Product information

THERAPEUTIC INDICATIONS

 Actavis Siprox  ((ciprofloxacin)) is indicated for treatment of infections due to susceptible organisms. Such infections include:

• Urinary Tract Infections caused by Escherichia coli,Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens,Proteus mirabilis, Providencia rettgeri, Morganella morganii,Citrobacter koseri (diversus),Citrobacter freundii,Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or vancomycin-susceptible Enterococcus faecalis.
• Acute Uncomplicated Cystitis in Females caused by Escherichia coli or Staphylococcus saprophyticus.
• Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
• Lower Respiratory Tract Infections caused by Escherichia coli,Klebsiella pneumoniae,Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae.* Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
• (ciprofloxacin) is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
• Acute Sinusitis caused by Haemophilusinfluenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis.
• Skin and Skin Structure Infections caused by Escherichia coli, Klebsiellapneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providenciastuartii, Morganellamorganii, Citrobacterfreundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.
• Bone and Joint Infections caused by Enterobacter cloacae, Serratiamarcescens, or Pseudomonas aeruginosa.
• Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiellapneumoniae, or Bacteroides Fragilis.
• Infectious Diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii†, Shigella dysenteriae, Shigella flexneri orShigella sonnei† when antibacterial therapy is indicated.

COMPOSITION

Actavis Siprox  (ciprofloxacin) ) is available for oral administration as:

• Actavis Siprox 250 mg Tablets , Each film-coated  tablet contains: (ciprofloxacin)  250  mg.
• Actavis Siprox 500 mg Tablets , Each film-coated  tablet contains: (ciprofloxacin)  500 mg.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The bactericidal action of Actavis Siprox (ciprofloxacin) results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.

 It is highly potent against a wide variety of aerobic gram positive and gram negative organisms.

Microbiology:

Actavis Siprox (ciprofloxacin) has shown to be active against the following microorganisms:

Aerobic gram-positive microorganisms

• Enterococcus faecalis (Many strains are only moderately susceptible.)
• Staphylococcus aureus (methicillin-susceptible strains only)
• Staphylococcus epidermidis (methicillin-susceptible strains only)
• Staphylococcus saprophyticus
• Streptococcus pneumoniae (penicillin-susceptible strains only)
• Streptococcus pyogenes
• Staphylococcus haemolyticus
• Staphylococcus hominis
• Streptococcus pneumoniae (penicillin-resistant strains only) 

Aerobic gram-negative microorganisms

• Campylobacter jejuni                         
•  Proteus mirabilis
• Citrobacter diversus                          
• Proteus vulgaris
• Citrobacter freundii                             
• Providencia rettgeri
• Enterobacter cloacae                        
•  Providencia stuartii
• Escherichia coli                               
•  Pseudomonas aeruginosa
• Haemophilus influenzae                    
• Salmonella typhi
• Haemophilus parainfluenzae             
• Serratia marcescens 
• Klebsiella pneumoniae                      
• Shigella boydii
• Moraxella catarrhalis                            
• Shigella dysenteriae
• Morganella morganii                          
• Shigella flexneri
• Neisseria gonorrhoeae                       
• Shigella sonnei 
• Acinetobacter Iwoffi 
• Pasteurella multocida
• Aeromonas hydrophila 
• Salmonella enteritidis
• Edwardsiella tarda 
• Vibrio cholerae
• Vibrio vulnificus
• Vibrio parahaemolyticus
• Enterobacter aerogenes 
• Klebsiella oxytoca 
• Legionella pneumophila 
• Yersinia enterocolitica 

Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to (ciprofloxacin) as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile. 

Pharmacokinetics

Absorption:

• (ciprofloxacin) given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism.
• Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.

