DRUGS & SUPPLEMENTS
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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.
NOTE: Although effective in clinical trials, Alcipro is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin susceptible Staphylococcus aureus, methicillin susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic strains), Campylobacter jejuni, Shigella boydii † , Shigella dysenteriae, Shigella flexneri or Shigella sonnei † when antibacterial therapy is indicated.
Typhoid Fever (Enteric Fever) caused by Salmonella typhi.
NOTE: The efficacy of Alcipro in the eradication of the chronic typhoid carrier state has not been demonstrated.
Uncomplicated cervical and urethral gonorrhea due to Neisseria gonorrhoeae.
NOTE: Although effective in clinical trials, Alcipro is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS, Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES .) Alcipro, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY .)
Alcipro serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication.5 Supportive clinical information for Alcipro for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001. (See also, INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION ).
†Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to Alcipro. Therapy with Alcipro Tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with Alcipro. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Alcipro Tablets and other antibacterial drugs, Alcipro Tablets 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.
Fluoroquinolones, including Alcipro Tablets, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotater cuff, the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Alcipro Tablets should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
Fluoroquinolones, including Alcipro, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Alcipro in patients with known history of myasthenia gravis..
In pre-clinical studies, oral administration of Alcipro caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY .)
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Alcipro. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS ).
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Alcipro Tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile .
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Central Nervous System
Quinolones, including Alcipro, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information for Patients, and Drug Interactions .)
Alteration of the dosage regimen is necessary for patients with impairment of renal function. (See DOSAGE AND ADMINISTRATION .)
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/Post-Marketing Adverse Events ).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.
Prescribing Alcipro Tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
As with some other quinolones, concurrent administration of Alcipro with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS .) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including Alcipro, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including Alcipro, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate,Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents with Alcipro.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of Alcipro.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant Alcipro.
The concomitant administration of Alcipro with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia.
Some quinolones, including Alcipro, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including Alcipro, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of Alcipro and produces an increase in the level of Alcipro in the serum. This should be considered if patients are receiving both drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of Alcipro potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant Alcipro therapy is indicated.
Metoclopramide significantly accelerates the absorption of oral Alcipro resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of Alcipro.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies.
Salmonella/Microsome Test (Negative)
E. coli DNA Repair Assay (Negative)
Mouse Lymphoma Cell Forward Mutation Assay (Positive)
Chinese Hamster V79 Cell HGPRT Test (Negative)
Syrian Hamster Embryo Cell Transformation Assay (Negative)
Saccharomyces cerevisiae Point Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to Alcipro at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5-times the highest recommended therapeutic dose based upon mg/m2).
Results from photo co-carcinogenicity testing indicate that Alcipro does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered Alcipro. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and Alcipro (mouse dose approximately equal to maximum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones.4
In this model, mice treated with Alcipro alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of Alcipro up to 100 mg/kg (approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of impairment.
There are no adequate and well-controlled studies in pregnant women. An expert review of published data on experiences with Alcipro use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk, but the data are insufficient to state that there is no risk.8
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to Alcipro and 68% first trimester exposures) during gestation.9 In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1 - 5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the Alcipro exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures).10 There were 70 Alcipro exposures, all within the first trimester. The malformation rates among live-born babies exposed to Alcipro and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to Alcipro.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to Alcipro during pregnancy.8,9 However, these small post-marketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of Alcipro in pregnant women and their developing fetuses. Alcipro should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS ).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to Alcipro. In rabbits, oral Alcipro dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See WARNINGS .)
Alcipro, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness.
Alcipro is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli. Although effective in clinical trials, Alcipro is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to the controls, including events related to joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were 9.3% versus 6% (21/349) for control agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the Alcipro arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS.)
Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 - 17 years), 67 patients received Alcipro I.V. 10 mg/kg/dose q8h for one week followed by Alcipro tablets 20 mg/kg/dose q12h to complete 10 - 21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 - 21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0 - 93 days). This study was not designed to determine long term effects and the safety of repeated exposure to Alcipro.
Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the Alcipro group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the Alcipro group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the Alcipro group and 11% in the comparison group. Other adverse events were similar in nature and frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after a ten-day course of treatment with Alcipro. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patient’s course of Alcipro can not be definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process.
