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D I R C DRUG INFORMATION AND RESEARCH CENTRE Drug Information Newsletter Jackie Campbell Doris Cheung Stephanie Chiu Susan Halasi Buu Huynh Lenka Janecka Nita Lakhani Carol Lee Shao Lee Elaina Mow Karina Malak Rohini Naipaul Mika Ng Anu Rajora Brent Ruddock, Editor Leam Tang Paul Thompson Dorothy Tscheng Margaret Wong NEW DRUGS/ DRUG NEWS May/June 2008 VOLUME 26 Number 3 DILTIAZEM: COMPARISON OF SOLID ORAL DOSAGE FORMS Diltiazem is available in a confusing array of solid oral dosage preparations having different release properties, and pharmacists often ask whether the differences among these preparations are clinically significant. This article compares regular- and modified- release diltiazem formulations, and provides recommendations for switching between the agents. HOW DO THE VARIOUS ORAL FORMULATIONS OF DILTIAZEM COMPARE WITH ONE ANOTHER? Diltiazem is marketed under several different brand names in a variety of dosage forms. Some of the key differences among available preparations are summarized in Table 1. Very few trials evaluating meaningful clinical outcomes that compare available Canadian formulations of diltiazem were identified. Upon reviewing the literature, it was noted that some studies involving the same patient groups were published multiple times, reporting different outcomes in each publication. The main findings from relevant trials are summarized in Table 2; additional information about the studies is provided below. TABLE 1 – COMPARISON OF ORAL DILTIAZEM FORMULATIONS1-8 Brand Name (Manufacturer) Dosage Form Usual Dosing* Cardizem (Biovail) Conventionalrelease‡ tablet 30-60 mg TID-QID Apo-Diltiaz Gen-Diltiazem Novo-Diltazem Nu-Diltiaz Cardizem SR§ Sustained-release capsule 60-180 mg BID Apo-Diltiaz SR Cardizem CD (Biovail) Sustained-release capsule 120-360 mg OD Tiazac (Biovail) Sustained-release capsule 120-360 mg OD Novo-Diltiazem HCL ER Sandoz Diltiazem T Tiazac XC (Biovail) Extended-release tablet 180-360 mg HS|| None Featured Topics • Diltiazem: Comparison of Solid Oral Dosage Forms • New Products/Product Updates DIRC Toll Free Number 1•800•268•8058 Interchangeable Products† [email protected] www.dirc.ca * † ‡ § || Approved indications: chronic stable angina, angina resulting from coronary artery spasm Approved indications: chronic stable angina, hypertension Approved indications: Apo-Diltiaz CD Gen-Diltiazem CD chronic stable angina, Novo-Diltazem CD hypertension Ratio-Diltiazem CD Can open and sprinkle Sandoz Diltiazem CD contents on food, but do not chew or crush Local Calls 416•385•DIRC (3472) Fax 416•385•2442 Comments Approved indications: chronic stable angina, hypertension Can open and sprinkle contents on food, but do not chew or crush Approved indications: hypertension Doses of 420-540 mg/day have been used, particularly with once-daily preparations. As listed in the electronic version of the Ontario Drug Benefit Formulary/Comparative Drug Index. The manufacturer describes the preparation as “modified-release” based on the dissolution profile. Cardizem SR has been discontinued by the manufacturer; only a generic formulation is currently available. When taken at night, the drug delivery system is designed to provide maximum antihypertensive effect in the morning, when the risk of cardiovascular events appears to be highest. Ontario Pharmacists’ Association, 375 University Ave., Suite 800, Toronto, ON M5G 2J5 NEW DRUGS/DRUG NEWS MAY/JUNE 2008 Telephone 416•441•0788 Fax 416•441•0791 www.opatoday.com I Hypertension In the study by Ruddy et al.,9 there were many exclusion criteria, including the presence of any cardiovascular disease other than systemic hypertension (e.g., cardiac surgery, congestive heart failure), cardiac conduction abnormalities (e.g., atrial fibrillation, left bundle branch block), secondary hypertension, impaired renal function, and significant hepatic disease. Prior to being randomized to one of the treatment groups, patients discontinued any previous antihypertensive medications and went through a single-blind placebo baseline phase for 1 to 4 