Canada - English - Health Canada
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1.0, 2.0, and 5.0 mg
150 Signet Drive
Canada M9L 1T9
Submission Control No.: 217479
DATE OF REVISION:
August 01, 2018
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Prazosin Hydrochloride Tablets
1.0, 2.0 and 5.0 mg
ACTIONS AND CLINICAL PHARMACOLOGY
APO-PRAZO is a formulation of prazosin hydrochloride and is a conventional release
formulation. Prazosin causes a decrease in total peripheral resistance. Animal studies suggest
that the vasodilator effect of prazosin is related to selective blockade of post-synaptic alpha
adrenoceptors. The results of dog forelimb experiments demonstrate that the peripheral
vasodilator effect is confined mainly to the level of the resistance vessels (arterioles).
Hemodynamic studies have been carried out in man following acute single dose administration
and during the course of long term maintenance therapy. The results confirm that the therapeutic
effect is a fall in blood pressure unaccompanied by a clinically significant change in heart rate,
renal blood flow and glomerular filtration rate. In patients with hypertension there is little change
in cardiac output. In addition, clinical pharmacology studies have shown that both prazosin and
prazosin GITS antagonize the vasopressor effect of intravenous phenylephrine, an alpha
In man blood pressure is lowered in both the supine and standing positions. The hypotensive
effect of prazosin hydrochloride is greater when the patient is standing, and a mild reflex
tachycardia can result. Tolerance has not been observed to develop in long term hypertensive
therapy. Rebound elevation of blood pressure does not seem to occur following abrupt cessation
of therapy with prazosin.
Following oral administration of prazosin in normal volunteers and hypertensive patients, plasma
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concentrations reach a peak at about 3 hours with a plasma half-life of 2-3 hours. The drug is
highly bound to plasma protein (97 percent). After chronic administration, no apparent drug
accumulation was observed nor were any obvious decreases in plasma concentrations noted.
Secondary plasma drug peaks and shoulders suggested probable enterohepatic circulation.
Animal studies indicate that prazosin hydrochloride is extensively metabolized, primarily by
demethylation and conjugation, and excreted (primarily as glucuronide conjugates) mainly via bile
and feces. Similar metabolism and excretion has been documented in human studies.
Most clinical studies indicate that chronic therapy with prazosin has little effect on plasma renin
activity. However one report suggests a transient increase in plasma renin activity following the
initial dose, as well as attenuated transient increase with subsequent doses.
Comparative bioavailability studies were performed using healthy human volunteers. The rate
and extent of absorption after a single 2 mg dose of APO-PRAZO 1 mg and MINIPRESS 1 mg
tablets was measured and compared. The results are summarized as follows:
Apo-Prazo (SO) 1 mg
Minipress (SO*) 1 mg
*SO= Standard Deviation.
*SD =Standard Deviation.
The rate and extent of absorption after a single 2 mg dose of APO-PRAZO 2 mg and
MINIPRESS 2 mg tablets was measured and compared. The results are summarized as follows:
Apo-Prazo (SO) 2 mg
Minipress (SO*) 2 mg
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*SO= Standard Deviation.
*SO= Standard Deviation.
INDICATIONS AND CLINICAL USE
APO-PRAZO (prazosin hydrochloride) is indicated in the treatment of mild to moderate essential
hypertension. It is employed in a general treatment program in association with a thiazide diuretic
and/or other antihypertensive agents as needed for proper patient response. APO-PRAZO may
be tried as a sole therapy in those patients in whom treatment with other agents caused adverse
effects or is inappropriate.
APO-PRAZO (prazosin hydrochloride) is contraindicated in patients with a known sensitivity to
APO-PRAZO (PRAZOSIN HYDROCHLORIDE) MAY CAUSE SYNCOPE AND/OR EXCESSIVE
HYPOTENSION WITH SUDDEN LOSS OF CONSCIOUSNESS. IN MOST CASES THIS IS
BELIEVED TO BE DUE TO AN EXCESSIVE POSTURAL HYPOTENSIVE EFFECT,
ALTHOUGH OCCASIONALLY THE SYNCOPAL EPISODE HAS BEEN ASSOCIATED WITH A
BOUT OF SEVERE TACHYCARDIA WITH HEART RATES OF 120-160 BEATS PER MINUTE.
