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D I
R C
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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