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Off-Label Drug Uses - Nifedipine: Ureteral Stones

Article  in  Hospital pharmacy · September 2007

DOI: 10.1310/hpj4209-816

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 Hospital Pharmacy
Volume 42, Number 9, pp 816–825
2007 Wolters Kluwer Health, Inc.

Off-Label Drug Uses

Nifedipine: Ureteral Stones
Joyce Generali, RPh, MS, FASHP* and Dennis J. Cada, PharmD, FASHP, FASCP (Editor)†

Off-Label Drug Uses — This Hospital Pharmacy feature is extracted from women) with distal or lower
Off-Label DrugFacts, a quarterly publication available from Wolters ureteral tract stones (juxtavesical
Kluwer Health. Off-Label DrugFacts is a practitioner-oriented resource or ureterovesical junction) less
for information about specific FDA-unapproved drug uses. This new than 1 cm in size.
guide to the literature will enable the health care professional/clinician
to quickly identify published studies on off-label uses and to determine DOSAGE AND DURATION
if a specific use is rational in a patient care scenario. The most relevant Nifedipine administered with
data are provided in tabular form, so the reader can easily identify the oral steroids (eg, methylpred-
scope of information available. A summary of the data—including back- nisolone or deflazacort with miso-
ground, study design, patient population, dosage information, therapy prostol) as an immediate-release
duration, results, safety, and therapeutic considerations—precedes each
product (20 mg daily) or sus-
table of published studies. References direct the reader to the full litera-
ture for more comprehensive information prior to patient care decisions. tained-release preparation (30 mg
Direct questions or comments regarding “Off-Label Drug Uses” to daily) for up to 20 to 45 days or
hospitalpharmacy@wolterskluwer.com. until stone expulsion.

BACKGROUND
The management of urinary
stone disease is determined by sev-
eral factors, including stone com-
position, location, duration, size,
recurrence status, presence of
other complications, and severity
of disease. It has been widely
acknowledged that most stones
(up to 98%) smaller than 5 mm
are likely to pass spontaneously.
The primary objective in urinary
stone disease is stone removal
through expulsion, shockwave
lithotripsy, or ureteroscopy. More
invasive therapies carry a greater
risk and expense, and thus, the
role of medication management
remains an important alternative
in appropriate patients.
The medical management of
urinary stones focuses on the sup-
portive treatment of pain, edema,
and possible infection, while also
promoting stone expulsion. Ureter-
al stone passage has been facilitat-
ed with the use of anti-inflamma-
tory agents (eg, corticosteroids) in
conjunction with agents that may
inhibit ureteral contractions (eg,
calcium channel blockers).
STUDY DESIGN
Controlled Trials
One randomized, double-
blind, placebo-controlled trial: 86
patients.
Randomized, Noncontrolled Trials
Four randomized, prospective
trials: 442 patients (approximately
290 patients receiving sustained-
release nifedipine).
PATIENT POPULATION
Adult patients (both men and
RESULTS
Controlled Trials
Nifedipine has been studied in
one double-blind, placebo-con-
trolled trial enrolling 86 patients
with unilateral ureteral
radiopaque stones not larger than
15 mm in diameter. Patients
received treatment for a maximum
of 45 days with oral methylpred-
nisolone (8 mg daily) and immedi-
ate-release nifedipine (20 mg
daily) or placebo. All patients
were required to drink 2 liters of
soft mineral water daily and were
allowed injectable diclofenac as
needed for pain. A total of 76
patients completed the study.
Stone expulsion within 45 days
(defined as success) was signifi-
cantly higher in the nifedipine
group compared with the placebo
group (87.2% vs 64.9%; P =
0.021). In addition, mean time to
expulsion was significantly shorter

*Director, Drug Information Center, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160,
e-mail: jgeneral@kumc.edu; †Editor-in-Chief, Hospital Pharmacy and Executive Editor, The Formulary, e-mail:
Dennis.Cada@wolterskluwer.com.