Effect of Food

• Do not take (ciprofloxacin) with dairy products such as milk or yogurt, or with calcium-fortified foods (e.g, cereal, juice). You may eat or drink dairy products or calcium-fortified foods with a regular meal, but do not use them alone when taking (ciprofloxacin). They could make the medication less effective. 
• When (ciprofloxacin) tablets are given with enteral (tube) feedings, (ciprofloxacin) may not work as well. You could interrupt the feeding for 1 hour before and 2 hours after the (ciprofloxacin) dose, or your doctor may decide to switch to a different treatment. (ciprofloxacin) oral suspension should not be given via nasogastric tubes or feeding tubes. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Distribution:

• The binding of (ciprofloxacin) to serum proteins is 20 to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs.
• After oral administration, (ciprofloxacin) is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. (ciprofloxacin) is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. (ciprofloxacin) has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.

Metabolism:

Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged (ciprofloxacin). (ciprofloxacin) is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of (ciprofloxacin) with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug.

Excretion:

The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. 

Special Populations

Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of (ciprofloxacin) indicate that plasma concentrations of (ciprofloxacin) are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. 

Patients withRenal Impairment:

In patients with reduced renal function, the half-life of (ciprofloxacin) is slightly prolonged. Dosage adjustments may be required.

Patients withHepatic Impairment:

 In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in (ciprofloxacin) pharmacokinetics have been observed. The kinetics of (ciprofloxacin) in patients with acute hepatic insufficiency, however, have not been fully elucidated.

DOSAGE AND ADMINISTRATION

Adults: 

• The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s host-defense mechanisms, and the status of renal function and hepatic function.
• The usual recommended dosage of  Actavis Siprox  ((ciprofloxacin)) is one  tablet twice daily.
• The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days; however, for severe and complicated infections more prolonged therapy may be required. 
• (ciprofloxacin) should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, other highly buffered drugs, or other products containing calcium, iron or zinc.

Renal Impaired Patients:

(ciprofloxacin) is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction.

CONTRAINDICATIONS

• Hypersensitivity to quinolones: (ciprofloxacin) is contraindicated in persons with a history of hypersensitivity to (ciprofloxacin), any member of the quinolone class of antimicrobial agents, or any of the product components.
• Tizanidine (SIRDALUD): Concomitant administration with tizanidine is contraindicated.

ADVERSE REACTIONS

• Adverse effects are mild at therapeutic doses and are mostly limited to gastrointestinal disruptions such as nausea and diarrhea. 
• The serious adverse effects of Actavis Siprox (ciprofloxacin) include:  peripheral neuropathy, prolonged QT interval, seizures, and other CNS effects, hyper or hypoglycemia, photosensitivity, tendonitis. 
• Black box warnings include tendinitis and tendon rupture (associated with the fluoroquinolone class). The most common type of tendon rupture involves the Achilles tendon. 
• There have also been reports of tendinopathies in the gluteal, iliopsoas, and triceps tendons.
• Rare interactions include drug-induced bullous pemphigoid.

