Acuatim

TOPICAL QUINOLONE ANTIBACTERIAL AGENT
ACUATIM® Cream
Nadifloxacin

DESCRIPTION
ACUATIM Cream is a white and odorless cream.

COMPOSITION
Each gram of cream contains 10 mg of nadifloxacin.

INDICATION
ACUATIM Cream is indicated for topical treatment of severe acne vulgaris (papulopustular acne)

DOSAGE AND ADMINISTRATION
ACUATIM Cream should be applied to the lesions twice daily, and in the case of acne vulgaris the drug should be applied after cleansing the skin.

PRECAUTIONS
As a role, susceptibility testing should be performed prior to actual use of this drug to estimate nadifloxacin susceptibility. To minimize the chance that resistant microorganisms will develop as a result of therapy, the treatment duration should be the shortest feasible.

PHARMACOLOGY

1. Antibacterial Spectrum; In vitro antibacterial activity of nadifloxacin showed a potent and broad spectrum against aerobic Gram-positive, Gram-negative and anaerobic bacteria, including Propionibacterium acnes and Staphylococcus epidermidis. The drug activity is bactericidal. Nadifloxacin showed potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) that was similar to the potency against methicillin-sensitive Staphylococcus aureus (MSSA). The drug was also active against new quinolone-resistant MRSA. Nadifloxacin was not cross-resistant with other new quinolones.
2. In VIVO Antibacterial Activity; The in vivo therapeutic effect of ACUATIM Cream was superior to the cream base alone in experimental models of infections in mice which were subcutaneously infected with P. acnes and S. epidermidis.
3. Antibacterial Effects; Results of follicular analysis obtained in clinical studies using acne patients indicated that ACUATIM Cream significantly decreased the counts of P. acnes and other microorganisms in the follicles, as compared to the control (cream base) treatment. Microbacterial tests were negative for Staphylococcus aureus, CNS, P. acnes and other microorganisms in 86.4% of the patients with folliculitis or sycosis vulgaris after the application of ACUATIM Cream. The minimum inhibitory concentrations (MlC) of nadifloxacin against 394 clinical isolates of P. acnes, 76 of Staphylococcus epidermidis, 45 of CNS and 24 of Staphylococcus aureus were not higher than 0.78, 0.39, 0.05 and 0.39/μg/mL, respectively, evidencing its potent antibacterial activity. In addition, no resistance to nadifloxacin developed.
4. Mechanism of Action; Nadifloxacin showed an inhibitory effect on bacterial DNA gyrase activity (involved in DNA synthesis and replication), i.e., converting relaxed DNA to supercoiled DNA.
5. Development of Resistance; The development of resistance after serial passage of nadifloxacin was rare as compared with that of other new quinolone antibacterial agents. The frequency of spontaneous mutants resistant to nadifloxacin was less than 10^-8.

PHARMACOKINETICS
Following a single topical application of nadifloxacin 1 % cream at 10 g to normal human back skin, the highest plasma concentration was determined to be 1.7 ng/ml with an elimination half-life of 19.4 hours. Approximately 0.09% of the administered dose was excreted in the urine over 48 hours post-dosing. The plasma concentration reached a steady state on Day 5 of the repeated administration study when nadifloxacin 1 % cream was administered at 5 g twice daily to normal healthy individuals for a period of 7 days. The plasma concentration reached a peak of 4.1 ng/ml at 8 hours post-final dosing with an elimination half-life of 23.2 hours. The urinary excretion rate reached 0.16% on Day 7.

CLINICAL STUDIES
Clinical Efficacy
Nadifloxacin was studied in a total of 519 acne patients using both the open and double-blind test methods. The drug was applied to the face twice (morning and evening) daily after washing for 4 weeks. Efficacy (effective or markedly effective) was obtained in 67.1% (348/519) of the subjects. A double-blind study in acne patients with multiple inflamed lesions demonstrated that 81.3% (39/48) of the treated patients showed a decrease in the lesion count and improvement of inflammation.

PRECAUTIONS

1. General Precaution; Antibacterial agent should be reserved for treatment of acne vulgaris with secondary bacterial infections
2. Important Precautions; ACUATIM Cream should be discontinued if the desired therapeutic effect is not achieved at the recommended dose within 4 weeks for the treatment of acne vulgaris. ACUATIM Cream should not be continued in acne patients after inflamed lesions disappear.
3. Use during Pregnancy, Delivery, or Lactation; The safety of this drug for use during pregnancy has not been established. (Clinical experience in pregnant women is insufficient.)
4. Pediatric Use; The safety of this drug in premature babies, newborns, and infants has not been established. (Clinical experience in those subjects is insufficient.)
5. Precautions Concerning Use; Route and method of administration; This drug is intended for topical (dermal) application only and is not intended for ophthalmological use. The product should not be applied to the cornea or conjunctiva.
6. Other
   • Photosensitivity has been reported in patients taking orally synthetic quinolone antibacterial agents.
   • No evidence of nadifloxacin-induced mutagenesis was seen in a reverse mutation assay with bacterial systems and gene mutation and chromosomal aberration assays with cultured Chinese hamster cells. A chromosome aberration assay was positive with cultured human peripheral blood lymphocytes, but an in vivo micronucleus assay was negative in mice. S(-)-Nadifloxacin was positive in both chromosomal aberration and micronucleus assays. Other new quinolones have been reported to be clastogenic.

CONTRA INDICATIONS
Hypersensitive to this drug

ADVERSE REACTIONS
Adverse reactions were reported in 60 of total 4,174 patients (1.44%) treated with ACUATIM cream. (Figures are total cases reported from the time of approval until completion of reexamination)

Body system / frequency	‹ 1 %
Skin	Pruritus, irritation, redness, flushing, feeling of facial warmth, papules, contact dermatitis, dry skin, and hot flushes

PHYSICOCHEMISTRY 
Nonproprietary name
Nadifloxacin (JAN)

Chemical name
(±)-9-Fluoro-6, 7 -dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo- lH,5H-benzo[ij] quinolizine-2-carboxylic acid

Molecular formula
C₁₉H_2lFN₂O₄

Molecular weight
360.39

STORAGE
Store at temperature 25° C, protecting from light during transfer to different containers.

PACKAGING
ACUATIM Cream, 10 g in tube
REG. NO: DKI 0356100929Al

HARUS DENGAN RESEP DOKTER

Manufactured by:
Otsuka Pharmaceutical Co., ltd.
2-9 Kanda Tsukasa-cho, Chiyoda-ku, Tokyo, Japan

Imported by:
PT. Otsuka Indonesia
Jl. Sumber Waras No. 25
Lawang, Malang 65216, Indonesia

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