacin is active against most strains of the following microorganisms.

Pharmacokinetics

Absorption

After oral administration, Ciprofloxacin is rapidly absorbed from the gastrointestinal tract. Cifran^® OD tablets provide prolonged, uniform release of ciprofloxacin, with the drug taken only once a day. A single dose of Cifran^® OD 500 mg or Cifran^® OD 1000 mg is able to maintain the necessary concentration of ciprofloxacin, which in other cases is provided by twice-daily administration of conventional ciprofloxacin 250 mg or 500 mg, respectively.

Distribution

After a single dose, maximum plasma concentrations (C_max) are reached within 6 hours and are 1.3±0.4 µg/ml and 2.4±0.7 µg/ml for Cifran^® OD 500 mg and Cifran^® OD 1000 mg, respectively. The corresponding area under the pharmacokinetic curve (AUC_0-t) values are 8.3±2.1 and 18.9±4.6 µg×ml/h. Plasma protein binding is from 20% to 40%. Ciprofloxacin penetrates well into body tissues and fluids: lungs, skin, adipose tissue, muscles, cartilage and bone tissue, prostate gland, into saliva, secretion of the nasal mucosa and bronchi, semen, lymph, peritoneal fluid, and prostate secretion.

Metabolism

Ciprofloxacin is partially metabolized in the liver.

Elimination

About 50% of the orally administered dose is excreted by the kidneys unchanged and about 15% as active metabolites. Approximately 20-35% of the administered dose is excreted by the intestines. The half-life (T_1/2) of Cifran^® OD is about 6.5-7.5 hours. T_1/2 may be prolonged in severe renal impairment and in the elderly.

Special patient groups

Renal impairment. In patients with mildly impaired renal function, the T_1/2 of ciprofloxacin may slightly increase. In this case, dose adjustment is necessary (see “Dosage Regimen”).

Hepatic impairment. In preliminary studies in patients with stable liver cirrhosis, no significant changes in the pharmacokinetics of ciprofloxacin were noted. However, studies on the kinetics of ciprofloxacin in patients with acute liver failure have not been conducted.

Indications

Cifran^® OD is indicated for the treatment of the following infectious and inflammatory diseases caused by susceptible microorganisms.

• Acute sinusitis;
• Infectious and inflammatory diseases of the lower respiratory tract, including pneumonia, exacerbation of chronic bronchitis, and infectious complications of cystic fibrosis;
• Pyelonephritis, cystitis (including complicated);
• Chronic bacterial prostatitis;
• Gonorrhea;
• Intra-abdominal infections (including peritonitis, intra-abdominal abscesses, cholangitis, cholecystitis, gallbladder empyema) used in combination with metronidazole;
• Infectious diseases of the skin;
• Infectious diseases of bones and joints (including acute and chronic osteomyelitis);
• Infectious diarrhea, including “traveler’s diarrhea”;
• Typhoid fever;
• Anthrax.

ICD codes

Dosage Regimen

The drug is taken orally. The tablets should be taken after meals, whole, with a sufficient amount of water. Do not break, chew, or otherwise destroy the tablets.

The use of Cifran^® OD should continue for at least another 2 days after the complete disappearance of disease symptoms.

Recommended doses for adults

If only the plasma creatinine concentration is known, the following formula is recommended to determine creatinine clearance.

Men

Women

Creatinine clearance (ml/min) = 0.85 × the value calculated for men.

When using fluoroquinolones in elderly patients, attention should be paid to the possible age-dependent decrease in renal function, therefore dose adjustment is necessary.

Adverse Reactions

From the digestive system nausea, vomiting, diarrhea, abdominal pain, flatulence, anorexia, cholestatic jaundice (especially in patients with previous liver diseases), hepatitis, hepatonecrosis.

From the nervous system dizziness, photophobia, insomnia, paresthesia, irritability, headache, increased fatigue, anxiety, tremor, nightmares, peripheral paralgesia (abnormality in pain perception), increased intracranial pressure, confusion, depression, hallucinations, as well as other manifestations of psychotic reactions (occasionally progressing to states in which the patient may harm themselves), migraine, fainting, cerebral artery thrombosis.

From the senses taste and smell disturbances, visual impairment (diplopia, color vision changes), tinnitus, hearing loss.

From the cardiovascular system tachycardia, cardiac arrhythmias, decreased blood pressure, facial flushing.

From the hematopoietic system eosinophilia, leukopenia, granulocytopenia, anemia, thrombocytopenia, leukocytosis, thrombocytosis, hemolytic anemia.

Laboratory parameters hypoprothrombinemia, increased activity of “liver” transaminases, hypercreatininemia, hyperbilirubinemia, hyperglycemia, increased activity of alkaline phosphatase and LDH.

From the urinary system hematuria, crystalluria (primarily with an alkaline urine reaction and low diuresis), acute interstitial nephritis (with possible development of acute renal failure), glomerulonephritis, dysuria, polyuria, urinary retention, albuminuria, urethral bleeding, decreased nitrogen-excreting function of the kidneys.

Allergic reactions skin itching, urticaria, blister formation accompanied by bleeding, and the appearance of small nodules forming scabs, drug fever, pinpoint skin hemorrhages (petechiae), swelling of the face or larynx, shortness of breath, vasculitis, erythema nodosum, multiforme exudative erythema, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).

From the musculoskeletal system arthralgia, arthritis, tenosynovitis, tendon ruptures, myalgia.

Other increased sweating, photosensitivity, general weakness, superinfections (candidiasis, pseudomembranous colitis).

