May 27, 2016
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Ketek




Side Effects
Interactions

SIDE EFFECTS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In Phase 3 clinical trials, 4,780 patients (n=2702 in controlled trials) received oral dosages of KETEK 800 mg once daily for 5 days or 7 to 10 days. Note that treatment with KETEK for 5 days duration is not a recommended dosage regimen. [see DOSAGE AND ADMINISTRATION]

In the combined Phase 3 studies, discontinuation due to adverse reactions occurred in 4.4% of KETEKtreated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the KETEK group were due to adverse reactions in the gastrointestinal body system, primarily diarrhea (0.9% for KETEK vs. 0.7% for comparators), and nausea (0.7% for KETEK vs. 0.5% for comparators).

Adverse reactions (ARs) occurring in clinical studies in 2% or more of KETEK patients are included below.

Table 1: Adverse Reactions Reported in 2% or more of Patients in Controlled Phase 3 Clinical Studies

Adverse Reaction * Percent Incidence
KETEK
n= 2702
Comparator†
n= 2139
Diarrhea 10% 8%
Nausea 7% 4.1%
Dizziness (excl. vertigo) 2.8% 1.5%
Vomiting 2.4% 1.4%
*Based on a frequency of all and possibly related adverse reactions of 2% or more in KETEK or comparator groups.
†Includes comparators from all controlled Phase 3 studies.

Less Common Adverse Reactions

Frequency Of 0.2% Or More And Less Than 2%

The following adverse reactions were observed at a frequency of 0.2% or more and less than 2% in KETEK-treated patients in clinical studies.

Gastrointestinal system: abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis.

Liver and biliary system: abnormal liver function tests: increased transaminases (i.e., ALT, AST). Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK. [see WARNINGS AND PRECAUTIONS]

Nervous system: dry mouth, somnolence, insomnia, vertigo, increased sweating

Body as a whole: abdominal pain, fatigue

Special senses: Visual adverse reactions, some of them severe, most often included blurred vision, diplopia, or difficulty focusing. Some patients discontinued therapy due to these adverse reactions. Visual adverse reactions were reported as having occurred after any dose during treatment, but most (65%) occurred following the first or second dose. Visual adverse reactions lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some visual adverse reactions resolved on therapy while others persisted through the full course of treatment. [see WARNINGS AND PRECAUTIONS]

Females and patients under 40 years old experienced a higher incidence of KETEK-associated visual adverse reactions. Table 2 provides the incidence of all visual adverse reactions in controlled Phase 3 studies by age and gender. The group with the highest incidence was females under the age of 40, while males over the age of 40 had rates of visual adverse reactions similar to comparator-treated patients.

Table 2: Incidence of All Visual Adverse Reactions in Controlled Phase 3 Studies

Gender/Age Telithromycin Comparators*
Female 40 and under 2.1% (14/682) 0.0% (0/534)
Female greater than 40 1.0% (7/703) 0.35% (2/574)
Male 40 and under 1.2% (7/563) 0.48% (2/417)
Male greater than 40 0.27% (2/754) 0.33% (2/614)
Total 1.1% (30/2702) 0.28% (6/2139)
*Includes all comparators combined

Urogenital system: vaginal candidiasis, vaginitis, vaginosis fungal

Skin: rash

Hematologic: increased platelet count

Frequency of Less Than 0.2%

Other clinically-significant adverse reactions occurring in less than 0.2% of patients treated with KETEK from the controlled Phase 3 studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of KETEK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic: face edema, severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis

Cardiovascular: atrial arrhythmias, ventricular arrhythmias (including ventricular tachycardia and torsades de pointes) with potential fatal outcome, palpitation, ischemic cardiac events in the context of hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]

Gastrointestinal system: pseudomembranous colitis, pancreatitis [see WARNINGS AND PRECAUTIONS]

Liver and biliary system: Hepatic dysfunction, fulminant hepatitis, hepatic necrosis, and hepatic failure, chromaturia [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS]

Musculoskeletal: muscle cramps, arthralgia, myalgia, exacerbation of myasthenia gravis [see CONTRAINDICATIONS]

Nervous system: loss of consciousness, in some cases associated with vagal syndrome, tremor, convulsions

Psychiatric disorders: confusion, hallucinations (mostly visual)

Special senses: taste/smell perversion and/or loss, hearing loss

Respiratory, thoracic and mediastinal disorders: dyspnea

Read the Ketek (telithromycin) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Telithromycin is a strong inhibitor of CYP3A4 and also a CYP3A4 substrate. Co-administration of KETEK and drugs that induce or inhibit the cytochrome P450 3A4 enzyme system may affect KETEK plasma concentrations resulting in diminished efficacy or an increase or prolongation of both the therapeutic and adverse effects; therefore, appropriate dosage adjustments may be necessary for drugs co-administered with telithromycin.

Studies were performed to evaluate the effect of CYP3A4 inhibitors on telithromycin and the effect of telithromycin on drugs that are substrates of CYP3A4 and CYP2D6. In addition, drug interaction studies were conducted with several other concomitantly prescribed drugs. Table 3 summarizes both drugs with pharmacokinetics that are affected by KETEK as well as drugs that affect the pharmacokinetics of KETEK.