816 Volume 42, September 2007


in the nifedipine group when com-
pared with placebo (11.2 vs 16.4
days; P = 0.036). In both groups,
stone size was larger in failed cases
than in successful cases. Nifedip-
ine with methylprednisolone was
more effective than methylpred-
nisolone alone in increasing stone
expulsion and decreasing expul-
sion time.1
Randomized, Noncontrolled Trials
To date, the use of nifedipine
in the treatment of ureteral stones
has been primarily evaluated as
adjunctive therapy in four non-
controlled trials enrolling approx-
imately 440 patients, 290 of
whom received sustained-release
nifedipine.
In these studies, sustained-
release nifedipine (30 mg daily),
alone or with a steroid (eg,
deflazacort, prednisolone), was
compared with tamsulosin,
phloroglucinol, steroids, or sup-
portive therapy. When used in
combination with steroids and
misoprostol, nifedipine was more
effective than supportive sympto-
matic therapy and was compara-
ble with tamsulosin (with miso-
prostol and steroids) in stone
expulsion rates, expulsion time,
and need for analgesic therapy.2,3
However, conflicting data in a
large trial of 210 patients suggest
tamsulosin with deflazacort was
more effective than nifedipine or
phloroglucinol with deflazacort
in expulsion rate, time to expul-
sion, and the need for hospital-
izations and endoscopic proce-
dures.4
SAFETY
In reviewed reports, nifedipine
was used in both men and women
and appeared to be well tolerated.
Cited side effects included stom-
achache, headache, palpitations,
erythema, hypotension, and asthe-
nia.
THERAPY CONSIDERATIONS
The majority of published
data evaluating nifedipine in the
management of ureteral stones is
based on noncontrolled study
design. Nifedipine, alone or with
steroids, may have some benefits
as adjunctive therapy in the man-
agement of ureteral stones. There
have been conflicting reports
regarding its efficacy in compari-
son to other agents (eg, tamsu-
losin); therefore, its place in thera-
py has not been established. Larg-
er controlled trials are needed.
REFERENCES
1. Borghi L, Meschi T, Amato F, et al.
Nifedipine and methylprednisolone in
facilitating ureteral stone passage: a ran-
domized, double-blind, placebo-con-
trolled study. J Urol. 1994;152(4):1095-
1098.
2. Porpiglia F, Destefanis P, Fiori C,
Fontana D. Effectiveness of nifedipine
and deflazacort in the management of
ureteral stones. Urology. 2000;56(4):
579-582.
3. Porpiglia F, Ghignone G, Fiori C,
Fontana D, Scarpa RM. Nifedipine ver-
sus tamsulosin for the management of
lower ureteral stones. J Urol.
2004;172(2):568-571.
4. Dellabella M, Milanese G, Muzzoni-
gro G. Randomized trial of the efficacy
of tamsulosin, nifedipine and phloroglu-
cinol in medical expulsive therapy for
Off-Label Drug Uses
distal ureteral calculi. J Urol. 2005;
174(1):167-172.
5. Saita A, Bonaccorsi A, Marchese F,
Condorelli SV, Motta M. Our experi-
ence with nifedipine and prednisolone as
expulsive therapy for ureteral stones.
Urol Int. 2004;72(suppl 1):43-45.
SUGGESTED READINGS
Anagnostou T, Tolley D. Management of
ureteric stones. Eur Urol. 2004;
45(6):714-721.
Chandhoke PS. Economics of urolithia-
sis: cost-effectiveness of therapies. Curr
Opin Urol. 2001;11(4):391-393.
Kakizaki H, Ameda K, Kobayashi S,
Tanaka H, Shibata T, Koyanangi T. Uro-
dynamic effects of alpha1-blocker tam-
sulosin on voiding dysfunction in
patients with neurogenic bladder. Int J
Urol. 2003;10(11):576-581.
Lotan Y, Gettman MT, Roehrborn CG,
Cadeddu JA, Pearle MS. Management of
ureteral calculi: a cost comparison and
decision making analysis. J Urol.
2002;167(4):1621-1629.
Reitz A, Haferkamp A, Kyburz T, Knapp
PA, Wefer B, Schurch B. The effect of
tamsulosin on the resting tone and the
contractile behaviour of the female ure-
thra: a functional urodynamic study in
healthy women. Eur Urol.
2004;46(2):235-240.
Sandhu C, Anson KM, Patel U. Urinary
tract stones—Part I: role of radiological
imaging in diagnosis and treatment
planning. Clin Radiol. 2003;58(6):415-
421.
Sandhu C, Anson KM, Patel U. Urinary
tract stones—Part II: current status of
treatment. Clin Radiol. 2003;58(6):422-
433.
Tiselius HG, Ackermann D, Alken P,
Buck C, Conort P, Gallucci M; Working
Party on Lithiasis, European Association
of Urology. Guidelines on urolithiasis.
Eur Urol. 2001;40(4):362-371.
Hospital Pharmacy 817
818
Summary of Clinical Literature on the Use of Nifedipine for the Treatment of Ureteral Stones