PRECAUTIONS

• Before taking Actavis Siprox (ciprofloxacin), tell your doctor or pharmacist if you are allergic to it; or to other quinolone antibiotics such as norfloxacin, gemifloxacin, levofloxacin, moxifloxacin, or ofloxacin; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.
• Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, heart problems (such as recent heart attack), joint/tendon problems (such as tendonitis, bursitis), kidney disease, liver disease, mental/mood disorders (such as depression), myasthenia gravis, nerve problems (such as peripheral neuropathy), seizures, conditions that increase your risk of seizures (such as brain/head injury, brain tumors, cerebral atherosclerosis), blood vessel problems (such as aneurysm or blockage of the aorta or other blood vessels, hardening of the arteries), high blood pressure, certain genetic conditions (Marfan syndrome, Ehlers-Danlos syndrome).
• Actavis Siprox (ciprofloxacin) may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can rarely cause serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that need medical attention right away.
• The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may cause QT prolongation. Before using (ciprofloxacin), tell your doctor or pharmacist of all the drugs you take and if you have any of the following conditions: certain heart problems (heart failure, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).
• Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/”water pills”) or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using (ciprofloxacin) safely.
• This medication may rarely cause serious changes in blood sugar, especially if you have diabetes. Check your blood sugar regularly as directed and share the results with your doctor. Watch for symptoms of high blood sugar such as increased thirst/urination. Actavis Siprox (ciprofloxacin) may increase the blood-sugar-lowering effects of the medication glyburide. Also watch for symptoms of low blood sugar such as sudden sweating, shaking, fast heartbeat, hunger, blurred vision, dizziness, or tingling hands/feet. It is a good habit to carry glucose tablets or gel to treat low blood sugar. If you don’t have these reliable forms of glucose, rapidly raise your blood sugar by eating a quick source of sugar such as table sugar, honey, or candy, or by drinking fruit juice or non- diet soda. Tell your doctor right away about the reaction and the use of this product. To help prevent low blood sugar, eat meals on a regular schedule, and do not skip meals. Your doctor may need to switch you to another antibiotic or adjust your diabetes medications if any reaction occurs.
• This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).
• This medication may make you more sensitive to the sun. Limit your time in the sun. Avoid tanning booths and sunlamps. Use sunscreen and wear protective clothing when outdoors. Tell your doctor right away if you get sunburned or have skin blisters/redness.
• (ciprofloxacin) may cause live bacterial vaccines (such as typhoid vaccine) to not work as well. Do not have any immunizations/vaccinations while using this medication unless your doctor tells you to.
• Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).
• This medication contains sucrose and is therefore not recommended if you have a rare hereditary metabolic condition (such as fructose intolerance, sucrase-isomaltase deficiency, glucose-galactose malabsorption).
• Children may be more sensitive to the side effects of this drug, especially joint/tendon problems.
• Older adults may be at greater risk for tendon problems (especially if they are also taking corticosteroids such as prednisone or hydrocortisone), QT prolongation, and a sudden tear/break in the main blood vessel (aorta).
• During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.
• This medication passes into breast milk and may have undesirable effects on a nursing infant. Consult your doctor before breast-feeding.
• Caution should be taken in administering (ciprofloxacin) to patients with impaired hepatic function.
•  consider its diagnosis in patients who develop severe diarrhea during or after therapy with (ciprofloxacin).
• Prolonged or repeated use of (ciprofloxacin) may result in super infections with insusceptible organisms. In case of superinfection, (ciprofloxacin) therapy should be stopped.
• (ciprofloxacin) should be used with caution whenever indicated for use in patients receiving treatment with an inducer of CYP3A4.
• (ciprofloxacin), is an inhibitor of the metabolising enzyme CYP3A4 should not be used concomitantly with different
• Avoid (ciprofloxacin) in patients with known history of myasthenia gravis. 
• (ciprofloxacin) has not been shown to be effective in the treatment of syphilis.

Pregnancy

Teratogenic Effects : Pregnancy category C.

There are no adequate or well-controlled studies in pregnant women. (ciprofloxacin) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

• Actavis Siprox (ciprofloxacin) and its active metabolite are excreted in breast milk. Therefore, diarrhea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility
• of sensitisation should be born in mind. The benefit of treatment of the mother should be weighed against the potential risk for the infant.

Drug interactions

.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

• Some products that may interact with this drug include: “blood thinners” (such as acenocoumarol, warfarin), strontium.
• Many drugs besides (ciprofloxacin) may affect the heart rhythm (QT prolongation), including amiodarone, dofetilide, quinidine, procainamide, sotalol, among others.
• This medication can slow down the removal of other medications from your body, which may affect how they work. Examples of affected drugs include duloxetine, flibanserin, lomitapide, pirfenidone, tasimelteon, tizanidine, among others.
• Avoid drinking large amounts of beverages containing caffeine (coffee, tea, colas), eating large amounts of chocolate, or taking over-the-counter products that contain caffeine. This drug may increase and/or prolong the effects of caffeine.

OVERDOSAGE

• In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of (ciprofloxacin). Adequate hydration must be maintained. Only a small amount of (ciprofloxacin) (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

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