Table 3: Clinically Significant Drug Interactions with KETEK USE IN SPECIFIC POPULATIONS

Drugs That Are Affected By KETEK
Drug(s) with Pharmacokinetics Affected by KETEK (Mechanism of interaction, if known) Recommendation (Exposure) Comments
Cisapride (CYP3A4 Substrate) Contraindicated (Plasma exposure increased) Co-administration of cisapride with repeated doses of KETEK resulted in significant increases in QTc. [see CONTRAINDICATIONS]
Pimozide (CYP3A4 Substrate) Contraindicated (Plasma exposure likely to be increased) Although there are no studies looking at the interaction between KETEK and pimozide, there is a potential risk of life-threatening QT prolongation. [see CONTRAINDICATIONS]
Colchicine (CYP3A4 and P-glycoprotein efflux transporter Substrate) Contraindicated in patients with renal or hepatic impairment. (Plasma exposure increased) Risk of life-threatening colchicine toxicity. If coadministration of KETEK and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor for symptoms of colchicine toxicity. [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS]
Simvastatin, Lovastatin, and Atorvastatin (HMG-CoA Reductase Inhibitors metabolized by CYP3A4) (CYP3A4 Substrate) Avoid Use (Plasma exposure increased) High levels of HMG-CoA reductase inhibitors increase the risk of myopathy and rhabdomyolysis. Avoid concomitant use of simvastatin, lovastatin, or atorvastatin with KETEK. If KETEK is prescribed, suspend therapy with simvastatin, lovastatin, or atorvastatin during the course of KETEK. An interaction may occur with simvastatin, lovastatin or atorvastatin but not with statins which are not metabolized by CYP3A4. [see WARNINGS AND PRECAUTIONS]
Ergot Alkaloids Not Recommended (Plasma exposure likely to be increased) No specific drug interaction studies have been performed. However, acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia has been reported when macrolide antibiotics were co-administered with ergot alkaloid derivatives (such as ergotamine or dihydroergotamine). Without further data, the coadministration of KETEK and these drugs is not recommended.
Calcium Channel Blockers (CYP3A4 Substrate) Use with Caution (Plasma exposure increased) Hypotension, bradyarrhythmia, and loss of consciousness have been observed in patients receiving concomitant treatment with calcium channel blockers that are substrates of CYP3A4 (e.g., verapamil, amlodipine, diltiazem). Monitor for these adverse reactions and toxicity related to calcium channel blockers and adjust calcium channel blocker dosage as necessary.
Midazolam (CYP3A4 Substrate) Use with Caution (Plasma exposure likely to be increased) Monitor for benzodiazepine-related adverse reactions and adjust midazolam dosage if necessary. Use caution with other benzodiazepines, which are metabolized by CYP3A4 and undergo a high first-pass effect (e.g., triazolam).
Other drugs metabolized by CYP3A4, such as carbamazepine, cyclosporine, tacrolimus, sirolimus, hexobarbital, and phenytoin (CYP3A4 Substrates) Use with Caution (Plasma exposure likely to be increased) No specific drug interaction studies have been performed to evaluate these drug-drug interactions with KETEK. However, increases or prolongation of the therapeutic and/or adverse effects of drugs metabolized by the cytochrome P450 system may be observed if administered with KETEK.
Metoprolol (CYP2D6 Substrate) Use with Caution (Plasma exposure increased) Co-administration of KETEK and metoprolol in patients with heart failure could lead to metoprolol toxicity and should be considered with caution. Monitor for metoprolol toxicity and adjust metoprolol dosage.
Digoxin Use with Caution (Plasma exposure increased) Monitor for digoxin side effects or serum levels during concomitant administration of digoxin and KETEK.
Theophylline Use with Caution (Plasma exposure minimally increased) Co-administration of theophylline may worsen gastrointestinal effects such as nausea and vomiting, especially in female patients. Administer theophylline and KETEK 1 hour apart to decrease the likelihood of gastrointestinal side effects.
Oral Anticoagulants Use with Caution (Plasma exposure increased) Spontaneous post-marketing reports suggest that administration of KETEK and oral anticoagulants concomitantly may potentiate the effects of the oral anticoagulants. Consider monitoring prothrombin times/INR while patients are receiving KETEK and oral anticoagulants simultaneously.
Drugs that Affect KETEK
Drug(s) that Affect the Pharmacokinetics of KETEK Recommendation Comments
Rifampin (CYP3A4 Inducer) Avoid Concomitant Use (Reduced KETEK exposure) Loss of KETEK effect is likely [see CLINICAL PHARMACOLOGY]
Other CYP3A4 inducers (phenytoin, carbamazepine, or phenobarbital) Avoid Concomitant Use (Reduced KETEK exposure) Loss of KETEK effect is likely [see CLINICAL PHARMACOLOGY]
Itraconazole and Ketoconazole Avoid Concomitant Use (Increased KETEK exposure) Increased KETEK toxicity is likely [see CLINICAL PHARMACOLOGY]

Read the Ketek Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 5/19/2016

Side Effects
Interactions

Ketek - User Reviews

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