387, Agege Motor Road, Cappa, Lagos, Nigeria
Tel: 234-17746708, 17358796
FEROZSONS LABORATORIES LIMITED P.O. Ferozsons, Amangarh Nowshera-Pakistan
Dosage Form, Composition & NAFDAC Registration Number (NRN)
Tablet (NRN: A4-7281): Each film coated tablet of Actigem contains Gemifloxacin mesylate equivalent to 320 mg of Gemifloxacin
Pack Size: available in 1 x 7’s Alu-Alu blister pack.
ACTIGEM (gemifloxacin mesylate) is a synthetic broad-spectrum antibacterial agent for oral administration. Gemifloxacin, a compound related to the fluoroquinolone class of antibiotics, is available as the mesylate salt in the sesquihydrate form. Chemically, gemifloxacin is (R,S)-7-[(4Z)-3 (aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro 1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
The pharmacokinetics of gemifloxacin are approximately linear over the dose range from 40 mg to 640 mg. There was minimal accumulation of gemifloxacin following multiple oral doses up to 640 mg a day for 7 days (mean accumulation <20%). Following repeat oral administration of 320 mg gemifloxacin once daily, steady-state is achieved by the third day of dosing.
Absorption and Bioavailability
Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%).
Following repeat oral doses of 320 mg to healthy subjects, the mean ± SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 ± 0.51 µg/mL (range 0.70-2.62 µg/mL) and 9.93 ± 3.07 µghr/mL (range 4.71-20.1 µghr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 µghr/mL; range 3.2 47.7 µghr/mL.
The pharmacokinetics of gemifloxacin were not significantly altered when a 320 mg dose was administered with a high-fat meal. Therefore, ACTIGEM tablets may be administered without regard to meals.
Distribution in vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent. After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age.
Renal impairment does not significantly affect the protein binding of gemifloxacin. The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1. The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 12.12 L/kg).
Gemifloxacin is widely distributed throughout the body after oral administration. Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids. After five daily doses of 320 mg gemifloxacin, concentrations in plasma, bronchoalveolar macrophages, epithelial lining fluid and bronchial mucosa at approximately 2 hours were as in Table 1.
|Ratio compared with
plasma (mean ± SD)
|Plasma||1.40 (0.442) µg/mL||-|
|Bronchoalveolar Macrophages||107 (77) µg/g||90.5 (106.3)|
|Epithelial Lining Fluid||2.69 (1.96) µg/mL||1.99 (1.32)|
|Bronchial Mucosa||9.52 (5.15) µg/g||7.21 (4.03)|
Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin, cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.
Gemifloxacin and its metabolites are excreted via dual routes of excretion. Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites.
The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6 17 .6L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. The mean (± SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 ± 2 hours (range 4-12 hours).
Pediatric: The pharmacokinetics of gemifloxacin in pediatric subjects have not been studied.
Geriatric: In adult subjects, the pharmacokinetics of gemifloxacin are not affected by age.
Gender: No gemifloxacin dosage adjustment based on gender is necessary.
Hepatic Insufficiency: The pharmacokinetics following a single 320 mg dose of gemifloxacin were studied in patients with mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) liver disease. There was a mean increase in AUC (0-inf) of 34% and a mean increase in Cmax of 255 in these patients with hepatic impairment compared to healthy volunteers.
The pharmacokinetics of a single 320 mg dose of gemifloxacin were also studied in patients with severe hepatic impairment (Child-Pugh Class C). There was a mean increase in AUC (0-inf) of 45% and a mean increase in Cmax of 41% in these subjects with hepatic impairment compared to healthy volunteers. These average pharmacokinetic increases are not considered to be clinically significant.
There was no significant change in plasma elimination half-life in the mild, moderate or severe hepatic impairment patients. No dosage adjustment is recommended in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.
Renal Insufficiency: Repeated doses of 320 mg indicate that the clearance of gemifloxacin is reduced and the plasma elimination is prolonged, leading to an average increase in AUC values of approximately 70% in patients with renal insufficiency. In the pharmacokinetic studies, gemifioxacin Cmax was not significantly altered in subjects with renal insufficiency.
Dose adjustment in patients with creatinine clearance >40 mL/min is not required. Modification of the dosage is recommended for patients with creatinine clearance ≤40 mL/min. Hemodialysis removes approximately 20 to 30% of an oral dose of gemifloxacin from plasma.
Gemifloxacin has in vitro activity against a wide range of Gram- negative and Gram-positive microorganisms. Gemifloxacin is bactericidal with minimum bactericidal concentrations (MBCs) generally within one dilution of the minimum inhibitory concentrations (MICs). Gemifloxacin acts by inhibiting DNA. synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TO PO IV), which are essential for bacterial growth. Streptococcus pneumoniae showing mutations in both DNA gyrase and Tapa IV (double mutants) are resistant to most fluoroquinolones.