Citation Indication Study Patient Drug (Route) Results Safety Author

Design Population/Profile Dose (Duration) Conclusion
CONTROLLED TRIALS

Borghi, Single Randomized 86 adult patients Group 1 Clinical outcomes: ADR profile: Nifedipine with
Off-Label Drug Uses

et al. unilateral Double-blind with a single radiopaque Methylprednisolone (PO): methylprednisolone

19941 ureteral Placebo- unilateral ureteral stone 8 mg twice daily Study withdrawals Withdrawals due increased the stone
stone controlled < 15 mm with 76 patients completed to ADRs expulsion rate and
Nifedipine (PO): the study. Four patients Four patients in decreased
Group 1: 43 patients 20 mg twice daily in Group 1 and two Group 1 experienced expulsion time.
Men/women: 29/10 for up to 45 days patients in Group 2 serious ADRs that
Mean age: 45 y stopped therapy because required stopping

Volume 42, September 2007

Mean stone size: 6.7 mm or of ADRs. Four additional the drug:
Partial obstruction: 20 patients dropped out in Stomachache 1
Without obstruction: 23 Control Group Group 2 due to an Perimalleolar 1
Methylprednisolone (PO): UTI (2) and loss to edema
Control group: 43 patients 8 mg twice daily follow-up (2) Headache 1
Men/women: 22/15 with Palpitations 1
Mean age: 43 y Placebo (PO): Results 1 2
Mean stone size: 6.8 mm for up to 45 days Mean stone 6.9 6.7 Two patients in
Partial obstruction: 19 size (mm) Group 2 experienced
Without obstruction: 24 Note: All patients were Stone expulsion 87.2 64.9 serious ADRs that
allowed injectable within 45 required stopping
diclofenac as needed days (%)a the drug:
and were required Mean time to 11.2 16.4 Stomachache 2
to drink 2 L of soft expulsion (days)b
mineral water daily. Blood pressure
Maximum stone size (mm) changes
c,d
Success 6.4 5.3 The patients in the
Failure 10.4 9.3 nifedipine group
had a significant
a
P = 0.021; Group 1 vs 2 decrease in mean
b
P = 0.036; Group 1 vs 2 systolic (-20 mm
c
P = 0.005; Group 1: Hg) and diastolic
success vs failure (-8 mm Hg)
d
P = 0.0001; Group 2: blood pressure
success vs failure (P < 0.05) and
a moderate in-
In both groups, stone size crease in mean
was larger in the failed heart rate (+8
than in the successful cases. beats/min).
These parameters
Diclofenac use were unchanged
The use of diclofenac was in the control
moderate and similar in group.
both groups.
 Summary of Clinical Literature on the Use of Nifedipine for the Treatment of Ureteral Stones (cont.)

Citation Indication Study Patient Drug (Route) Results Safety Author

Design Population/Profile Dose (Duration) Conclusion
RANDOMIZED, UNBLINDED TRIALS