THE INCIDENCE OF SYNCOPAL EPISODES IS APPROXIMATELY 0.8% WHEN THE
GRADUAL DOSE BUILD UP DESCRIBED UNDER DOSAGE AND ADMINISTRATION IS
FOLLOWED. THE INCIDENCE IS HIGHER IF THE INITIAL DOSE EXCEEDS 0.5 MG.
SYNCOPAL EPISODES HAVE OCCURRED WITHIN 30 TO 90 MINUTES OF THE INITIAL
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DOSE OF THE DRUG. THEY HAVE ALSO BEEN REPORTED IN ASSOCIATION WITH
DOSAGE INCREASES OR THE INTRODUCTION OF APO-PRAZO INTO THE REGIMEN OF A
PATIENT TAKING ANOTHER ANTIHYPERTENSIVE AGENT OR A DIURETIC. PHYSICIANS
ARE THEREFORE ADVISED TO LIMIT THE INITIAL DOSE OF THE DRUG TO 0.5 MG B.I.D.
OR T.I.D., TO SUBSEQUENTLY INCREASE THE DOSAGE SLOWLY, AND TO INTRODUCE
ANY ADDITIONAL ANTIHYPERTENSIVE DRUGS INTO THE PATIENT'S REGIMEN WITH
PATIENTS WHOSE BLOOD PRESSURE IS NOT ADEQUATELY CONTROLLED BY HIGH
DOSES OF A BETA-ADRENERGIC BLOCKING AGENT SUCH AS PROPRANOLOL MAY
DEVELOP ACUTE HYPOTENSION WHEN PRAZOSIN IS ADDED. TO MINIMIZE THE
INCIDENCE OF ACUTE HYPOTENSION IN SUCH PATIENTS, THE DOSE OF BETA-
ADRENERGIC BLOCKING AGENT SHOULD BE REDUCED BEFORE APO-PRAZO IS
ADMINISTERED. A LOW INITIAL DOSE OF APO-PRAZO IS ALSO STRONGLY
RECOMMENDED (SEE DOSAGE AND ADMINISTRATION).
If syncope occurs, the patient should be placed in the recumbent position and supportive
measures instituted. This adverse effect is self-limiting and in most cases does not recur once a
steady maintenance level is initiated. Patients should be cautioned to avoid situations where
injury could result should syncope occur during APO-PRAZO therapy especially in the initial dose
More common than loss of consciousness are the symptoms often associated with lowering of
the blood pressure, namely, dizziness and lightheadedness. The patient should be cautioned
about these possible adverse effects and advised what measures to take should they develop.
Use During Pregnancy
Although no teratogenic effects were seen in animal testing, there are no adequate and well
controlled studies which establish the safety of APO-PRAZO in pregnant women. Limited
uncontrolled use in the management of hypertension in the later stages of pregnancy suggests
that prazosin hydrochloride in combination with a beta-blocker can lower blood pressure in
pregnant patients. The drug appears to be less effective in patients with proteinuria in whom the
addition of i.v. hydralazine was usually required. Accordingly APO-PRAZO should be used during
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pregnancy only if in the opinion of the physician the potential benefit outweighs potential risk to
mother and child.
Use During Lactation
Prazosin has been shown to be excreted in small amounts in human milk. Caution should be
exercised when APO-PRAZO is administered to nursing mothers.
Use For Children
APO-PRAZO is not recommended for the treatment of children under the age of twelve years
since safe conditions for its use have not been established in this group.