weeks. If they qualified based on blood pressure measurements during the baseline phase, they were randomized to one of the double-blind treatment groups. During the initial 6 weeks of treatment, doses were titrated to the “optimal dose”, which was defined as the dose necessary to reduce the seated diastolic blood pressure (DBP) to less than 90 mmHg. The optimal dose was then continued for another 6 weeks. The primary efficacy analysis was carried out on the intent-to-treat population, comprised of patients for whom data were available from all visits during the treatment period.9 As noted in Table 2, there were no statistically significant differences between treatments in the change from baseline in seated systolic blood pressure (SBP) or DBP. Nor were there any statistically significant differences between diltiazem CD and diltiazem SR in change in heart rate from baseline (−4.1 beats per minute in each group), proportion of patients reaching a seated DBP less than 90 mmHg (60% [28 of 47] and 55% [27 of 49], respectively; p=0.685), or proportion of patients achieving a reduction in seated DBP of at least 10 mmHg (57% [27 of 47] and 53% [26 of 49], respectively; p=0.69).9 A separate publication10 of the trial described above reported that there were no statistically significant differences between diltiazem CD and diltiazem SR in mean reduction in DBP, SBP, or heart rate based on 24-hour ambulatory blood pressure monitoring, either for the entire 24-hour period or for the early morning, waking, or night periods. Interestingly, however, a further publication11 of the same trial reported that diltiazem CD was associated with statistically significant differences from diltiazem SR in the change from baseline in early morning changes (i.e., from 5:00 a.m. to 8:00 a.m.) in mean arterial pressure (p<0.005) and mean DBP (p<0.001). It is unclear if the latter publication was the result of a post-hoc analysis or if the reported results are clinically significant. In the study by Smith et al.,12 it is of note that the primary efficacy variable—difference in mean ambulatory blood pressure during the 10 to 16 hour post-dose period—was selected based on previous pharmacokinetic studies that demonstrated significant differences in diltiazem concentrations between Cardizem CD and Tiazac during this time period. Several other outcome measures were also evaluated. The authors reported that there were statistically significant differences between Tiazac and Cardizem CD during the 3 to 13 hour post-dose period (when diltiazem levels were significantly higher for Tiazac than Cardizem CD) in ambulatory SBP (147.6 mmHg and 150.6 mmHg, respectively; p≤0.05) and DBP (90.9 mmHg and 93.5 mmHg, respectively; p≤0.05). They also reported that, when compared with baseline blood pressure, reductions achieved with Tiazac exceeded reductions achieved with Cardizem CD by at least 2 mmHg for 10 out of 24 hourly post-dose measurements. However, there were no statistically significant differences between the treatments in mean 24-hour SPB or DBP, mean daytime SBP or DBP, or mean night time SBP or DBP.12 The study by Neutel et al.13 was designed to reflect practicebased treatment and employed much less rigid methodology than the other controlled trials described, with the exception that failure to take all of the prescribed medication resulted in mandatory discontinuation from the trial. The investigator could II remove a patient from the study at any time if an adequate response was not achieved, without affecting efficacy results (only patients with data available from all scheduled follow-up visits were included in the efficacy analysis).13 Overall, the results of available studies indicate that the various modified-release diltiazem formulations are generally comparable in efficacy with respect to control of blood pressure, although Tiazac appears to offer better control than Cardizem CD at certain time points during the dosing interval. There are currently no data to suggest that any such differences translate into a reduction in major cardiovascular endpoints (e.g., myocardial