The original NDA for this drug was submitted on December 15, 1999. In the original NDA submission the Applicant sought claims for the treatment of adults for three indications in the respiratory tract (community-acquired pneumonia (CAP), acute bacterial exacerbation of chronic bronchitis (ABECB), acute bacterial sinusitis (ABS)) and two indications in the urinary tract (uncomplicated urinary tract infection (uUTI) and complicated urinary tract infection (cUTI)). While the efficacy of gemifloxacin, in general, in 4 of the originally proposed five indications (CAP, ABS, ABECB, uUTI) was found to be non-inferior to the comparator regimens, during the course of the NDA review significant questions arose regarding the safety of gemifloxacin. These questions centered around the higher than expected rate of rash reported in patients receiving gemifloxacin and related questions regarding the mechanism of the observed rash, the potential for cross-sensitization, and the possibility that the frequent occurrence of rash may portend a risk for more serious infrequent cutaneous drug reactions. In addition, there were also unresolved questions regarding the hepatic safety profile of gemifloxacin.

During the review of the initial submission of NDA 21-158 for gemifloxacin a higher than expected rate of rash was noted in the clinical studies. The rates of rash ranged from less than 1% to higher than 25% depending upon the population or subset of the population being analyzed. Analyses of the rash data have shown that female gender, age (younger adults), and longer duration of therapy are associated with an increased rate of rash.

In addition to gemifloxacin-associated rash, there have also been questions regarding the hepatic safety of gemifloxacin. In preclinical studies in dogs, gemifloxacin was associated with cholangitis and pericholangitis associated with hepatocellular degeneration and single cell necrosis. Also noted was crystalline material that had deposited in the bile ducts and bile canaliculi. Spectroscopic analysis found the deposited material to be gemifloxacin or gemifloxacin-derived material. In studies in women who received a single dose of 640 mg (twice the proposed dose of 320 mg) there was a greater proportion of patients that developed elevations of AST and ALT at the On-therapy visit compared to women receiving a ciprofloxacin comparator.

Gemifloxacin, similar to some of the other members of the quinolone class, appears to have the capacity to effect cardiac repolarization.

In the clinical studies combined population, 44.7% of patients treated with gemifloxacin reported having at least one adverse event.

In the combined population of clinical studies there were 33 deaths in the gemifloxacin treated population:

Cardiac Arrest (5)
Respiratory Insufficiency (5)
Cardiac Failure (3)
Sudden Death (3)
COPD (2)
MI (2)
Pneumonia (2)
Lung Cancer (2)
Pulmonary Edema (2)
Acute Renal Failure (2)
Dyspnea (1)

Rash, increase in hepatic enzymes, pyelonephritis, sudden death, and injury are noteworthy SAE's which occurred more frequently in the gemifloxacin population than in the all comparators group.

Patients with at least one SAE 247
Pneumonia 21
Chronic Obstructive Airways Disease 14
Bronchitis 13
Dyspnea 13
Pulmonary Carcinoma 13
Respiratory Insufficiency 12
Injury 10
Therapeutic Response Increased 10
Respiratory Disorder 8
Cardiac Arrest 6
Cardiac Failure 6
Chest Pain 6
Pleural Effusions 5
Pyelonephritis 5
Rash* 6
Fever 4
GI Hemmorrhage 4
Myocardial Infarction 4
Neoplasm NOS 4
Pleurisy 4
Renal Failure Acute 4
Angina Pectoris 3
Cerebrovascular Disorder 3
Coughing 3
Dehydration 3
Atrial Fibrillation 3
Hepatic Enzymes Increased 3
Sudden Death 3
Suicide Attempt 3
Vomiting 3
Asthma 2
Abdominal Pain 1
Abscess 1
Angina Pectoris Aggravated 1
Embolism Pulmonary 1
Hemoptysis 1
Infection TBC 1
Myelomatosis Multiple 1
Sepsis 1
Diarrhea 0
One patient did experience a serum sickness like reaction.

The FDA has recently approved this drug in spite of the safety issues raised above.