Ranexa is contraindicated in patients with pre-existing QT prolongation; with hepatic impairment (mild, moderate, or severe); on QT- prolonging drugs; on potent and moderately potent CYP3A inhibitors, including diltiazem.

Identifying and Managing Electrocardiographic Effects

Use of Ranexa

• Because Ranexa prolongs the QT interval, it should be reserved for patients who have not achieved an adequate response with other antianginal drugs.

Electrocardiographic effects of Ranexa

• Dose and plasma concentration-related increases in the QTc interval, reductions in T wave amplitude and, in some cases, notched T waves, have been observed in patients treated with Ranexa
• The variable blood levels after a given dose of Ranexa give a wide range of effects on QTc
• A mean effect of 6 msec on QTc was observed at the highest recommended dose of Ranexa
• 5% of patients experienced QTc changes of at least 15 msec
• QT changes were not related to age, weight, gender, race, heart rate, CHF class, and diabetes
• While the clinical significance of the QTc prolongation in the case of Ranexa is unknown, other drugs with this potential have been associated with torsades de pointes–type arrhythmias and sudden death

Ranexa should be avoided in the following patients:

• With known QT prolongation including long QT syndrome, uncorrected hypokalemia, or known history of ventricular tachycardia
• On QT-prolonging drugs, including Class Ia (eg, quinidine) and III (eg, dofetilide, sotalol) antiarrhythmics and certain antipsychotics (eg, thioridazine, ziprasidone)
• On potent and moderately potent CYP3A inhibitors, including diltiazem
• On inducers of CYP3A and P-gp, including rifampin
• With hepatic impairment (Child-Pugh Classes A [mild], B [moderate], or C [severe]) because of observed increase in the QTc effect

Baseline and follow-up ECGs should be obtained to evaluate effects on
QT interval

Doses >1000 mg b.i.d. should not be used

Tolerability at Recommended Doses

In CARISA and ERICA, the incidence of dizziness with Ranexa 1000 mg b.i.d. was 6% (vs 2% placebo), while the incidence of syncope was 0.7% (vs 0% placebo)

• Small, reversible elevations of serum creatinine and BUN levels
• The general nature and frequency of treatment-emergent adverse events
  in patients with CHF, diabetes, and reactive airway disease were similar
  to those in the broader population treated with Ranexa

Discontinuations

• Discontinuations due to adverse events were about 6% with Ranexa
  vs about 3% with placebo

Use in older patients

• Of the patients with chronic angina treated with Ranexa in controlled studies, 496 (48%) were ≥ 65 years of age and 114 (11%) were ≥75 years of age
• No overall differences in efficacy were observed between older and younger patients
• A higher incidence of placebo-subtracted adverse events (23%) and discontinuations (11%) were observed in patients ≥75 years of age on Ranexa
• There were no differences in safety for patients ≥ 65 years compared to younger patients
• In general, dose selection for an elderly patient should be cautious

A published study reported that Ranexa promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily. The clinical significance of this finding is unclear.