Accuretic

Name: Accuretic

What is the most important information I should know about Accuretic (hydrochlorothiazide and quinapril)?

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away.

If you have diabetes, do not use hydrochlorothiazide and quinapril together with any medication that contains aliskiren (Amturnide, Tekturna, Tekamlo).

What should I avoid while taking Accuretic (hydrochlorothiazide and quinapril)?

Do not use salt substitutes or potassium supplements while taking quinapril, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of this medicine.

Accuretic (hydrochlorothiazide and quinapril) side effects

Get emergency medical help if you have signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • a light-headed feeling, like you might pass out;

  • eye pain, vision problems;

  • swelling, weight gain, shortness of breath;

  • sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, trouble swallowing;

  • high potassium--nausea, slow or unusual heart rate, weakness, loss of movement;

  • low potassium--confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling;

  • low levels of sodium--headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady; or

  • severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

  • cough;

  • headache, dizziness;

  • tired feeling; or

  • muscle pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What are some things I need to know or do while I take Accuretic?

  • Tell all of your health care providers that you take Accuretic. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Have your blood pressure checked often. Talk with your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • This medicine may affect certain lab tests. Tell all of your health care providers and lab workers that you take Accuretic.
  • If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
  • If you are taking a salt substitute that has potassium, potassium-sparing diuretics, or potassium, talk with your doctor.
  • If you are on a low-salt or salt-free diet, talk with your doctor.
  • Talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
  • Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
  • If you are taking lithium, talk with your doctor. You may need to have your blood work checked more closely while you are taking it with this medicine.
  • Low white blood cell counts have happened with captopril, a drug like this one. This may lead to more chance of getting an infection. Most of the time, this has happened in people with kidney problems, mainly if they have certain other health problems. Call your doctor right away if you have signs of infection like fever, chills, or sore throat. Talk with your doctor.
  • If you take cholestyramine or colestipol, talk with your pharmacist about how to take them with Accuretic.
  • Watch for gout attacks.
  • If you have lupus, this medicine can make your lupus active or get worse. Tell your doctor right away if you get any new or worse signs.
  • Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
  • Tell your doctor if you have too much sweat, fluid loss, throwing up, or loose stools. This may lead to low blood pressure.
  • A very bad reaction called angioedema has happened with Accuretic. Sometimes, this has been deadly. The chance of angioedema may be higher in black patients. Talk with the doctor.

Accuretic - Clinical Pharmacology

Mechanism of Action

The principal metabolite of quinapril, quinaprilat, is an inhibitor of ACE activity in human subjects and animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine, or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).

While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldolsterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Pharmacokinetics and Metabolism

The rate and extent of absorption of quinapril and hydrochlorothiazide from Accuretic tablets are not different, respectively, from the rate and extent of absorption of quinapril and hydrochlorothiazide from immediate-release monotherapy formulations, either administered concurrently or separately. Following oral administration of Accupril (quinapril monotherapy) tablets, peak plasma quinapril concentrations are observed within 1 hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The absorption of hydrochlorothiazide is somewhat slower (1 to 2.5 hours) and more complete (50% to 80%).

The rate of quinapril absorption was reduced by 14% when Accuretic tablets were administered with a high-fat meal as compared to fasting, while the extent of absorption was not affected. The rate of hydrochlorothiazide absorption was reduced by 12% when Accuretic tablets were administered with a high-fat meal, while the extent of absorption was not significantly affected. Therefore, Accuretic may be administered without regard to food.

Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours postdose. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, consistent with measured plasma protein binding of 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma.

Some placental passage occurred when quinapril was administered to pregnant rats. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. Hydrochlorothiazide crosses the placenta freely but not the blood-brain barrier.

Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. Hydrochlorothiazide is excreted unchanged by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.

In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat is reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.

The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5- to 80-mg doses and 40- to 160-mg in multiple daily doses.

Pharmacodynamics and Clinical Effects

Single doses of 20 mg of quinapril provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20-mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg.

Administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS).

Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect.

While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice-daily dosing tended to give a somewhat lower trough blood pressure than once-daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness.

Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction.

Therapeutic effects of quinapril appear to be the same for elderly (≥65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. In patients with hypertension, quinapril 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics.