infarction, stroke, cardiovascular death). Angina Klinke et al.14 summarized two independent studies that were conducted using the same design. Each employed washout and placebo run-in phases prior to randomization to the study drug protocol. Other than sublingual nitroglycerin tablets or nitroglycerin spray, no antianginal medications were permitted during the study. In addition to the outcome measures listed in Table 2, the authors reported that both diltiazem formulations were equivalent in significantly reducing the incidence of angina attacks and the use of nitroglycerin compared with placebo in studies 1 and 2.14 An additional study15 that evaluated the efficacy of once-daily diltiazem CD in patients with stable angina pectoris switched from twice-daily diltiazem SR was identified; however, no statistical comparisons between the two diltiazem formulations during the active treatment phase of the study were provided. Nonetheless, the authors concluded that diltiazem CD was of equal efficacy to diltiazem SR based on non-statistical comparisons.15 Overall, the limited available information indicates that regularand modified-release diltiazem formulations are comparable in efficacy with respect to control of angina. HOW SHOULD A PATIENT BE SWITCHED FROM ONE FORMULATION OF DILTIAZEM TO ANOTHER? In general, switching from one formulation of diltiazem to another can be done using the same total daily dose of diltiazem,1,2 administered according to the frequency recommended by the manufacturer of the product being switched to. For example, a patient taking diltiazem sustainedrelease capsules (e.g., Apo-Diltiaz SR) 120 mg twice daily could be switched to diltiazem sustained-release capsules (e.g., Cardizem CD or Tiazac) or extended-release tablets (Tiazac XC) at a dose of 240 mg once daily. Medical supervision is prudent when switching between formulations, as some patients may require minor dose adjustments based on therapeutic response and tolerance to the drug. WHICH IS THE BEST FORMULATION FOR A GIVEN PATIENT? Available comparative data suggest that most diltiazem formulations generally appear to be comparable in efficacy for the management of hypertension and chronic stable angina. Therefore, selection of a particular product will likely depend on cost and convenience of dosing. It should also be kept in mind that compliance with once-daily dosing regimens is likely to be superior to that seen with preparations dosed more frequently, which may have implications for disease control. Whether chronotherapeutic delivery systems such as that employed with Tiazac XC will provide clinically relevant benefits over other diltiazem delivery systems remains to be established. NEW DRUGS/DRUG NEWS MAY/JUNE 2008 TABLE 2 – SUMMARY OF TRIALS COMPARING DIFFERENT DILTIAZEM FORMULATIONS9,12-14 Study & Design Intervention Participants Outcomes Hypertension Ruddy et al.9 R, DB, PG, MC Smith et al.12 R, DB, CO Patients with mild to moderate Dilt-CD OD (n=54) or Dilt-SR BID (n=57), each for 12 weeks HTN (sDBP 95-114 mmHg and sSBP ≤200 mmHg) Doses titrated from 180 mg/day Baseline sDBP: 99.7-99.9 mmHg to 360 mg/day to achieve a sDBP <90 mmHg Baseline sSBP: 146-150 mmHg Patients with moderate HTN (mean office sDBP between 100 and 114 mmHg and mean daytime aDBP >90 mmHg based on ABPM) Change from baseline in sDBP (mmHg), ITT* Dilt-CD (n=47): −10.9 Dilt-SR (n=49): −10.1 (p=NS) Change in sSBP from baseline (mmHg), ITT Dilt-CD (n=47): −9 Dilt-SR (n=49): −9 (p=NS) Cardizem CD 240 mg OD for 4 weeks followed by Tiazac 240 mg OD for 4 weeks (n=21)† or Tiazac 240 mg OD for 4 weeks followed by Cardizem CD 240 mg OD for 4 weeks (n=19)† aSBP at 10-16 hours post-dose (mmHg)* Cardizem CD: 147.6 Tiazac: 143.9 (p≤0.05 vs. Cardizem CD) Tiazac 180 mg or 240 mg OD for 2 weeks, titrated as necessary to 360 mg OD for a total of 6 weeks of therapy‡ (n=3082) Change from baseline in sDBP in patients switched from another diltiazem formulation (mmHg)§ 180 mg start dose (n=126): −3.21 240 mg start dose (n=133): −3.97 Current antihypertensive therapy (if any) could be continued or tapered/discontinued; other