Dellabella, Distal Randomized 210 adult patients Group 1 Clinical outcomes: ADR profile: Tamsulosin was
et al. ureteral Prospective with distal ureteral stones Phloroglucinol (PO): more effective
20054 calculi Parallel > 4 mm viewed on 80 mg daily Mean Data 1 2 3 The frequency than nifedipine in
ultrasonography and/or for up to 28 days Stone expulsion 64 97 77 of side effects expulsion rate and
radiographically (%)a-c observed was time to expulsion,
or Median time to 120 72 120 not different as well as de-
Group 1 expulsion (h)d-f among the creasing the
Phloroglucinol: 70 patients Group 2 Hospitalizations three groups number of hospi-
Men/women: 50/20 Tamsulosin (PO): (%) (specific data talizations and
Mean age: 39.8 y 0.4 mg daily Urgentg-i 16 0 4 not provided). endoscopic
Mean stone size: 6.2 mm for up to 28 days Delayedj-l 19 1 16 No ADR re- procedures.
No R/L stones: 39/31 Ureteroscopy 31 1 20 treatment dis-
or (%)m-o continuation
Group 2 Median 2 0 1
Tamsulosin: 70 patients Group 3 analgesic
Men/women: 54/16 Nifedipine-SR (PO): use (75 mg
Mean age: 43.8 y 30 mg daily vials)p-r
Mean stone size: 7.2 mm for up to 28 days Median work 5 2 3
No R/L stones: 41/29 days losts-u
Note: All patients received
a
Group 3 concurrent therapy with: P < 0.0001; Group 2 vs 1
b
Nifedipine: 70 patients Cotrimoxazole P < 0.001; Group 2 vs 3
c
Men/women: 51/19 (2 tablets daily x 8 days) NS, P = 0.190; Group 1 vs 3
d
Mean age: 41.8 y and P = 0.001; Group 2 vs 1
e
Mean stone size: 6.2 mm Deflazacort P < 0.0001; Group 2 vs 3
f
No R/L stones: 40/30 (1 tablet daily x 10 days) NS, P < 0.455; Group 1 vs 3
g
and P = 0.001; Group 2 vs 1
h
Note: Group 2 had Diclofenac 75 mg IM P = 0.045; Group 3 vs 1
i
significantly larger as needed NS, P = 0.245; Group 2 vs 3
j
mean stone size than P = 0.001; Group 2 vs 1
k
groups 1 and 3 P = 0.004; Group 2 vs 3
l
(P = 0.002). NS, P = 0.823; Group 1 vs 3
m
P < 0.0001; Group 2 vs 1
n
P < 0.001; Group 2 vs 3
o
NS, P = 0.175; Group 1 vs 3
p
P < 0.0001; Group 2 vs 1
q
P < 0.0001; Group 2 vs 3
r
P < 0.0001; Group 1 vs 3
s
P < 0.0001; Group 1 vs 2
t
P < 0.003; Group 1 vs 3
u
P = 0.001; Group 2 vs 3

There was no correlation

Hospital Pharmacy
between stone size and
expulsion time in all patients.

819
Off-Label Drug Uses
820
Summary of Clinical Literature on the Use of Nifedipine for the Treatment of Ureteral Stones (cont.)

Citation Indication Study Patient Drug (Route) Results Safety Author

Design Population/Profile Dose (Duration) Conclusion
RANDOMIZED, UNBLINDED TRIALS

Saita, et al. Lower Prospective 50 adult patients Nifedipine SR (PO): Clinical outcomes: ADR profile: Nifedipine admin-
Off-Label Drug Uses

20045 ureteral with radiopaque ureteral 30 mg daily istered with

stones stones < 15 mm with Study withdrawals ADRs resulting prednisolone
(juxta- Prednisolone (PO): 37 patients completed in withdrawal N/P P promotes passage
vesical tract 25 mg daily the study. A total of Erythema 5 0 of ureteral stones.
and uretero- for up to 20 days 13 patients withdrew Stomachache 1 4
vesical due to side effects, Renal colic 0 3
junction) or six patients in the

Volume 42, September 2007

nifedipine group
Prednisolone (PO): and seven in the
25 mg daily prednisolone group.
for up to 20 days
Results NIF/PRED PRED
Note: All patients were Number 19 18
allowed NSAIDs if patients
needed. Mean stone 12 12.8
size (mm)
Success (%) 81 68
Failure (%) 19 32
Mean 6 10
expulsion
time (days)
 Summary of Clinical Literature on the Use of Nifedipine for the Treatment of Ureteral Stones (cont.)

Citation Indication Study Patient Drug (Route) Results Safety Author

Design Population/Profile Dose (Duration) Conclusion
RANDOMIZED, UNBLINDED TRIALS

