Phase three clinical trials Ofloxin
ADVERSE REACTIONS
The following is a compilation of the data for ofloxacin based on
clinical experience with both the oral and intravenous formulations.
The incidence of drug-related adverse reactions in patients during
Phase 2 and 3 clinical trials was 11%. Among patients receiving
multiple-dose therapy, 4% discontinued ofloxacin due to adverse
experiences. In clinical trials, the following events were considered
likely to be drug-related in patients receiving multiple doses of
ofloxacin:
nausea 3%, insomnia 3%, headache 1%, dizziness 1%, diarrhea 1%,
vomiting 1%, rash 1%, pruritus 1%, external genital pruritus in women
1%, vaginitis 1%, dysgeusia 1%.
In clinical trials, the most frequently reported adverse events,
regardless of relationship to drug, were:
nausea 10%, headache 9%, insomnia 7%, external genital pruritus in
women 6%, dizziness 5%, vaginitis 5%, diarrhea 4%, vomiting 4%.
In clinical trials, the following events, regardless of
relationship to drug, occurred in 1 to 3% of patients:
Abdominal pain and cramps, chest pain, decreased appetite, dry mouth,
dysgeusia, fatigue, flatulence, gastrointestinal
distress, nervousness, pharyngitis, pruritus, fever, rash, sleep
disorders, somnolence, trunk pain, vaginal discharge, visual
disturbances, and constipation.
Additional events, occurring in clinical trials at a rate of less than
1%, regardless of relationship to drug, were:
Body as a whole: asthenia, chills, malaise, extremity pain, pain,
epistaxis
Cardiovascular System: cardiac arrest, edema, hypertension,
hypotension, palpitations, vasodilation
Gastrointestinal System: dyspepsia
Genital/Reproductive
System: burning, irritation, pain and rash of the female genitalia;
dysmenorrhea; menorrhagia;
metrorrhagia
Musculoskeletal System: arthralgia, myalgia
Nervous System: seizures, anxiety, cognitive change, depression, dream
abnormality, euphoria,
hallucinations, paresthesia, syncope, vertigo, tremor, confusion
Nutritional/Metabolic: thirst, weight loss
Respiratory System: respiratory arrest, cough, rhinorrhea
Skin/Hypersensitivity: angioedema, diaphoresis, urticaria, vasculitis
Special Senses: decreased hearing acuity, tinnitus, photophobia
Urinary System: dysuria, urinary frequency, urinary retention
The following laboratory abnormalities appeared in =1.0% of patients
receiving multiple doses of ofloxacin. It is not known
whether these abnormalities were caused by the drug or the underlying
conditions being treated.
Hematopoietic: anemia, leukopenia, leukocytosis, neutropenia,
neutrophilia, increased band forms, lympho-cytopenia,
eosinophilia, lymphocytosis, thrombocytopenia, thrombocytosis,
elevated ESR
Hepatic: elevated: alkaline phosphatase, AST (SGOT), ALT (SGPT)
Serum chemistry: hyperglycemia, hypoglycemia, elevated creatinine,
elevated BUN
Urinary: glucosuria, proteinuria, alkalinuria, hyposthenuria,
hematuria, pyuria
Post-Marketing Adverse Events:
Additional adverse events, regardless of relationship to drug,
reported from worldwide marketing experience with quinolones,
including ofloxacin:
Clinical:
Cardiovascular System: cerebral thrombosis, pulmonary edema,
tachycardia, hypotension/shock, syncope
Endocrine/Metabolic: hyper- or hypoglycemia, especially in diabetic
patients on insulin or oral hypoglycemic agents
Gastrointestinal System: hepatic dysfunction including: hepatic
necrosis, jaundice (cholestatic or hepatocellular), hepatitis;
intestinal perforation; pseudomembranous colitis (the onset of
pseudomembranous colitis symptoms may occur during or after
antimicrobial treatment),
GI hemorrhage; hiccough, painful oral mucosa, pyrosis
Genital/Reproductive System: vaginal candidiasis
Hematopoietic: anemia, including hemolytic and aplastic; hemorrhage,
pancytopenia, agranulocytosis,
leukopenia, reversible bone marrow depression, thrombocytopenia,
thrombotic thrombo-cytopenic
purpura, petechiae, ecchymosis/bruising
Musculoskeletal: tendinitis/rupture; weakness; rhabdomyolysis
Nervous System: nightmares; suicidal thoughts or acts, disorientation,
psychotic reactions, paranoia;
phobia, agitation, restlessness, aggressiveness/hostility, manic
reaction, emotional lability; peripheral neuropathy, ataxia,
incoordination; possible exacerbation of:myasthenia gravis and
extrapyramidal disorders; dysphasia, lightheadedness
Respiratory System: dyspnea, bronchospasm, allergic pneumonitis,
stridor (See WARNINGS.)
Skin/Hypersensitivity: anaphylactic (-toid) reactions/shock; purpura,
serum sickness, erythema
multiforme/Stevens-Johnson Syndrome, erythema nodosum, exfoliative
dermatitis,
hyperpigmentation, toxic epidermal necrolysis, conjunctivitis,
photosensitivity,
vesiculobullous eruption
Special Senses: diplopia, nystagmus, blurred vision, disturbances of:
taste, smell, hearing and equilibrium, usually reversible following
discontinuation
Urinary System: anuria, polyuria, renal calculi, renal failure,
interstitial nephritis, hematuria
One patient with resistance to Ofloxacin alone (regimen O3) had a
favourable response at the
end of treatment, but died in the nineteenth month of follow-up for
reasons unrelated to tuberculosis.
Intention-to-treat Analysis The Intention-to-treat analysis was done
for 469 patients (416 in efficacy analysis plus 53 patients who either
received less than 75% of the prescribed treatment (48) or
missed more than one month of treatment continuously (5). Of these 469
patients
(404 with drug susceptible tuberculosis, 56 with initial Adverse
reactions attributable to anti-tuberculosis drugs occurred in 31 %
(regimen O2-2)-44% (regimen O3-2) of the 512 patients who were
eligible for admission to the study (Table 5). This analysis, thus,
includes patients who were excluded from the efficacy analysis.
Modification of the treatment regimen was required in only 24 (5%) of
all the patients. Arthralgia was reported by 25% to 36% of patients in
the four regimens, but only four patients required a change in the
regimen: temporary withholding of Pyrazinamide in three patients, and
a reduction of the dose in one. Patients who received 2 months of
Pyrazinamide were less likely to develop arthralgia (25%) compared
with patients who received 3 months of Pyrazinamide (36%) though this
difference was not statistically significant (P=0.08).
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