Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead 2191
Category and Class: A.15.3 Combination antibiotics and/or sulphonamides and corticosteroids
Pharmacotherapeutic group: Anti-inflammatory agents and anti-infectives in combination, corticosteroids and anti-infectives in combination
ATC code: S01CA01
VOXIDEX is a fixed dose combination of two active substances: levofloxacin and dexamethasone. These two active substances have a completely different mechanism of actions being a topically combination of an antibiotic and a corticosteroid. Dexamethasone is a steroid used in ophthalmic therapy, while levofloxacin is an antibiotic of the quinolone class that is characterized by a broad spectrum of action, with confirmed activity on, both Gram-positive and Gram-negative bacteria. VOXIDEX is used for ocular inflammation, after surgery when an antibiotic and a corticosteroid are indicated.
As a fluoroquinolone antibacterial medicine, levofloxacin, that is the active L-isomer of ofloxacin, inhibits bacterial type II topoisomerases—DNA gyrase and topoisomerase IV. Levofloxacin preferentially targets DNA gyrase in Gram negative bacteria and topoisomerase IV in Gram positive bacteria. The spectrum of activity against ocular pathogens includes aerobic Gram-positive microorganisms (e.g. S. aureus MSSA, S. pyogenes, S. pneumoniae, viridans group streptococci), aerobic Gram-negative bacteria (e.g. E. coli, H. influenzae, M. catarrhalis, P. aeruginosa community isolates), other organisms (e.g. Chlamydia trachomatis).
The efficacy of corticosteroids for the treatment of inflammatory conditions of the eye is well established. Corticosteroids achieve their anti-inflammatory effects through suppression of vascular endothelial cell adhesion molecules, cyclooxygenase I or II, and cytokine expression. This action culminates in a reduced expression of proinflammatory mediators and the suppression of adhesion of circulating leukocytes to the vascular endothelium, thereby preventing their migration into inflamed ocular tissue. Dexamethasone has marked anti-inflammatory activity with reduced mineralocorticoid activity compared with some other steroids and is one of the most potent anti-inflammatory medicine.
The efficacy of levofloxacin/dexamethasone has been investigated in a controlled study to evaluate the non-inferiority of the levofloxacin/dexamethasone vs. a standard treatment with a commercial formulation of tobramycin (0,5%) and dexamethasone (0,1%) eye drops for the prevention and treatment of inflammation and prevention of infection associated with cataract surgery in adults. The Investigator in charge of evaluating study parameters was blinded to treatment assignment. Patients who completed their cataract surgery without complications were assigned to levofloxacin/dexamethasone eye drops, 1 drop 4 times a day for 7 days, followed by dexamethasone 0,1% eye drops, 1 drop 4 times a day, for an additional 7 days, or to reference tobramycin + dexamethasone eye drops, 1 drop 4 times a day for 14 days.
Data of efficacy were available in 395 patients given levofloxacin/dexamethasone and in 393 patients given the reference product after cataract surgery. After 14 days of treatment, the proportion of patients with no signs of inflammation (primary endpoint of the study) in the levofloxacin/dexamethasone followed by dexamethasone group compared to the tobramycin + dexamethasone group was 95,19% vs. 94,91%, respectively. The difference between the two proportions was 0,0028 (95% CI: [-0,0275; 0,0331]), which demonstrated the non-inferiority of the test vs. reference treatment regimen. No occurrence of endophthalmitis was reported during the study for either group. Signs of anterior chamber inflammation were absent in levofloxacin/dexamethasone arm in 73,16% at day 4 and in 85,57% of patients at day 8 after surgery. In tobramycin + dexamethasone arm, signs of anterior chamber inflammation were absent in 76,84% at day 4 and in 86,77% of patients at day 8. Conjunctival hyperaemia was already absent at day 4 in 85,75% in levofloxacin/dexamethasone treatment arm vs. 82,19% in tobramycin + dexamethasone arm, respectively. The safety profile was similar in both groups.
The ocular instillation of levofloxacin/dexamethasone results in absorption of both active ingredients to the ocular tissues and, at a much lower extent, to the systemic circulation. After instillation to rabbit eyes, the plasma concentrations of levofloxacin increase with the dose after both single and repeated administration. Low levels of dexamethasone sodium phosphate are measured in plasma. In fact, dexamethasone sodium phosphate is rapidly metabolised in vivo to dexamethasone, which is the active metabolite. Dexamethasone exposure increases with the dose and after repeated doses a minor accumulation of both levofloxacin and dexamethasone is evident.
Both levofloxacin and dexamethasone levels in ocular tissues (aqueous humour, cornea and conjunctiva) result to be higher than the maximum plasma levels after single and repeated doses. In particular, after 28-day treatment levofloxacin and dexamethasone levels in ocular tissues are 50 to 100-fold and 3 to 4-fold higher than the Cmax in plasma, respectively.
One-hundred-twenty-five patients undergoing cataract surgery have been randomized to 3 groups: levofloxacin, dexamethasone and levofloxacin/dexamethasone. One drop of each medicine was administered 60 and 90 minutes before limbal paracentesis. The mean of the observed values for the concentration of levofloxacin was equal to 711,899 ng/mL (95% CI: 595.538; 828.260) in the levofloxacin/dexamethasone group compared to 777,307 ng/mL (95% CI: 617.220; 937.394) when levofloxacin was administered alone. The concentrations of levofloxacin in the aqueous humour are well above the minimum inhibitory concentrations for the ocular pathogens in levofloxacin’s spectrum of activity. When levofloxacin/dexamethasone was administered dexamethasone reached an aqueous humour concentration of 11,774 ng/mL (95% CI: 9,812; 13,736) compared to 16,483 ng/mL (95% CI: 13,736; 18,838) when dexamethasone was administered alone.
Both levofloxacin and dexamethasone are eliminated via urine.
Preclinical effects were observed only at exposures considerably in excess of the maximum human exposure after instillation of levofloxacin/dexamethasone, indicating little relevance to clinical use. Gyrase inhibitors have been shown to cause growth disorders of weight bearing joints in animal studies. In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs after high oral doses.
Levofloxacin is not teratogenic in animal studies. Dexamethasone after topical and systemic administration caused the formation of cleft palate, delayed foetal growth and foetal mortality at the same dose levels. Peri- and postnatal toxicity of dexamethasone was also observed.
Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have phototoxic activity only at very high doses.
Dexamethasone doesn’t show any potential phototoxicity.
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