In a retrospective analysis of 23 multiple-dose controlled clinical trials of Alcipro encompassing over 3500 Alcipro treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Alcipro is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION .)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Alcipro Tablets with concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of Alcipro therapy were nausea, diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
Additional medically important events that occurred in less than 1% of Alcipro patients are listed below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities, injection side reaction (ciprofloxacin intravenous)
CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis, phlebitis, tachycardia, migraine, hypotension
CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia, abnormal gait, grand mal convulsion
GASTROINTESTINAL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding, cholestatic jaundice, hepatitis
HEMIC/LYMPHATIC: lymphadenopathy, petechia
METABOLIC/NUTRITIONAL: amylase increase, lipase increase
MUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout
RENAL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention, urethral bleeding, vaginitis, acidosis, breast pain
RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis, bronchospasm, pulmonary embolism
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity/phototoxicity reaction, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum, sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste, chromatopsia
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with Alcipro.
In randomized, double-blind controlled clinical trials comparing Alcipro tablets (500 mg BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, Alcipro demonstrated a CNS adverse event profile comparable to the control drugs.
Alcipro, administered I.V. and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the U.S., Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint.
The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6% (21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment.
Radiological evaluations were not routinely used to confirm resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they received I.V. or oral therapy. Ciprofloxacin-treated patients were more likely to report more than one event and on more than one occasion compared to control patients. These events occurred in all age groups and the rates were consistently higher in the Alcipro group compared to the control group. At the end of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued Alcipro for wrist pain that developed during treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from Alcipro cannot be excluded. The patient recovered by 4 months without surgical intervention.
| *The study was designed to demonstrate that the arthropathy rate for the Alcipro group did not exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be concluded that Alcipro group had findings comparable to the control group. |
| All Patients (within 6 weeks) || 31/335 (9.3%) || 21/349 (6%) |
| 95% Confidence Interval* || (-0.8%, +7.2%) |
| Age Group || || |
| ≥ 12 months < 24 months || 1/36 (2.8%) || 0/41 |
| ≥ 2 years < 6 years || 5/124 (4%) || 3/118 (2.5%) |
| ≥ 6 years < 12 years || 18/143 (12.6%) || 12/153 (7.8%) |
| ≥ 12 years to 17 years || 7/32 (21.9%) || 6/37 (16.2 %) |
| All Patients (within 1 year) || 46/335 (13.7%) || 33/349 (9.5%) |
| 95% Confidence Interval* || (-0.6%, + 9.1%) |
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the Alcipro group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6 weeks of treatment initiation were 41% (138/335) in the Alcipro group versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of Alcipro patients compared to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of Alcipro patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3%, rhinitis 3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in adults during clinical trials or post-marketing experience may also occur in pediatric patients.
Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum), photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS .)
Adverse events were also reported by persons who received Alcipro for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION .)
Changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below:
Hepatic – Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic – Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal – Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA, CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.
To report SUSPECTED ADVERSE EVENTS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Single doses of Alcipro were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In rabbits, significant mortality was seen at doses of Alcipro > 2500 mg/kg. Mortality was delayed in these animals, occurring 10 to 14 days after dosing.
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 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. Alcipro should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, or sucralfate, Videx® chewable/buffered tablets or pediatric powder for oral solution, other highly buffered drugs, or other products containing calcium, iron or zinc.
|ADULT DOSAGE GUIDELINES|
| Urinary Tract || Acute Uncomplicated || 250 mg || q 12 h || 3 Days |
| Mild/Moderate || 250 mg || q 12 h || 7 to 14 Days |
| Severe/Complicated || 500 mg || q 12 h || 7 to 14 Days |
| Chronic Bacterial Prostatitis || Mild/Moderate || 500 mg || q 12 h || 28 Days |
| Lower Respiratory Tract || Mild/Moderate || 500 mg || q 12 h || 7 to 14 days |
| Severe/Complicated || 750 mg || q 12 h || 7 to 14 days |
| Acute Sinusitis || Mild/Moderate || 500 mg || q 12 h || 10 days |
| Skin and Skin Structure || Mild/Moderate || 500 mg || q 12 h || 7 to 14 Days |
| Severe/Complicated || 750 mg || q 12 h || 7 to 14 Days |
| Bone and Joint || Mild/Moderate || 500 mg || q 12 h || ≥4 to 6 weeks |
| Severe/Complicated || 750 mg || q 12 h || ≥4 to 6 weeks |
| Intra-Abdominal* || Complicated || 500 mg || q 12 h || 7 to 14 Days |
| Infectious Diarrhea || Mild/Moderate/Severe || 500 mg || q 12 h || 5 to 7 Days |
| Typhoid Fever || Mild/Moderate || 500 mg || q 12 h || 10 Days |
| Urethral and Cervical |
| Uncomplicated || 250 mg || single dose || single dose |
| Inhalational anthrax(post-exposure)** || || 500 mg || q 12 h ||60 Days|
* used in conjunction with metronidazole
† Generally Alcipro should be continued for at least 2 days after the signs and symptoms of infection
have disappeared, except for inhalational anthrax (post-exposure).