Use in Patients with Moderate to Severe Grades of Renal Impairment
Because some patients with moderate to severe grades of renal impairment have responded to
smaller than usual doses of prazosin hydrochloride, it is recommended that therapy be initiated
with APO-PRAZO (prazosin hydrochloride) at 0.5 mg and that dose increases be instituted
Prazosin has been administered without any adverse drug interaction in limited clinical
experience to date with the following: (1) cardiac glycosides - digitalis and digoxin; (2)
hypoglycemics - insulin, chlorpropamide, tolazamide and tolbutamide; (3) tranquilizers and
sedatives - chlordiazepoxide, diazepam and phenobarbital; (4) antigout - allopurinol, colchicine
and probenecid; (5) antiarrhythmics -procainamide, propranolol (see WARNINGS however), and
quinidine; and (6) analgesics, antipyretics and anti-inflammatories - propoxyphene, ASA,
indomethacin and phenylbutazone.
Addition of a diuretic or other antihypertensive agent to prazosin hydrochloride has been
shown to cause an additive hypotensive effect. (See WARNINGS and DOSAGE AND
ADMINISTRATION sections.) An exaggerated hypotensive response has also been observed.
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Drug/Laboratory Test Interactions
False positive results may occur in screening tests for pheochromocytoma (urinary
vanillylmandelic acid [VMA] and methoxyhydroxyphenyl glysol (MHPG) urinary metabolites of
norepinephrine in patients who are being treated with prazosin hydrochloride. If an elevated VMA
is found, APO-PRAZO should be discontinued and the patient retested after a month.
The most common reactions associated with prazosin hydrochloride therapy are postural
dizziness (11%), nausea (9.5%), drowsiness (8.7%), headache (8.4%), palpitations (6.6%), dry
mouth (5.6%), weakness (4.6%), and fatigue/malaise (4.5%). In most instances side effects have
disappeared with continued therapy or have been tolerated with no decrease in dose of drug. The
following reactions have also been observed during prazosin hydrochloride administration.
vomiting, diarrhea, constipation, abdominal discomfort and/or pain.
syncope (See WARNINGS), orthostatic hypotension, edema,
dyspnea, tachycardia, faintness.
Central Nervous System:
nervousness, vertigo, depression, paresthesia, hallucinations.
rash, pruritus, alopecia, lichen planus.
urinary frequency, incontinence, impotence, priapism.
blurred vision, reddened sclera, epistaxis, tinnitus, nasal
liver function abnormalities, pancreatitis.
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diaphoresis, fever, arthralgia, positive ANA titer.
Single reports of pigmentary mottling and serous retinopathy have been reported. In these
instances, the exact causal relationship has not been established because the baseline
observations were frequently inadequate.
In more specific slit-lamp and funduscopic studies, which included adequate baseline
examinations, no drug-related abnormal ophthalmological findings have been reported.
Literature reports exist associating prazosin hydrochloride therapy with a worsening of pre-
existing narcolepsy. A causal relationship is uncertain in these cases.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
A few reports of prazosin hydrochloride overdose have been documented with prazosin
hydrochloride. The most frequently observed symptoms of overdose include hypotension and
Accidental ingestion of at least 50 mg of prazosin in a two-year-old child resulted in profound
drowsiness and depressed reflexes. No decrease in blood pressure was noted. Recovery was
Should overdosage lead to hypotension, support of the cardiovascular system is of first
importance. Restoration of blood pressure and normalization of heart rate may be accomplished
by keeping the patient in the supine position. If necessary, vasopressors should be used. If this
measure is inadequate, shock should then be treated with volume expanders. Renal function
should be monitored and supported as needed. Laboratory data indicate prazosin is not
dialysable because it is protein bound.
DOSAGE AND ADMINISTRATION
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APO-PRAZO CONVENTIONAL RELEASE TABLETS (prazosin hydrochloride)
When titration is to be undertaken using the tablet formulation it will be necessary to
split the 1 mg scored tablet to obtain the 0.5 mg starting dose.
It is recommended that the starting dose of 0.5 mg be given with food preferably with the evening
meal, at least two or three hours before retiring. The dose should be built up gradually with 0.5
mg being given b.i.d. or t.i.d. for at least three days. Unless adverse effects occur and subject to
the blood pressure lowering effect this dose should be increased to 1 mg given b.i.d. or t.i.d. for
at least a further three days.
