Plot 1 Junaid Dosunmu Street,Central Business District, Alausa, P.0. Box 3560 Ikeja, Lagos, Nigeria.
Tel: + 234-1-774-1205
Osaka Pharmaceuticals Pvt. Ltd.
Old National Highway No. 8, Sankarda - 391 350, Ditl. Vadodara, India.
Dosage Form, Composition & NAFDAC Registration Number (NRN)
Tablet (NRN: NRN: A4-5636): Each uncoated tablet contains Lisinopril Dihydrate BP Equivalent to Lisinopril 20 mg, Hydrochlorothiazide 12.5 mg
Pack size: Available as blister of 14 tablets in a pack of 2 x 14 tablets.
ALSTORETIC®-20 (Lisinopril and Hydrochlorothiazide) combines an angiotensin converting enzyme inhibitor, lisinopril, and a diuretic, hydrochlorothiazide. Lisinopril, a synthetic peptide derivative, is an oral long-acting angiotensin converting enzyme inhibitor.
It is chemically described as (2S)-1-[(2S)-6-Amino- 2-[[(1 S)-1-carboxy-3-phenylpropyl)amino)hexanoyl)pyrrolidine-2-carboxylic acid dihydrate. Its empirical formula is C21H31N3O52H2O
Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in water, sparingly soluble in methanol, and practically insoluble in ethanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1, 1-dioxide. Its empirical formula is C7H8CIN3O4S2
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Lisinopril and hydrochlorothiazide is available for oral use in three tablet combinations of
lisinopril and hydrochlorothiazide: 10-12.5 mg containing 10 mg lisinopril and 12.5 mg hydrochlorothiazide,
lisinopril and hydrochlorothiazide: 20-12.5 mg containing 20 mg lisinopril and 12.5 mg hydrochlorothiazide and
lisinopril and hydrochlorothiazide: 20-25 mg containing 20 mg lisinopril and 25 mg hydrochlorothiazide.
As a result of its diuretic effects, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium. Administration of lisinopril blocks the renin-angiotensin-aldosterone axis and tends to reverse the potassium lose associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the combination of lisinopril and hydrochlorothiazide was approximately additive.
The lisinopril and hydrochlorothiazide 10-12.5 mg combination worked equally well in black and white patients.
The lisinopril and hydrochlorothiazide 20-12.5 mg and lisinopril and hydrochlorothiazide combinations appeared somewhat less effective in black patients, but relatively few black patients were studied.
In most patients, the antihypertensive effect of lisinopril and hydrochlorothiazide was sustained for at least 24 hours.
In a randomized, controlled comparison, the mean antihypertensive effects of Lisinopril and Hydrochlorothiazide 20-12.5 mg and Lisinopril and Hydrochlorothiazide 20-25 mg were similar, suggesting that many patients who respond adequately to the latter combination may be controlled with Lisinopril and Hydrochlorothiazide 20-12.5 mg.
(See DOSAGE AND ADMINISTRATION.)
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Lisinopril and hydrochlorothiazide is indicated for the treatment of hypertension. These fixed-dose combinations are not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).
In using lisinopril and hydrochlorothiazide, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that lisinopril does not have a similar risk.
In considering use of lisinopril and hydrochlorothiazide it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
Lisinopril and hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, lisinopril and hydrochlorothiazide should be discontinued as soon as possible.
It is not known whether lisinopril is secreted in human milk. However, milk of lactating rats contains radioactivity following administration of 14C lisinopril. In another study, lisinopril was present in rat milk at levels similar to plasma levels in the dams. Thiazides do appear in human milk.
Because of the potential for serious reactions in nursing infants from ACE inhibitors and hydrochlorothiazide, a decision should be made whether to discontinue nursing or to discontinue lisinopril and hydrochlorothiazide, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Lisinopril with Hydrochlorothiazide did not include significant numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In a multiple dose pharmacokinetic study in elderly versus young hypertensive patients using the lisinopril/hydrochlorothiazide combination, area under the plasma concentration time curve (AUC) increased approximately 120% for lisinopril and approximately 80% for hydrochlorothiazide in older patients.
This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.
Evaluation of the hypertensive patient should always include assessment of renal function.
Lisinopril and hydrochlorothiazide has been evaluated for safety in 930 patients, including 100 patients treated for 50 weeks or more.