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Use of quinapril with a thiazide diuretic gives blood pressure lowering effect greater than that seen with either agent alone. In clinical trials of quinapril/hydrochlorothiazide using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects were sustained for at least 24 hours, and increased with increasing dose of either component. Although quinapril monotherapy is somewhat less effective in blacks than in non-blacks, the efficacy of combination therapy appears to be independent of race. By blocking the renin-angiotensin-aldosterone axis, administration of quinapril tends to reduce the potassium loss associated with the diuretic. In clinical trials of Accuretic, the average change in serum potassium was near zero when 2.5 to 40 mg of quinapril was combined with hydrochlorothiazide 6.25 mg, and the average subject who received 10 to 20/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.

Accuretic Dosage and Administration

As individual monotherapy, quinapril is an effective treatment of hypertension in once-daily doses of 10 to 80 mg and hydrochlorothiazide is effective in doses of 12.5 to 50 mg. In clinical trials of quinapril/hydrochlorothiazide combination therapy using quinapril doses of 2.5 to 40 mg and hydrochlorothiazide doses of 6.25 to 25 mg, the antihypertensive effects increased with increasing dose of either component.

The side effects (see WARNINGS) of quinapril 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 quinapril and hydrochlorothiazide will be associated with both sets of dose-independent side effects, but regimens that combine low doses of hydrochlorothiazide with quinapril produce minimal effects on serum potassium. In clinical trials of Accuretic, the average change in serum potassium was near zero in subjects who received HCTZ 6.25 mg in the combination, and the average subject who received 10 to 40/12.5 to 25 mg experienced a milder reduction in serum potassium than that experienced by the average subject receiving the same dose of hydrochlorothiazide monotherapy.

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.

Therapy Guided by Clinical Effect

Patients whose blood pressures are not adequately controlled with quinapril monotherapy may instead be given Accuretic 10/12.5 or 20/12.5. Further increases of either or both components could depend on clinical response. The hydrochlorothiazide dose should generally not be increased until 2 to 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 blood pressure control with less electrolyte disturbance if they are switched to Accuretic 10/12.5 or 20/12.5.

Replacement Therapy

For convenience, patients who are adequately treated with 20 mg of quinapril and 25 mg of hydrochlorothiazide and experience no significant electrolyte disturbances may instead wish to receive Accuretic 20/25.

Use in Renal Impairment

Regimens of therapy with Accuretic need not take account of renal function as long as the patient's creatinine clearance is >30 mL/min/1.73 m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, loop diuretics are preferred to thiazides. Therefore, Accuretic is not recommended for use in these patients.

For Healthcare Professionals

Applies to hydrochlorothiazide / quinapril: oral tablet

Respiratory

Common (1% to 10%): Dry cough, rhinitis, upper respiratory infection, bronchitis, pharyngitis
Uncommon (0.1% to 1%):
Rare (less than 0.1%): Pneumonia, asthma, respiratory infiltration, lung disorder, acute noncardiogenic pulmonary edema
Frequency not reported: Rash, acute pulmonary edema, interstitial cystitis[Ref]

Renal

Patients with renal artery stenosis maintain glomerular filtration rate (GFR) by efferent arteriolar vasoconstriction, which is blocked by quinapril.

Although quinapril may be associated with a rise in serum creatinine and BUN, GFR has been shown to remain unchanged or improve in most patients.

HCTZ has been used to treat nephrogenic diabetes insipidus. However, a case in which the drug was believed to have caused this condition has been reported.[Ref]

Frequency not reported: New or worsened renal insufficiency (especially in patients with preexisting renal insufficiency or who are angiotensin-dependent, such as those with CHF)

Quinapril:
Frequency not reported: Acute renal failure, new onset proteinuria

Hydrochlorothiazide:
Rare (less than 0.1%): Interstitial nephritis[Ref]

Cardiovascular

Common (1% to 10%): Vasodilation, vertigo, chest pain
Uncommon (0.1% to 1%): Palpitations, tachycardia
Rare (less than 0.1%): Heart failure, myocardial infarction, cerebrovascular accident, hypertensive crisis, orthostatic hypotension, cardiac rhythm disturbance
Frequency not reported: Hydrochlorothiazide-induced hypokalemia can predispose some patients to various cardiac arrhythmias, such as ventricular ectopy and complete AV heart block
Postmarketing reports: Bradycardia, cor pulmonale, vasculitis, deep thrombosis[Ref]

Hypotension is most likely in patients who are sodium and intravascular volume depleted.[Ref]

Hypersensitivity

Patients with intestinal angioedema generally present with abdominal pain (with or without nausea or vomiting) and in some cases there was no prior history of facial angioedema, and C-1 esterase levels were normal. These symptoms resolve after stopping the ACE inhibitor..