Thereafter, as determined by the patient's response to the blood pressure lowering effect, the
dose should be increased gradually. Response to APO-PRAZO (prazosin hydrochloride) is
usually seen within one to fourteen days if it is to occur at any particular dose. When a response
is seen, therapy should be continued at that dose until the degree of response has reached the
optimum before the next dose increment is added.
Incremental increases should be continued until a desired effect is achieved or a maximum daily
dose of 20 mg is reached.
The maintenance dose of APO-PRAZO may be given as a twice or three times daily dosage
In patients with moderate to severe grades of renal impairment, it is recommended that therapy
be initiated at 0.5 mg daily and that dose increases be instituted gradually.
Use With Other Drugs
Patients Receiving Diuretic Therapy
The diuretic should be reduced to a maintenance dose level for the particular agent and APO-
PRAZO initiated at 0.5 mg h.s. then proceeding to 0.5 mg b.i.d. or t.i.d. After the initial period of
observation, the dose of APO-PRAZO should be gradually increased as determined by the
Patients Receiving Other Antihypertensive Agents
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Because some additive effect is anticipated, the other agent (e.g., propranolol* or other beta-
adrenergic blocking agents*, alpha methyldopa, reserpine, clonidine*, etc.) should be reduced
and APO-PRAZO initiated at 0.5 mg h.s. then proceeding to 0.5 mg b.i.d. or t.i.d. Subsequent
dosage increase should be made depending upon the patient's response.
Patients on APO-PRAZO to Whom Other Antihypertensive Agents Are Added
When adding a diuretic or other antihypertensive agent, the dose of APO-PRAZO should be
reduced to 1 mg or 2 mg b.i.d. or t.i.d. and retitration then carried out.
*Appropriate precautions should be observed when the dosage of these other antihypertensive
agents is reduced.
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Prazosin hydrochloride is a white, crystalline substance, slightly
soluble in water and isotonic saline.
APO-PRAZO tablets contain prazosin hydrochloride equivalent to
1.0, 2.0 and 5.0 mg of prazosin. The tablets also contain
croscarmellose sodium, lactose, magnesium stearate,
microcrystalline cellulose and polysorbate. The 1 mg tablets also
contain the dyes D&C yellow #10 and FD&C yellow #6.
Stability and Storage Recommendations
Store at room temperature (15°C to 30°C).
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Each capsule-shaped, peach, flat-faced with bevelled edge tablet, scored and engraved
APO P1 on one side contains prazosin hydrochloride equivalent to 1.0 mg prazosin.
Available in bottles of 100 and 500.
Each round, white, biconvex tablet, scored and engraved APO over P2 on one side,
contains prazosin hydrochloride equivalent to 2.0 mg prazosin. Available in bottles of 100
Each diamond shaped, white, biconvex tablet, scored and engraved APO over P5 on one
side, contains prazosin hydrochloride equivalent to 5.0 mg of prazosin. Available in bottles
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The nature of the hypotensive action of prazosin hydrochloride was studied both by in vitro and in
vivo methodology. Intravenously administered prazosin hydrochloride in dogs caused prolonged
hypotension and reduction in total peripheral resistance. Cardiac output, heart rate, and blood
flow in the femoral, renal, and splanchnic vascular beds were increased transiently. Cardiac
responses to electrical stimulation of cardioaccelerator nerves were not depressed, nor was there
sympathetic ganglion or adrenergic neurone blockade. Although prazosin hydrochloride reversed
the epinephrine pressor response in intact animals, vasodilator activity was only slightly
diminished when the vessels were deprived of sympathetic tone by ganglionic blockade.