Porpiglia, Lower Randomized 86 adult patients Group 1 Clinical outcomes: ADR profile: Tamsulosin and
et al. ureteral Prospective with stones < 1 cm Deflazacort (PO): nifedipine produced
20043 stones in the lower tract 30 mg daily Study withdrawals ADRs 1 2 3 comparable effects
(juxtavesical of the ureter for up to 10 days 84 patients completed the study. Hypo- 1 0 0 in the successful
tract and with Two patients withdrew due to tension expulsion of lower
ureterovesical Group 1: 30 patients Nifedipine SR (PO): side effects, one patient each Asthenia 0 1 0 ureteral stones.
junction) Men/women: 19/11 30 mg daily in Groups 1 and 2. Minor 3 3 0
Mean age: 45.6 y for up to 28 days effects
Mean stone size: 4.7 mm and Mean data 1 2 3
(range, 3.5 to 10 mm) Misoprostol (PO): Stone expul- 80 85 43
200 mcg twice daily sion (% )a-c
Group 2: 28 patients Time to expul- 9.3 7.9 12
Men/women: 18/10 Group 2: sion (d)d-f
Mean age: 50.5 y Deflazacort (PO): Not stone free 6 4 16
Mean stone size: 5.4 mm 30 mg daily at 28 days
(range, 3 to 10 mm) for up to 10 days Diclofenac 19.5 26 105
with dose/patient
Group 3: 28 patients Tamsulosin (PO): (mg)g-i
Men/women: 16/12 0.4 mg daily
a
Mean age: 42.7 y for up to 28 days P < 0.01; Group 1 vs 3
b
Mean stone size: 5.3 mm and P < 0.001; Group 2 vs 3
c
Misoprostol (PO): NS, P < 0.5; Group 1 vs 2
d
200 mcg twice daily NS, P = 0.09; Group 1 vs 3
e
P = 0.02; Group 2 vs 3
f
Group 3: NS, P = 0.2; Group 1 vs 2
g
Control group P < 0.0001; Group 1 vs 3
h
Supportive P < 0.0001; Group 2 vs 3
i
symptomatic NS, P < 0.05; Group 1 vs 2
therapy
Patients who were not
Note: All patients were stone free at the end of 4 wk
allowed injectable diclo- were successfully treated with
fenac 75 mg as needed ureteroscopy (20) or ESWL (6)
and were required to
drink 2 L of water daily. No differences in expulsion rates
were observed between genders
or between right- and left-sided
stones.

Hospital Pharmacy
821
Off-Label Drug Uses
 822
Summary of Clinical Literature on the Use of Nifedipine for the Treatment of Ureteral Stones (cont.)

View publication stats

Citation Indication Study Patient Drug (Route) Results Safety Author
Design Population/Profile Dose (Duration) Conclusion
RANDOMIZED, UNBLINDED TRIALS

Porpiglia, Distal Randomized 96 adult patients Group 1 Clinical outcomes: ADR Profile Nifedipine and
Off-Label Drug Uses

et al. 20002 ureteral Prospective with stones < 1 cm in the Deflazacort (PO): deflazacort
stones distal tract of the ureter 30 mg daily Study withdrawals ADRs 1 2 increased
for up to 10 days 92 patients completed the Headache 2 0 ureteral stone
Group 1: 48 patients with study. Two patients in Group 1 Asthenia 7 0 expulsion rate,
Men/women: 26/22 Nifedipine SR (PO): stopped therapy due to ADRs. Headache/ 1 0 decreased expul-
Mean age: 44 y 30 mg daily Two patients in Group 2 asthenia sion time, and
Mean stone size: 5.8 mm for up to 28 days dropped out, one due to an reduced the need

Volume 42, September 2007

(range, 3.5 to 10 mm) and UTI and the other because Two patients in for analgesic
Misoprostol (PO): of repeated urinary colic. Group 1 experienced therapy.
Control group: 48 patients 200 mcg twice daily serious ADRs that
Men/women: 24/24 Mean data 1 2 reversed after therapy
Mean age: 49 y Group 2 Stone 79 35 was stopped (transient
Mean stone size: 5.5 mm Control group expulsion (%)a hypotension, systolic
(range, 3 to 10 mm) Supportive Time to expul- 7 20 BP less than 100 mm
symptomatic sion (days)a Hg, and palpitations).
therapy Not stone-free 10 31
at 28 days
Diclofenac dose/ 15 105
patinet (mg)a
a
P < 0.05; Group 1 vs 2
ABBREVIATIONS
Patients who were not stone-
ESWL = extracorporeal shock wave lithotripsy
free at the end of 4 wk were
IM = intramuscular successfully treated with
N, NIF = nifedipine ureteroscopy (14) or ESWL
NS = not statistically significant (27).
NSAIDs = nonsteroidal anti-inflammatory drugs
PO = oral No differences in exulsion
P, PRED = prednisolone rates were observed beween
R/L = right/left genders or between right-
UTI = urinary tract infection and left-sided stones in
Group 1. There was no
correlation between stone
size and expulsion time
for patients in Group 1.