antihypertensives could be added Change from baseline in sSBP in patients switched from another diltiazem formulation (mmHg)§ 180 mg start dose (n=125): −7.40 240 mg start dose (n=133): −8.23 Study 1 (n=35) Each patient received Dilt-IR 60 mg TID, Dilt-CD 180 mg OD, and placebo, each for 7-10 days (randomized according to 1 of 3 sequences) Change from baseline in time to termination of ETT, 24-hours post AM dose (seconds)¶ Dilt-IR 60 mg: +7 Dilt-CD 180 mg: +42 (p<0.05 vs. Dilt-IR) Baseline aDBP: 95.3 mmHg aDBP at 10-16 hours post-dose (mmHg)* Cardizem CD: 89.6 Tiazac: 87.2 (p ≤0.1 vs. Cardizem CD; i.e., NS) Baseline aSBP: 151.7 mmHg Neutel et al.13 OL, MC Patients with HTN (any severity; could be normotensive on current therapy) Angina Patients with stable angina Klinke et al.14 R, DB, PC, CO, MC pectoris for at least 2 months who met ETT qualifications|| Study 2 (n=33) Each patient received Dilt-IR 120 mg TID, Dilt-CD 360 mg OD, and placebo, each for 7-10 days (randomized according to 1 of 3 sequences) Time to onset of angina, 24-hours post AM dose (seconds)¶ Dilt-IR 60 mg: +33 Dilt-CD 180 mg: +67 (p<0.01 vs. Dilt-IR) ABPM = ambulatory blood pressure monitoring; aDBP = ambulatory diastolic blood pressure; aSBP = ambulatory systolic blood pressure; CO = crossover; DB = double-blind; Dilt-CD = diltiazem controlled-delivery; Dilt-IR = diltiazem immediate-release; Dilt-SR = diltiazem sustained-release; ETT = exercise tolerance test; HTN = hypertension; ITT = intent-to-treat population; MC = multicentre; NS = non-significant; OL = open-label; PC = placebo-controlled; PG = parallel-group; R = randomized; sDBP = seated diastolic blood pressure; sSBP = seated systolic blood pressure * The primary efficacy variable(s). † Before being randomized to treatment, all patients were weaned from existing antihypertensive medications and underwent a 4-week single-blind placebo lead-in period. ‡ The starting dose was left to the clinical discretion of the investigator; titration to 360 mg daily occurred if the goal of a sitting diastolic blood pressure <90 mmHg was not achieved. § It was not explicitly stated that patients were switched from current diltiazem formulations to Tiazac on a mg-per-mg basis; statistical comparisons were not provided. || Exercise tolerance test qualifications required termination of exercise due to chest pain between 3 and 10 minutes with occurrence of 1-mm ST-segment depression during that time, as well as reproducible duration of exercise, on specified visits prior to the use of study medication. ¶ Values were approximated from figures in the original publication; comparisons between diltiazem immediate-release 60 mg and diltiazem CD 180 mg at 2 and 8 hours post AM dose were not statistically significantly different, nor were any comparisons between diltiazem immediate-release 120 mg and diltiazem CD 360 mg. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. Biovail Pharmaceuticals Canada. Cardizem/Cardizem CD product monograph. Mississauga, ON; March 26, 2007. Apotex Inc. Apo-Diltiaz/Apo-Diltiaz SR/Apo-Diltiaz CD product monograph. Weston, ON; September 25, 1997. Biovail Pharmaceuticals Canada. Tiazac product monograph. Mississauga, ON; June 27, 2003. Biovail Pharmaceuticals Canada. Tiazac XC product monograph. Mississauga, ON; September 7, 2005. Regier L, Jensen B. Calcium channel blocker (CCB): comparison chart. Saskatoon: Saskatoon Health Region; 2008 [cited March 16, 2008]. Available: http://www.rxfiles.ca/acrobat/CHT-HTN-ccb.pdf Ministry of Health and Long-Term Care. Ontario Drug Benefit Formulary/ Comparative Drug Index [electronic version; cited April 18, 2008]. Available: https://www.healthinfo.moh.gov.on.ca/formulary/index.jsp Health Canada. Drug Product Search [database on the Internet; cited April 4, 2008]. Available: http://cpe0013211b4c6d-cm0014e88ee7a4.cpe.net.cable.rogers.com/ dpdonline/startup.do?applanguage=en_CA White WB, LaRocca GM. Chronopharmacology of cardiovascular therapy.Blood Press Monit. 2002 Aug;7(4):199-207. NEW DRUGS/DRUG NEWS MAY/JUNE 2008 9. 10. 11. 12. 13. 14. 