Physiologic and direct radioligand binding data from studies in experimental animals indicates
that the hypotensive effect of prazosin hydrochloride ascribed to peripheral vasodilation is
achieved primarily by competitive blockade of the vascular postsynaptic alpha
receptors. As prazosin acts preferentially on postsynaptic alpha
-adrenergic receptors, the
feedback control of neuronal norepinephrine release by presynaptic alpha
In the dog, the hypotensive effect of prazosin hydrochloride intravenously was reversed by
metaraminol and norephinephrine given by intravenous infusion.
At doses considerably higher than those required for antihypertensive activity, prazosin
hydrochloride has mild CNS depressant activity, decreases heart norepinephrine and adrenal
epinephrine in rats, causes diuresis in anesthetized dogs, but fluid retention in conscious dogs
and mice, and is hyperglycemic in rats.
In clinical studies in which lipid profiles were followed, there were generally no adverse changes
noted between pre- and post-treatment lipids levels.
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The results of single-dose acute toxicity studies on prazosin hydrochloride are presented in
Acute Toxicity of Prazosin Hydrochloride
(95% Confidence limits)mg/kg
M & F
M & F
The signs of toxicity observed following the administration of this compound were, for the most
part, common to both mice and rats by both routes and included blanching, depression,
decreased respiration, ptosis, writhing, ataxia, tremors and convulsions.
Mongrel dogs given 250 and 500 mg/kg as a single oral dose showed ataxia, depression,
occasional diarrhea, relaxed nictitating membrane, ptosis, and occasional tremors. Tachycardia
was also noted in the three dogs at 250 mg/kg. Anorexia was noted 48 hours post dose in one
dog receiving 500 mg/kg.
Prazosin hydrochloride was administered to dogs in doses of 2, 10 and 25 mg/kg/day seven days
per week for one year. Testicular atrophy and degeneration accompanied by prostatic atrophy
and fibrosis occurred in male dogs receiving doses of 25 mg/kg/day.
(Urinary 17-ketosteroid excretion in human clinical studies was monitored in 105 patients for any
possible effect on testicular function for periods ranging from 3 to 33 months. A trend analysis of
the 17-ketosteroid data disclosed a seasonal variation, but did not suggest a drug effect. Routine
semen analysis in 27 male patients on prazosin hydrochloride alone for up to 51 months revealed
no semen abnormalities.)
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Rats received prazosin hydrochloride in doses of 5, 25, 75 and 150 mg/kg/day for 18 months.
During the first 18 weeks of study, drug-induced hepatocellular degeneration and/or necrosis and
renal corticomedullary necrosis occurred at the dose level of 150 mg/kg; mild hepatocellular
degenerative changes and/or necrosis were found at the dose level of 75 mg/kg.
Between 19 and 53 weeks, the following pathologic changes were observed at dose levels of 150
and 75 mg/kg: testicular necrosis with accompanying inguinal and/or scrotal adhesions; chronic
nephrotoxic nephritis; degenerative folding and contracture of the retina (retinitis proliferans);
adrenal plethora; gastric necrosis and hepatic necrosis. At the dose level of 25 mg/kg, there was
a low percent incidence of testicular, renal and gastric alterations; since these same changes
occurred in larger numbers of animals at the two higher dose levels, they appear drug-related.
Between 54 weeks and 18 months, the following changes occurred at dose levels of 150, 75 and
25 mg/kg: testicular atrophy and/or degeneration with accompanying inguinal and/or scrotal
adhesions; retinitis proliferans (150 and 75 mg/kg levels only) and hepatic degeneration and/or
necrosis. Additionally, bilateral cataracts (not observed previously) occurred at the dose levels of
150 and 75 mg/kg. Chronic nephritis and adrenal plethora (cystic degeneration) which previously
(19 - 53 weeks) had a higher percent incidence at the dose levels of 150, 75 and 25 mg/kg, and
150 and 75 mg/kg respectively, appeared with approximately the same frequency at all dose
levels including the controls.
In a chronic study with rats, prazosin hydrochloride fed at levels up to 75 mg/kg/day for 18
months showed no evidence of carcinogenicity.
