ASPRUZYO SPRINKLE (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays.

There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m² /day) and 50 mg/kg/day for 24 months in mice (150 mg/m² /day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the daily maximum recommended human dose (MRHD) of 2,000 mg on a surface area basis. A published study reported that ranolazine 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.

In male and female rats, oral administration of ranolazine that produced exposures (AUC) approximately 3-fold or 5-fold higher, respectively, than the MRHD had no effect on fertility.

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 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 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 2. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750-mg dose.

Table 2 Exercise Treadmill Results (CARISA)

	Mean Difference from Placebo (sec)
Study	CARISA (N = 791)
Ranolazine 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 35b

a p-value ≤ 0.05 b p-value ≤ 0.005

The effects of ranolazine on angina frequency and nitroglycerin use are shown in Table 3.

Table 3 Angina Frequency and Nitroglycerin Use (CARISA)

		Placebo	Ranolazine 750 mga	Ranolazine 1000 mga
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

a Twice daily

Tolerance to ranolazine 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.

Ranolazine 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 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with ranolazine 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 4. Statistically significant decreases in angina attack frequency (p = 0.028) and nitroglycerin use (p = 0.014) were observed with ranolazine compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.

Table 4 Angina Frequency and Nitroglycerin Use (ERICA)

		Placebo	Ranolazinea
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

a 1000 mg twice daily

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.