2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

Initiate ranolazine extended-release tablets dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take ranolazine extended-release tablets with or without meals. Swallow ranolazine extended-release tablets whole; do not crush, break, or chew.

The maximum recommended daily dose of ranolazine extended-release tablets is 1000 mg twice daily.

If a dose of ranolazine extended-release tablets is missed, take the prescribed dose at the next scheduled time; do not double the next dose.

2.2 Dose Modification

Dose adjustments may be needed when ranolazine extended-release tablets are taken in combination with certain other drugs [see Drug Interactions (7.1)]. Limit the maximum dose of ranolazine extended-release tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of ranolazine extended-release tablets with strong CYP3A inhibitors is contraindicated [see Contraindications (4), Drug Interactions (7.1)]. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to ranolazine extended-release tablets. Titrate ranolazine extended-release tablets based on clinical response [see Drug Interactions (7.1)].

14 CLINICAL STUDIES

14.1 Chronic Stable Angina

CARISA (Combination Assessment of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily ranolazine extended-release tablets 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed.

In this trial, statistically significant (p <0.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each ranolazine extended-release tablets dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. The changes versus placebo in exercise parameters are presented in Table 1. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose.

Table 1 Exercise Treadmill Results (CARISA)

a p-value ≤ 0.05 b p-value ≤ 0.005
	** Mean Difference from Placebo (sec)**
** Study**	** CARISA (N=791)**
** Ranolazine extended-release tablets Twice-daily Dose**	** 750 mg**	** 1000 mg**
Exercise Duration Trough Peak	24a 34b	24 a 26 a
Time to Angina Trough Peak	30 a 38 b	26 a 38 b
Time to 1 mm ST-Segment Depression Trough Peak	20 41 b	21 35 b

The effects of ranolazine extended-release tablets on angina frequency and nitroglycerin use are shown in Table 2.

Table 2 Angina Frequency and Nitroglycerin Use (CARISA)

a Twice daily
	** Placebo**	** Ranolazine extended-release tablets** ** 750 mg**a	** Ranolazine extended-release tablets** ** 1000 mg**a
** Angina Frequency (attacks/week)**	N	258	272	261
Mean	3.3	2.5	2.1
P -value vs placebo	—	0.006	<0.001
** Nitroglycerin Use (doses/week)**	N	252	262	244
Mean	3.1	2.1	1.8
P -value vs placebo	—	0.016	<0.001

Tolerance to ranolazine extended-release tablets did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of ranolazine extended-release tablets.

Ranolazine extended-release tablets has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of ranolazine extended-release tablets 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with ranolazine extended-release tablets 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In addition, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Table 3. Statistically significant decreases in angina attack frequency (p=0.028) and nitroglycerin use (p=0.014) were observed with ranolazine extended-release tablets compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.

Table 3 Angina Frequency and Nitroglycerin Use (ERICA)

a 1000 mg twice daily
	** Placebo**	** Ranolazine extended-release tablets****a**
** Angina Frequency (attacks/week)**	N	281	277
Mean	4.3	3.3
Median	2.4	2.2
** Nitroglycerin Use (doses/week)**	N	281	277
Mean	3.6	2.7
Median	1.7	1.3

Gender

Effects on angina frequency and exercise tolerance were considerably smaller in women than in men. In CARISA, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level.

In ERICA, where the primary endpoint was angina attack frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males.

Race

There were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup.

14.2 Lack of Benefit in Acute Coronary Syndrome

In a large (n=6560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine [see Clinical Pharmacology (12.2)], and there was no difference between ranolazine extended- release tablets and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).