15. Ruddy TD, Wright JM, Savard D, Handa SP, Chockalingam A, Boulet AP. Comparison of the efficacy and safety of once-daily versus twice-daily formulations of diltiazem in the treatment of systemic hypertension. The Canadian Multicenter Diltiazem-CD Hypertension Trial Group. Cardiovasc Drugs Ther. 1995 Jun;9(3):413-20. Ruddy TD, Wright JM, Savard D, Handa SP, Chockalingam A, Fischer L, et al. 24 hour blood pressure control with once-daily versus twice-daily formulations of diltiazem. Cardiovasc Drugs Ther. 1995 Dec;9(6):799-807. Savard D, Ruddy TD, Chockalingam A, Wright JM, Handa SP, Jensen ML, et al. Effect of two formulations of diltiazem on the early morning rise in blood pressure. Can J Clin Pharmacol. 1996;3(1):16-20. Smith DH, Neutel JM, Weber MA. Comparisons of the effects of different longacting delivery systems on the pharmacokinetics and pharmacodynamics of diltiazem. Am J Hypertens. 1999 Oct;12(10 Pt 1):1030-7. Neutel JM, Smith DH, Frishman WH. Optimization of antihypertensive therapy with a novel, extended-release formulation of diltiazem: results of a practice-based clinical study. Clin Ther. 1997 Nov-Dec;19(6):1379-93. Klinke WP, Baird M, Juneau M, Waters D, Warnica W, Lakhani Z, et al. Antianginal efficacy and safety of controlled-delivery diltiazem QD versus an equivalent dose of immediate-release diltiazem TID. Cardiovasc Drugs Ther. 1995 Apr;9(2):319-30. Savard D, Lenis J, Juneau M, Jacob C, Boulet AP. Clinical efficacy and safety of oncedaily diltiazem in patients with stable angina pectoris switched from twice-daily diltiazem. J Cardiovasc Pharmacol. 1995 Jul;26(1):85-9. III NEW PRODUCTS/PRODUCT UPDATES TRADE NAME GENERIC NAME ADVAGRAF Tacrolimus SOURCE Astellas Pharma Canada, Inc. CLASSIFICATION Immunosuppressant SUPPLIED/COMMENTS 0.5 mg and 1 mg extended-release capsules; bottles of 50 5 mg extended-release capsules; bottles of 30 ERDOL Ergocalciferol Odan Laboratories Ltd. Antirachitic agent 8288 IU/mL oral solution; bottles of 60 mL FROVA Frovatriptan succinate Teva Neuroscience* Migraine therapy 2.5 mg tablets; packages of 7 INTELENCE Etravirine Janssen-Ortho Inc. HIV non-nucleoside reverse transcriptase inhibitor 100 mg tablets; bottles of 120 LEVAQUIN Levofloxacin Janssen-Ortho Inc. Antibacterial agent OMNARIS Ciclesonide Nycomed Canada Inc. Corticosteroid for nasal use PHENOBARBITAL Phenobarbital sodium SODIUM INJECTION USP New Dosing Regimen: 750 mg once daily for 5 days for the treatment of patients with complicated urinary tract infections or acute pyelonephritis Sandoz Canada Inc. Anticonvulsanthypnotic-sedative PICODAN Sodium picosulfate, magnesium oxide, plus citric acid Odan Laboratories Ltd. Purgative PICO-SALAX SINGLES Sodium picosulfate, magnesium oxide, plus citric acid Ferring Inc. Purgative TORISEL Temsirolimus Wyeth Canada Antineoplastic agent TRAMACET Tramadol HCl plus acetaminophen Janssen-Ortho Inc. Centrally acting analgesic 50 mcg/metered nasal spray; 120 sprays per bottle Return to the Canadian Market: 30 mg/mL and 120 mg/mL solution; packages of 10 x 1 mL ampoules 10 mg/3.5 g/12 g powder for solution per sachet; packages of 2 New Package Size: Packages of 1 sachet per carton 25 mg/mL temsirolimus concentrate for injection; packages of 1 x 1.2 mL vial plus diluent Revised Indication: For the management of moderate to moderately severe pain in adults * Teva Neuroscience Tel: 1 (866) 530 6065 Disclaimer The Drug Information and Research Centre (DIRC) of the Ontario Pharmacists’ Association provides this material to health professionals for informational purposes only. It is provided without warranty of any kind by DIRC and DIRC assumes no responsibility for any errors, omissions or inaccuracies therein. It is the responsibility of the health professional to use professional judgment in evaluating this material in light of any relevant clinical or situational data. Drug Information and Research Centre, Ontario Pharmacists’ Association, 375 University Ave., # 800, Toronto ON M5G 2J5 Tel: (416) 385-DIRC (3472) 1-800-268-8058 (Ontario only) Fax: (416) 385-2442 Email: [email protected] © OPA DIRC 05/2008 IV NEW DRUGS/DRUG NEWS MAY/JUNE 2008