In clinical trials with lisinopril and hydrochlorothiazide no adverse experiences peculiar to this combination drug have been observed.
Adverse experiences that have occurred have been limited to those that have been previously reported with lisinopril or hydrochlorothiazide.
The most frequent clinical adverse experiences in controlled trials (including open label extensions) with any combination of lisinopril and hydrochlorothiazide were: dizziness (7.5 percent), headache (5.2 percent), cough (3.9 percent), fatigue (3.7 percent) and orthostatic effects (3.2 percent), all of which were more common than in placebo-treated patients.
Generally, adverse experiences were mild and transient in nature; but see WARNINGS regarding angioedema and excessive hypotension or syncope. Discontinuation of therapy due to adverse effects was required in 4.4 percent of patients, principally because of dizziness, cough, fatigue and muscle cramps.
Adverse experiences occurring in greater than one percent of patients treated with lisinopril plus hydrochlorothiazide in controlled clinical trials are shown below.
|Percent of Patients in controlled Studies
|Upper Respiratory Infection||2.2(0.0)||0.0|
Clinical adverse experiences occurring in 0.3 to 1.0 percent of patients in controlled trials included:
Body as a Whole: Chest pain, abdominal pain, syncope, chest discomfort, fever, trauma, virus infection.
Cardiovascular: Palpitation, orthostatic hypotension.
Digestive: Gastrointestinal cramps, dry mouth, constipation, heartburn.
Musculoskeletal: Back pain, shoulder pain, knee pain, back strain, myalgia, foot pain.
Nervous/Psychiatric: Decreased libido, vertigo, depression, somnolence.
Respiratory: Common cold, nasal congestion, influenza, bronchitis, pharyngeal pain, dyspnea, pulmonary congestion, chronic sinusitis, allergic rhinitis, pharyngeal discomfort.
Skin: Flushing, pruritus, skin inflammation; diaphoresis.
Special Senses: Blurred vision, tinnitus, otalgia.
Urogenital: Urinary tract infection.
Dosage & Administration
Lisinopril is an effective treatment of hypertension in once daily doses of 10- 80 mg, while hydrochlorothiazide is effective in doses of 12.5-50 mg. In clinical trials of lisinopril/hydrochlorothiazide combination therapy using lisinopril doses of 10-80 mg and hydrochlorothiazide doses of 6.25-50 mg, the antihypertensive response rates generally increased with increasing dose of either component.
The side effects of lisinopril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter.
Therapy with any combination of lisinopril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but addition of lisinopril in clinical trials blunted the hypokalemia normally seen with diuretics.
To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
Dose Titration Guided by Clinical Effect
A patient whose blood pressure is not adequately controlled with either lisinopril or hydrochlorothiazide monotherapy may be switched to Lisinopril and Hydrochlorothiazide Tablets 10/12.5 mg or Lisinopril and Hydrochlorothiazide Tablets 20/12.5 mg.
Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2-3 weeks have elapsed.
Patients whose blood pressures are adequately controlled with 25 mg of daily hydrochlorothiazide, but who experience significant potassium loss with this regimen, may achieve similar or greater blood pressure control with less potassium loss if they are switched to Lisinopril and Hydrochlorothiazide Tablets 10/12.5 mg. Dosage higher than lisinopril 80 mg and hydrochlorothiazide 50 mg should not be used.
The combination may be substituted for the titrated individual components.
Use in Renal Impairment
The usual regimens of therapy with lisinopril and hydrochlorothiazide need not be adjusted as long as the patient's creatinine clearance is >30 mL/min/1.73m2 (serum creatinine approximately=3 mg/dL or 265 µmol/L).
ln patients with more severe renal impairment, loop diuretics are preferred to thiazides, so lisinopril and hydrochlorothiazide is not recommended.
No specific information is available on the treatment of overdosage with lisinopril and hydrochlorothiazide. Treatment is symptomatic and supportive. Therapy with lisinopril and hydrochlorothiazide should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.
Following a single oral dose of 20 mg/kg, no lethality occurred in rats and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril can be removed by hemodialysis.
Oral administration of a single oral dose of 10 mg/kg to mice and rats was not lethal. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.
If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.
Store in a cool, dry & dark place. Keep out of reach of children.