** Drug administration should begin as soon as possible after suspected or confirmed exposure.
This indication is based on a surrogate endpoint, Alcipro serum concentrations achieved in humans,
reasonably likely to predict clinical benefit.4 For a discussion of Alcipro serum concentrations in various
human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION .
Conversion of I.V. to Oral Dosing in Adults
Patients whose therapy is started with Alcipro I.V. may be switched to Alcipro Tablets when clinically indicated at the discretion of the physician (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens).
|Alcipro Oral Dosage||Equivalent Alcipro I.V. Dosage|
| 250 mg Tablet q 12 h || 200 mg I.V. q 12 h |
| 500 mg Tablet q 12 h || 400 mg I.V. q 12 h |
| 750 mg Tablet q 12 h || 400 mg I.V. q 8 h |
Adults with Impaired Renal Function
Alcipro 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. The following table provides dosage guidelines for use in patients with renal impairment:
|Creatinine Clearance (mL/min)||Dose|
| > 50 || See Usual Dosage. |
| 30 – 50 || 250 – 500 mg q 12 h |
| 5 – 29 || 250 – 500 mg q 18 h |
Patients on hemodialysis
or Peritoneal dialysis
250 – 500 mg q 24 h
When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance.
Weight (kg) x (140 - age)
Men: Creatinine clearance (mL/min) = 72 x serum creatinine (mg/dL)
Women: 0.85 x the value calculated for men.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored.
Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
| Complicated |
Urinary Tract or
| Intravenous || 6 to 10 mg/kg |
(maximum 400 mg
per dose; not to be exceeded
even in patients weighing
> 51 kg)
| Every 8 hours || |
| (patients from |
1 to 17 years of
| Oral || 10 mg/kg to 20 mg/kg |
(maximum 750 mg per
dose; not to be exceeded
even in patients weighing
> 51 kg)
| Every 12 hours |
| Inhalational |
| Intravenous || 10 mg/kg |
(maximum 400 mg per
| Every 12 hours || |
| Oral || 15 mg/kg |
(maximum 500 mg per dose)
| Every 12 hours |
** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of Alcipro serum concentrations in various human populations, see INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION .
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of complicated urinary tract infection and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with Alcipro. This is primarily related to the reduced solubility of Alcipro under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon mg/m2).
In dogs, Alcipro at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also produces hypotension but the effect in this species is inconsistent and less pronounced.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Alcipro, administered I.V. and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the U.S., Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between Alcipro and the comparator group as shown below.
| * Patients with baseline pathogen(s) eradicated and no new infections or |
superinfections/total number of patients. There were 5.5% (6/211) Alcipro and
9.5% (22/231) comparator patients with superinfections or new infections.
| Randomized Patients || 337 || 352 |
| Per Protocol Patients || 211 || 231 |
| Clinical Response at 5 to 9 Days |
| 95.7% (202/211) || 92.6% (214/231) |
| || 95% CI [-1.3%, 7.3%] |
| Bacteriologic Eradication by |
Patient at 5 to 9 Days
| 84.4% (178/211) || 78.3% (181/231) |
| || 95% CI [-1.3%, 13.1%] |
| Bacteriologic Eradication of the |
Baseline Pathogen at 5 to 9 Days
| Escherichia coli || 156/178 (88%) || 161/179 (90%) |
The mean serum concentrations of Alcipro associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND ADMINISTRATION .) Alcipro pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 μg/mL, and 4.56 μg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 μg/mL.