Gemifloxacin has the ability to inhibit both enzyme systems at therapeutically relevant drug levels in S. pneumoniae (dual targeting), and has MIC values that are still in the susceptible range for some of these double mutants. However, the presence of double mutants was not evaluated in clinical trials; therefore, the clinical significance of these in vitro data are unknown.
The mechanism of action of quinolones, including gemifloxacin, is different from that of macrolides, beta-Iactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to gemifloxacin and other quinolones. There is no known cross resistance between gemifloxacin and the above mentioned classes of antimicrobials. The man mechanism of fluoroquinolone resistance is due to mutations in DNA gyrase and/or TOPO IV.
Resistance to gemifloxacin develops slowly via multistep mutations and efflux in a manner similar to other fluoroquinolones. The frequency of spontaneous mutation is low (10-7 to <10-10). Although cross-resistance has been observed between gemifloxacin and other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to gemifloxacin.
Aerobic Gram-positive microorganisms
Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP])*
*MDRSP: multi-drug resistant Streptococcus/pneumoniae, includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 µg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
Aerobic Gram-negative microorganisms
Haemophilus influenzae, Haemophilus parainfluenzae Klebsiella pneumoniae (many strains are only moderately susceptible), Moraxella catarrhalis
Other microorganisms Chlamydia pneumoniae, Mycoplasma pneumoniae The following data are available, but their clinical significance is unknown.
Gemifloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 0.25 µg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of gemifloxacin in treating clinical infections due to these microorganisms has not been established in adequate and well controlled clinical trials:
Aerobic Gram-positive microorganisms
Staphylococcus aureus (methicillin-susceptible strains only) Streptococcus pyogenes
Aerobic Gram-negative microorganisms
Acinetobacter Iwoffii, Klebsiella oxytoca, Legionella pneumophila, Proteus vulgaris
ACTIGEM is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below.
Acute bacterial exacerbation of chronic bronchitis caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis.
Community-acquired pneumonia (of mild to moderate severity) caused by Streptococcus pneumoniae (including multi drug resistant strains [MDRSP])*, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae.
*MDRSP: multi-drug resistant Streptococcus pneumoniae, includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 µg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole. It is also indicated for the treatment of Typhoid Fever (Enteric Fever) caused by salmonella Typhi.
ACTIGEM is contraindicated in patients with a history of hypersensitivity to gemifioxacin, fluoroquinolone antibiotic agents, or any of the product components.
Concerns related to adverse effects:
Altered cardiac conduction: Fluoroquinolones may prolong QTc interval; avoid use in patients with a history of QTc prolongation, uncorrected hypokalemia, hypomagnesemia, or concurrent administration of other medications known to prolong the QT interval (including Class la and Class III antiarrhythmics, cisapride, erythromycin, antipsychotics, and tricyclic antidepressants).
CNS stimulation: Tremor, restlessness, confusion, and very rarely hallucinations or seizures may occur; use with caution in patients with known or suspected CNS disorder. Discontinue in patients who experience significant CNS adverse effects (eg, dizziness, hallucinations, suicidal ideations or actions).
Glucose regulation: Fluoroquinolones have been associated with the development of serious, and sometimes fatal, hypoglycemia. These events have occurred most often in elderly patients with diabetes, but have also been reported in patients without a prior history of diabetes. Prompt identification and treatment of hypoglycemia is essential.
Individual quinolones may differ in their potential to cause this effect. It was most evident with gatifloxacin (no longer marketed as s systemic formulation). Hyperglycemia has also been associated with the use of fluoroquinolones. Patients should be monitored closely for signs/symptoms of disordered glucose regulation.
Severe hypersensitivity reactions, including anaphylaxis, have occurred with quinolone therapy. The spectrum of these reactions can vary widely; reactions may present as typical allergic symptoms (eg, itching, urticaria, rash, edema) after a single dose, or may manifest as severe idiosyncratic dermatologic (eg, Stevens-Johnson, toxic epidermal necrolysis), vascular (eg, vasculitis), pulmonary (eg, pneumonitis), renal (eg, nephritis), hepatic (eg, hepatic failure or necrosis), and/or hematologic (eg, anemia, cytopenias) events, usually after multiple doses.
May cause maculopapular rash, usually 8-10 days after treatment initiation; risk factors may include age 7 days. Prompt discontinuation of drug should occur if skin rash or other symptoms arise.
The use of quinolones has been linked to peripheral neuropathy (rare); discontinue if symptoms of sensory or sensorimotor neuropathy occur.