Contraindications

• Pseudomembranous colitis;
• Age under 18 years;
• Pregnancy;
• Lactation period;
• Hypersensitivity to ciprofloxacin or other drugs from the fluoroquinolone group;
• Concomitant use of tizanidine (risk of pronounced decrease in blood pressure, drowsiness);
• Chronic renal failure (creatinine clearance less than 29 ml/min, including patients on hemodialysis).

With caution: severe cerebral atherosclerosis; cerebrovascular accident; mental illness; epilepsy; renal failure (creatinine clearance 35-50 ml/min); severe hepatic failure, elderly age; tendon damage during previous treatment with fluoroquinolones.

Use in Pregnancy and Lactation

The use of Cifran^® OD during pregnancy is not recommended.

Ciprofloxacin is excreted in breast milk, therefore, during lactation, if it is necessary to use Cifran^® OD, based on the degree of importance of its use for the mother, a decision should be made to either discontinue the drug or stop breastfeeding.

Use in Hepatic Impairment

The drug should be prescribed with caution in severe hepatic insufficiency.

Use in Renal Impairment

The use of the drug is contraindicated in chronic renal failure (creatinine clearance less than 29 ml/min, including patients on hemodialysis).

The drug should be prescribed with caution in renal failure (creatinine clearance 35-50 ml/min).

Pediatric Use

The use of the drug is contraindicated in children under 18 years of age.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

Photosensitivity reactions have been observed in some patients receiving fluoroquinolones. Excessive exposure to direct sunlight and UV radiation should be avoided. If a photosensitivity reaction occurs, it is recommended to discontinue the drug.

Since Cifran^® OD is a drug with possible reversible toxic effects on the kidneys, it is not recommended for use in patients with impaired renal function, with a CrCl <29 ml/min, or in patients undergoing hemodialysis or peritoneal dialysis.

With the use of almost all antimicrobial drugs, including Cifran^® OD, the development of pseudomembranous colitis, ranging in severity from mild to life-threatening, is possible. If severe and prolonged diarrhea occurs during or after treatment, the diagnosis of pseudomembranous colitis should be excluded, which requires immediate discontinuation of the drug and the appointment of appropriate treatment.

To avoid the development of crystalluria, exceeding the recommended daily dose is unacceptable; sufficient fluid intake and maintenance of an acidic urine reaction are also necessary.

In patients with epilepsy, a history of seizures, vascular diseases, and organic brain lesions, due to the threat of developing adverse reactions from the central nervous system, Cifran^® OD should be prescribed only for vital indications.

If pain in the tendons occurs or at the first signs of tenosynovitis, treatment should be discontinued (isolated cases of inflammation and even tendon rupture during treatment with fluoroquinolones have been described).

Effect on the ability to drive vehicles and mechanisms

During treatment, one should refrain from engaging in potentially hazardous activities that require increased attention and speed of mental and motor reactions.

Overdose

Reversible toxic effects on the kidneys are possible.

Treatment There is no specific antidote, so it is necessary to induce vomiting or perform gastric lavage and carry out symptomatic therapy

– take measures for adequate body hydration (infusion therapy);

– implementation of supportive therapy.

Only small amounts of ciprofloxacin (<10%) can be removed by hemodialysis and peritoneal dialysis.

Drug Interactions

Due to the inhibition of microsomal enzymes in the liver, it increases the concentration and prolongs the T_1/2 of theophylline and other xanthines (e.g., caffeine), oral hypoglycemic drugs (e.g., glibenclamide), and indirect anticoagulants (e.g., warfarin and its derivatives). If concomitant use with drugs of these groups is necessary, the drug concentration in the blood should be monitored and the dosage regimen should be adjusted accordingly.

In the presence of antacid preparations containing magnesium hydroxide or aluminum hydroxide, the absorption of ciprofloxacin is reduced. Thus, the simultaneous administration of these drugs should be avoided. In such cases, Ciprofloxacin should be taken either 1-2 hours before or 4 hours after taking these drugs. Didanosine reduces the absorption of ciprofloxacin. This is due to the formation of complexes with magnesium salts contained in didanosine preparations.

When used concomitantly with probenecid and other drugs that block tubular secretion, the renal excretion of ciprofloxacin is reduced.

Metoclopramide accelerates the absorption of the drug, leading to a decrease in the time to reach its C_max.

Concomitant administration of uricosuric drugs leads to a slowdown in excretion (up to 50%) and an increase in the plasma concentration of ciprofloxacin.

When combined with other antimicrobial drugs (beta-lactam antibiotics, aminoglycosides, clindamycin, metronidazole), synergy is usually observed; it can be successfully used in combination with azlocillin and ceftazidime for infections caused by Pseudomonas spp.; with mezlocillin, azlocillin and other beta-lactam antibiotics – for streptococcal infections; with isoxazolylpenicillins and vancomycin – for staphylococcal infections; with metronidazole and clindamycin – for anaerobic infections.

Ciprofloxacin enhances the nephrotoxic effect of cyclosporine. An increase in serum creatinine concentration is noted. In such patients, this indicator must be monitored twice a week.

Concomitant use of tizanidine with ciprofloxacin, which is an inhibitor of the CYP1A2 isoenzyme, leads to a 10-fold increase in the AUC of tizanidine. The result of combined use may be a clinically significant and prolonged decrease in blood pressure, leading to drowsiness, dizziness, and slowed psychomotor reactions.

In patients receiving therapy with ciprofloxacin and phenytoin, variability (decrease or increase) in the plasma concentration of phenytoin has been noted.

Concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs) increases the likelihood of developing side effects of ciprofloxacin from the central nervous system (risk of seizures).

The absorption of ciprofloxacin when taken orally is reduced after cytotoxic therapy with antitumor and immunosuppressive drugs.

Storage Conditions

The drug should be stored in a dry place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.