In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 μg/mL and trough concentrations range from 0.09 to 0.26 μg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 μg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of Alcipro to pediatric patients are limited. (For additional information, see PRECAUTIONS, Pediatric Use .) Alcipro serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.5
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105 spores (range 5 to 30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of Alcipro for the anthrax strain used in this study was 0.08 μg/mL. In the animals studied, mean serum concentrations of Alcipro achieved at expected Tmax (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 μg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 μg/mL.6 Mortality due to anthrax for animals that received a 30-day regimen of oral Alcipro beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.7
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic prophylaxis against possible inhalational exposure to B. anthracis during 2001. Alcipro was recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were also given anthrax vaccine or were switched to alternative antibiotics. No one who received Alcipro or other therapies as prophylactic treatment subsequently developed inhalational anthrax. The number of persons who received Alcipro as all or part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported receiving Alcipro as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more frequent than had been previously reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional stress or other confounding factors, and/or a longer treatment period with Alcipro. Because of these factors and limitations in the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
Read the Medication Guide that comes with Alcipro Tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Tendon rupture or swelling of the tendon
Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in patients who take fluoroquinolones who do not have the above risk factors.
Children less than 18 years of age have a higher chance of getting bone, joint, or tendon (musculoskeletal) problems such as pain or swelling while taking Alcipro Tablets. Alcipro Tablets should not be used as the first choice of antibiotic medicine in children under 18 years of age. Alcipro Tablets should not be used in children under 18 years old, except to treat specific serious infections, such as complicated urinary tract infections and to prevent anthrax disease after breathing the anthrax bacteria germ (inhalational exposure).
Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics, including Alcipro Tablets, do not kill viruses.
Call your healthcare provider if you think your condition is not getting better while you are taking Alcipro Tablets.
Do not take Alcipro Tablets if you:
See “What is the most important information I should know about Alcipro Tablets?”
Tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal and dietary supplements. Alcipro Tablets and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:
Ask your healthcare provider if you are not sure if any of your medicines are listed above.
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
If you have been prescribed Alcipro Tablets after being exposed to anthrax:
Other serious side effects of Alcipro Tablets include:
Seizures have been reported in people who take fluoroquinolone antibiotics including Alcipro Tablets. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking Alcipro Tablets will change your risk of having a seizure.
Central Nervous System side effects may happen as soon as after taking the first dose of Alcipro Tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:
Allergic reactions can happen in people taking fluoroquinolones, including Alcipro Tablets, even after only one dose. Stop taking Alcipro Tablets and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:
Skin rash may happen in people taking Alcipro tablets even after only one dose. Stop taking Alcipro tablets at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to Alcipro tablets.
Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Alcipro Tablets may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are higher in people:
Pseudomembranous colitis can happen with most antibiotics, including Alcipro Tablets. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.
Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including Alcipro Tablets. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:
Alcipro Tablets may need to be stopped to prevent permanent nerve damage.
People who take Alcipro Tablets and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance)can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar with Alcipro Tablets. Your antibiotic medicine may need to be changed.
See “What should I avoid while taking Ciprofloxacin Tablets?”
Increased chance of problems with joints and tissues around joints in children under 18 years old. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with Alcipro Tablets.
The most common side effects of Alcipro Tablets include:
These are not all the possible side effects of Alcipro Tablets. Tell your healthcare provider about any side effect that bothers you, or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Keep Alcipro Tablets and all medicines out of the reach of children.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Alcipro Tablets for a condition for which it is not prescribed. Do not give Alcipro Tablets to other people, even if they have the same symptoms that you have. They may harm them.
This Medication Guide summarizes the most important information about Alcipro Tablets. If you would like more information about Alcipro Tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Alcipro Tablets that is written for healthcare professionals. For more information call 1-866-850-2876.
Active ingredient: Alcipro
Inactive ingredients: colloidal silicon dioxide, corn starch, hydrogenated vegetable oil, hypromellose, magnesium stearate, microcrystalline cellulose, polyacrylate dispersion (methylacrylate and ethylacrylate copolymer), polyethylene glycol, purified water, simethicone emulsion, sodium starch glycolate, talc, and titanium dioxide.
Revised March 2009
This Medication Guide has been approved by the U.S. Food and Drug Administration.
West-ward Pharmaceutical Corp.
Eatontown, NJ 07724
P.O. Box 182400
Amman 11118 - Jordan
Depending on the reaction of the Alcipro after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Alcipro not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Alcipro addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology