Mass Tort Update- |
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Mass Tort Update
Side Effects
In Phase III clinical trials, 4,780 patients (n=2702 in controlled trials) received daily oral doses of KETEK 800 mg once daily for 5 days or 7 to 10 days. Most adverse events were mild to moderate in severity. In the combined Phase III studies, discontinuation due to treatment-emergent adverse events occurred in 4.4% of KETEK-treated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the KETEK group were due to treatment-emergent adverse events in the gastrointestinal body system, primarily diarrhea (0.9% for KETEK vs. 0.7% for comparators), nausea (0.7% for KETEK vs. 0.5% for comparators).
All and possibly related treatment-emergent adverse events (TEAEs) occurring in controlled clinical studies in ≥2.0% of all patients are included below:
Table 5: All and Possibly Related Treatment-Emergent Adverse Events Reported in Controlled Phase III Clinical Studies (Percent Incidence)
| Adverse Event* | All TEAEs | Possibly-Related TEAEs | ||
| KETEK n= 2702 |
Comparator† n= 2139 |
KETEK n= 2702 |
Comparator† n= 2139 |
|
| Diarrhea | 10.8% | 8.6% | 10.0% | 8.0% |
| Nausea | 7.9% | 4.6% | 7.0% | 4.1% |
| Headache | 5.5% | 5.8% | 2.0% | 2.5% |
| Dizziness (excl. vertigo) | 3.7% | 2.7% | 2.8% | 1.5% |
| Vomiting | 2.9% | 2.2% | 2.4% | 1.4% |
| Loose Stools | 2.3% | 1.5% | 2.1% | 1.4% |
| Dysgeusia | 1.6% | 3.6% | 1.5% | 3.6% |
| *Based on a frequency of all and possibly related treatment-emergent adverse events of 2% in KETEK or comparator groups. † Includes comparators from all controlled Phase III studies. |
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The following events judged by investigators to be at least possibly drug related were observed infrequently (≥0.2% and < 2%), in KETEK-treated patients in the controlled Phase III studies.
Gastrointestinal system: abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis, watery stools.
Liver and biliary system: abnormal liver function tests: increased transaminases, increased liver enzymes (e.g., ALT, AST) were usually asymptomatic and reversible. ALT elevations above 3 times the upper limit of normal were observed in 1.6%, and 1.7% of patients treated with KETEK and comparators, respectively. Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK, and was reversible.
Nervous system: dry mouth, somnolence, insomnia, vertigo, increased sweating
Body as a whole: abdominal pain, upper abdominal pain, fatigue
Special senses: Visual adverse events most often included blurred vision, diplopia, or difficulty focusing. Most events were mild to moderate; however, severe cases have been reported. Some patients discontinued therapy due to these adverse events. Visual adverse events were reported as having occurred after any dose during treatment, but most visual adverse events (65%) occurred following the first or second dose. Visual events lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some resolved on therapy while others continued to have symptoms until they completed the full course of treatment.
Females and patients under 40 years old experienced a higher incidence of telithromycin-associated visual adverse events.
Urogenital system: vaginal candidiasis, vaginitis, vaginosis fungal
Skin: rash
Hematologic: increased platelet count
Other possibly related clinically-relevant events occurring in <0.2% of patients treated with KETEK from the controlled Phase III studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria.
Post-Marketing Adverse Event Reports
In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with KETEK.
Allergic: face edema, rare reports of severe allergic reactions, including angioedema and anaphylaxis.
Cardiovascular: atrial arrhythmias, palpitations
Gastrointestinal system: pancreatitis
Liver and biliary system: Hepatic dysfunction has been reported.
Severe and in some cases fatal hepatotoxicity, including fulminant hepatitis, hepatic necrosis and hepatic failure have been reported in patients treated with KETEK. These hepatic reactions were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of only a few doses of KETEK. Severe reactions, in some but not all cases, have been associated with serious underlying diseases or concomitant medications.
Data from post-marketing reports and clinical trials show that most cases of hepatic dysfunction were mild to moderate.
Musculoskeletal: muscle cramps, rare reports of exacerbation of myasthenia gravis.
Nervous system: loss of consciousness, in some cases associated with vagal syndrome.
Drug Interactions
Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system. Co-administration of KETEK tablets and a drug primarily metabolized by the cytochrome P450 3A4 enzyme system may result in increased plasma concentration of the drug co-administered with telithromycin that could increase or prolong both the therapeutic and adverse effects. Therefore, appropriate dosage adjustments may be necessary for the drug co-administered with telithromycin.
The use of KETEK is contraindicated with cisapride.
The use of KETEK is contraindicated with pimozide. Although there are no studies looking at the interaction between KETEK and pimozide, there is a potential risk of increased pimozide plasma levels by inhibition of CYP 3A4 pathways by KETEK as with macrolides.
In a pharmacokinetic study, simvastatin levels were increased due to CYP 3A4 inhibition by telithromycin. Similarly, an interaction may occur with lovastatin or atorvastatin, but not with pravastatin or fluvastatin. High levels of HMG-CoA reductase inhibitors increase the risk of myopathy. Use of simvastatin, lovastatin, or atorvastatin concomitantly with KETEK should be avoided. If KETEK is prescribed, therapy with simvastatin, lovastatin, or atorvastatin should be suspended during the course of treatment.
Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and KETEK.
Patients should be monitored with concomitant administration of midazolam and dosage adjustment of midazolam should be considered if necessary. Precaution should be used with other benzodiazepines, which are metabolized by CYP 3A4 and undergo a high first-pass effect.
Concomitant treatment of KETEK with rifampin, a CYP 3A4 inducer, should be avoided. Concomitant administration of other CYP 3A4 inducers such as phenytoin, carbamazepine, or phenobarbital is likely to result in subtherapeutic levels of telithromycin and loss of effect.
In patients treated with metoprolol for heart failure, the increased exposure to metoprolol, a CYP 2D6 substrate, may be of clinical importance. Therefore, co-administration of KETEK and metoprolol in patients with heart failure should be considered with caution.
Spontaneous post-marketing reports suggest that administration of KETEK and oral anticoagulants concomitantly may potentiate the effects of the oral anticoagulants. Consideration should be given to monitoring prothrombin times/INR while patients are receiving KETEK and oral anticoagulants simultaneously.
No specific drug interaction studies have been performed to evaluate the following potential drug-drug interactions with KETEK. However, these drug interactions have been observed with macrolide products. Drugs metabolized by the cytochrome P450 system such as carbamazepine, cyclosporine, tacrolimus, sirolimus, hexobarbital, and phenytoin: elevation of serum levels of these drugs may be observed when co-administered with telithromycin. As a result, increases or prolongation of the therapeutic and/or adverse effects of the concomitant drug may be observed. Ergot alkaloid derivatives (such as ergotamine or dihydroergotamine): acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia has been reported when macrolide antibiotics were co-administered. Without further data, the co-administration of KETEK and these drugs is not recommended.
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