Avoid excessive sunlight and take precautions to limit exposure (eg, loose fitting clothing, sunscreen); may cause moderate-tosevere phototoxicity reactions. Discontinue use if photosensitivity occurs.
Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months post antibiotic treatment.
Tendon inflammation/rupture: There have been reports of tendon inflammation and/or rupture with quinolone antibiotics; risk may be increased with concurrent corticosteroids, organ transplant recipients, and in patients >60 years of age.
Rupture of the Achilles tendon sometimes requiring surgical repair has been reported most frequently; but other tendon sites (eg, rotator cuff, biceps) have also been reported. Strenuous physical activity may be an independent risk factor for tendonitis. Discontinue at first sign of tendon inflammation or pain. May occur even after discontinuation of therapy.
Cardiovascular disease: Use with caution in patients with significant bradycardia or acute myocardial ischemia.
Myasthenia gravis: Some quinolones may exacerbate myasthenia gravis, use with caution (rare, potentially life-threatening weakness of respiratory muscles may occur).
Use with caution in renal impairment; dosage adjustment required for Clcr ≤40 mL/minute. May increase risk of tendon rupture.
Rheumatoid arthritis: Use with caution in patients with rheumatoid arthritis; may increase risk of tendon rupture.
Seizures: Use with caution in individuals at risk of seizures (CNS disorders or concurrent therapy with medications which may lower seizure threshold). Potential for seizures, although very rare, may be increased with concomitant NSAID therapy.
Elderly: Adverse effects (eg, tendon rupture, QT changes) may be increased in the elderly.
Hemolytic reactions may (rarely) occur with quinolone use in patients with latent or actual G6PD deficiency.
Safety and effectiveness have not been established in children.
PREGNANCY RISK FACTOR C
Excretion in breast milk unknown/not recommended
Antacids/Di- and Trivalent Cations: The systemic availability of gemifloxacin is significantly reduced when an aluminum- and magnesium- containing antacid is concomitantly administered (AUC decreased 85%; Cmax decreased 87%). Administration of an aluminum- and magnesium- containing antacid or ferrous sulfate (325 mg) at 3 hours before or at 2 hours after gemifloxacin did not significantly alter the systemic availability of gemifloxacin.
Therefore, aluminum- and/or magnesium- containing antacids, ferrous sulfate (iron), multivitamin preparations containing zinc or other metal cations, or didanosine chewable/ buffered tablets or the pediatric powder for oral solution should not be taken within 3 hours before or 2 hours after taking ACTIGEM tablets.
Calcium carbonate (1000 mg) given either 2 hr before or 2 hr after gemifloxacin administration showed no notable reduction in gemifloxacin systemic availability. Calcium carbonate administered simultaneously with gemifloxacin resulted in a small, not clinically Significant, decrease in gemifloxacin exposure [AUC (0-inf) decreased 21% and Cmax decreased].
Sucralfate: When sucralfate (2 g) was administered 3 hours prior to gemifloxacin, the oral bioavailability of gemifloxacin was significantly reduced (53% decrease in AUC; 69% decrease in Cmax). When sucralfate (2 g) was administered 2 hours after gemifloxacin, the oral bioavailability of gemifloxacin was not significantly affected; therefore, ACTIGEM should be taken at least 2 hours before sucralfate. In Vitro
Metabolism: Results of in vitro inhibition studies indicate that hepatic cytochrome P450 (CYP450) enzymes do not play an important role in gemifloxacin metabolism. Therefore, gemifloxacin should not cause Significant in vivo pharmacokinetic interactions with other drugs that are metabolized by CYP450 enzymes.
Theophylline: Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of theophylline (300 to 400 mg BID to healthy male subjects).
Digoxin: Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of digoxin (0.25 mg once daily to healthy elderly subjects).
Oral Contraceptives: The effect of an oral estrogen/progesterone contraceptive product (once daily for 21 days) on the pharmacokinetics of gemifloxacin (320 mg once daily for 6 days) in healthy female subjects indicates that concomitant administration caused an average reduction in gemifloxacin AUC and Cmax of 19% and 12%. These changes are not considered clinically significant. Gemifloxacin 320 mg at steady-state did not affect the repeat dose pharmacokinetics of an ethinylestradiol/levonorgestrol oral contraceptive product (30 µg/150 µg once daily for 21 days to healthy female subjects).
Cimetidine: Co-administration of a single dose of 320 mg gemifloxacin with cimetidine 400 mg four times daily for 7 days resulted in slight average increases in gemifloxacin AUC(0-inf) and Cmax, of 10% and 6%, respectively. These increases are not considered clinically significant.