Reproductive and Teratologic Studies
Reproductive and teratologic studies were carried out at dose levels of 25 and 75 mg/kg/day in
rats and rabbits. No drug-induced changes were observed.
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1. Awan NA, Miller RR, Maxwell K, Mason DT. Effects of prazosin on forearm resistance and
capacitance vessels. Clin Pharmacol Ther 1977;22( 1):79-84.
2. Brogden RN, Heel RC, Speight TM, Avery GS. Prazosin: a review of its pharmacological
properties and therapeutic efficacy in hypertension. Drugs 1977; 14: 163-97.
3. Cambridge D, Davey MJ, Massingham R. Prazosin, a selective antagonist of post-synaptic
alpha-adrenoceptors. Brit J Pharmacol 1977;59:514P-5P.
4. Colluci WS. Alpha-adrenergic receptor blockade with prazosin. Ann Intern Med 1982;97:67-
5. Curtis JR. Prazosin in patients with chronic renal failure. Br Med J 1974;3:742-43.
6. Davey MJ. The pharmacology of prazosin, an alpha
-adrenoceptor antagonist and the basis
for its use in the treatment of essential hypertension. Clin and Exper Hyper-Theory and
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combination in the therapy of hypertension. J Cardiovasc Pharmacol 1980;2(Suppl.3):S387-
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9. Grahnen A, Seideman P, Lindstrom B, Haglund K, von Bahr C. Prazosin kinetics in
hypertension. Clin Pharmacol Ther 1981;30(4):439-46.
10. Hobbs DC, Twomey TM, Palmer RF. Pharmacokinetics of prazosin in man. J Clin Pharmacol
11. Johnson BF, Romero L, Johnson J, Marwaha R. Comparative effects of propranolol and
prazosin upon serum lipids in thiazide-treated hypertensive patients. Am J Med
12. Karlberg BE, Thulin T, Fageerberg SE, Scherten B, Tolagen K, Vikesdal O, Malmberg L.
Effects of prazosin on plasma renin activity and blood pressure. J Clin Pharmacol
13. Kincaid-Smith P, Fang P, Laver MC. A new look at the treatment of severe hypertension. Clin
Sci Molec Med 1973;45:75s-87s.
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14. Kincaid-Smith P. Vasodilators in the treatment of hypertension. Med J Aust 1975;1(Spec
15. Kwan CM, Shepard AMM, Johnson J, Taylor F, Brockway B. Forearm and finger
hemodynamics, blood pressure control, and lipid changes in diabetic hypertensive patients
treated with atenolol and prazosin: a brief report. Am J Med 1989;86:55-58.
16. Leren P, Helgeland A, Holme I, Foss PO, Hjermann I, Lund-Larsen PG. Effect of propranolol
and prazosin on blood lipids: the Oslo Study. Lancet 1984;2(8184):4-6.
17. Lowenstein J, Neusy AJ. Effects of prazosin and propranolol on serum lipids in patients with
essential hypertension. Am J. Med 1984;76:79-84.
18. McAreavey D, Cumming AMM, Sood VP, Leckie BJ, Morton JJ, Murray GD, Robertson JIS.
The effect of oral prazosin on blood pressure and plasma concentrations of renin and
angiotensin II in man. Clin Sci 1981;61:457s-460s.
19. Meredith P, Elliott MH, Vincent J, Reid JA. A clinical pharmacological assessment of a new
osmotic pump formulation of prazosin. Br J Clin Pharmacol 1986;22:235P.
20. Rouffy J, Jaillard J. Comparative effects of prazosin and atenolol on plasma lipids in
hypertensive patients. Am J Med 1984; 76(2A):105-108.
21. Richardson DW, Ramaswamy D, Ramirez A. Effect of prazosin on arterial pressure and
cardiac output in human hypertension. Circulation 1968;38(suppl 6): 164.
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24. Product Monograph – MINIPRESS (prazosin hydrochloride) Tablets, 1.0 mg, 2.0 mg and 5.0
Aspri Pharma Canada Inc.. Date of Revision:
November 2, 2016, Control No.