Omeprazole: Co-administration of a single dose of 320 mg gemifloxacin with omeprazole 40 mg once daily for 4 days 5 resulted in slight average increases in gemifloxacin AUC(0-inf) and Cmax of 10% and 11%, respectively. These increases are not considered clinically significant.
Warfarin: Administration of repeated doses of gemifloxacin (320 mg once daily for 7 days) to healthy subjects on stable warfarin therapy had no significant effect on warfarin-induced anticoagulant activity (i.e., International Normalized Ratios for Prothrombin Time).
Probenecid: Administration of a single dose of 320 mg gemifloxacin to healthy subjects who also received repeat doses of probenecid (total dose = 4.5 g) reduced the mean renal clearance of gemifloxacin by approximately 50%, resulting in a mean increase of 45 in gemifloxacin AUC (0-inf) and a prolongation of mean half-life by 1.6 hours. Mean gemifloxacin Cmax increased 8%.
1% to 10%: Central nervous system: Headache (4%), dizziness (2%) Dermatologic: Rash (4%) Gastrointestinal: Diarrhea (5%), nausea (4%), abdominal pain (2%), vomiting (2%) Hematologic: Neutropenia/neutrophilia (1%), platelets increased (1%), thrombocythemia (1%) Hepatic: Transaminases increased (1 to 4), GGT increased (1%) Neuromuscular & skeletal: CPK increased (1%).
<1% (Limited to important or life-threatening):
Acute renal failure, alkaline phosphatase increased, anaphylactic reaction, anemia, anorexia, arthralgia, back pain, bilirubin increased, BUN increased, constipation, cramps (leg), dermatitis, dyspepsia, dyspnea, eczema, eosinophilia, erythema multiforme, facial edema, fatigue, flatulence, flushing, fungal infection, gastritis, gastroenteritis, genital moniliasis, granulocytopenia, hematocrit decreased/increased, hemoglobin decreased/increased, hemorrhage, hot flashes, hyperglycemia, hyper-/hypocalcemia, hyper-/hypokalemia, hyper /hyponatremia,
hypoalbuminemia, INR increased, insomnia, leukopenia, moniliasis, myalgia, nervousness, pain, pharyngitis, photosensitivity, pneumonia, pruritus, pseudomembranous colitis, QT, prolongation, retinal hemorrhage, serum creatinine increased, skin exfoliation, somnolence, supraventricular tachycardia, syncope, taste perversion, tendonitis, tendon rupture, thrombocytopenia, TIA, tremor, urticaria, vaginitis, vertigo, vision abnormal, weakness, xerostomia
Important adverse effects reported with other agents in this drug class include (not reported for gemifloxacin): Allergic reactions, CNS stimulation, hepatic necrosis/failure, hepatitis, hypersensitivity, jaundice, pancytopenia, peripheral neuropathy, pneumonitis (eosinophilic). seizure, sensorimotor-axonal neuropathy (paresthesia, hypoesthesias, dysesthesias, weakness), serum sickness, severe dermatologic reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome), thrombotic thrombocytopenia purpura, torsade de pointes, vasculitis
Dosage & Administration
ACTIGEM can be taken with or without food and should be swallowed whole with a liberal amount of liquid.
The recommended dose of ACTIGEM is 320 mg daily, according to the following table (Table 2).
Table 2. Recommended Dosage Regimen of ACTIGEM
The use of a 5 day or 7 day regimen
|Acute bacterial exacerbation of chronic bronchitis||One 320 mg tablet daily for 5 days|
|Community-acquired pneumonia (of mild to moderate severity)|
|Due to known or suspected S. pneumoniae, H. influenzae, M. pneumoniae, or C. pneumoniae infection||One 320 mg tablet daily for 5 days|
|due to known or suspected MDRSP*, K. pneumoniae, or M. catarrhalis infection||One 320 mg tablet daily for 7 days|
|Typhoid Fever (Enteric Fever) caused by Salmonella typhoid.||One 320 mg tablet daily for 7 days|
*MDRSP: multi-drug resistant Streptococcus pneumoniae, includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin (MIC ≥2 µg/mL), 2nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines and trimethoprim/sulfamethoxazole. Use in Renally
Impaired Patients: Dose adjustment in patients with creatinine clearance >40 mL/min is not required. Modification of the dosage is recommended for patients with creatinine clearance ≤40 mL/min.
Table 3 provides dosage guidelines for use in patients with renal impairment.
|>40||See Usual Dosage|
|≤40 or patients on hemodialysis/CAPD||160 mg every 24 hours|
Any signs or symptoms of overdosage should be treated symptomatically. No specific antidote is known.
Store at or below 25°C in a dry place protect from light.
Keep out of the reach of children.