There have been approximately 34 known cases of thiazide-induced pulmonary edema, encompassing 52 episodes of pulmonary edema, as of 1991 (per a 1996 review). In some cases, doses as small as 12.5 mg were associated with the development of pulmonary edema. The average time to onset of this adverse reaction was 44 minutes, women have a relative risk of 9:1, and the average age was 56 years. The mortality rate was 6%. Some experts consider this side effect grossly underreported.[Ref]

Quinapril:
Rare (less than 0.1%): Angioedema of the face, extremities, lips, tongue, glottis and/or pharynx, intestinal angioedema

Hydrochlorothiazide:
Uncommon (0.1% to 1%): Rash, anaphylaxis[Ref]

Nervous system

Common (1% to 10%): Headache, dizziness, fatigue, insomnia, somnolence, asthenia
Postmarketing reports: Speech disorder, meningism, amnesia[Ref]

Metabolic

Quinapril:
Rare (less than 0.1%): Angioedema of the face, extremities, lips, tongue, glottis and/or pharynx, intestinal angioedema

Hydrochlorothiazide:
Frequency not reported: Metabolic alkalosis, hyponatremia, hypomagnesemia, hypercalcemia, hyperglycemia, elevated serum uric acid levels, increased serum cholesterol[Ref]

HCTZ may increase total serum cholesterol by 11%, LDL lipoprotein cholesterol by 12%, and VLDL lipoprotein cholesterol levels by 50%, as well as reduce insulin secretion. It should be used with caution in patients with diabetes or hypercholesterolemia.

Hyperuricemia may be an important consideration in patients with a history of gout. Hypophosphatemia and low serum magnesium concentrations may also occur, but are usually clinically insignificant except in malnourished patients.[Ref]

Hematologic

Quinapril:
Rare (less than 0.1%): Neutropenia, bone marrow depression

Hydrochlorothiazide:
Very rare (less than 0.01%): Immune complex hemolytic anemia, aplastic anemia, thrombocytopenia[Ref]

Gastrointestinal

Thiazide diuretics may increase serum cholesterol and triglycerides, resulting in an increased risk of cholesterol gallstone formation. Reports of bowel strictures associated with thiazide ingestion were reported in the 1960's (although patients in these reports were on a combination HCTZ-potassium product).[Ref]

Common (1% to 10%): Nausea, vomiting, abdominal pain, diarrhea, dyspepsia
Uncommon (0.1% to 1%): Dry mouth, gastrointestinal hemorrhage

Hydrochlorothiazide:
Rare (less than 0.1%): Pancreatitis, acute cholecystitis[Ref]

Dermatologic

Hydrochlorothiazide:
Rare (less than 0.1%): A distinct entity with clinical and laboratory features indistinguishable from those of subacute cutaneous lupus erythematosus, pruritus, increased sweating, erythema, alopecia, pemphigus
Frequency not reported: Erythema annular centrifugum, acute eczematous dermatitis, morbilliform or leukocytoclastic vasculitis, phototoxic dermatitis
Postmarketing reports: Urticaria, maculopapular rash, petechiae[Ref]

Endocrine

A prospective study of 34 patients who received oral thiazide diuretics for 14 years without interruption revealed an increased mean fasting blood glucose level after treatment. Withdrawal of thiazide therapy for seven months in 10 of the patients resulted in mean reductions of 10% in fasting blood glucose and 25% in the 2-hour glucose tolerance test value. A control group was not reported.[Ref]

Hydrochlorothiazide:
Frequency not reported: Glucose intolerance and a potentially deleterious effect on the lipid profile (either of which may be important in some patients with or at risk for diabetes or coronary artery disease)[Ref]

Musculoskeletal

Rare (less than 0.1%): Myalgias, chills, myopathy, myositis, muscle spasm, back pain, arthritis
Postmarketing reports: Paralysis, hemiplegia, abnormal gait[Ref]

Genitourinary

Rare (less than 0.1%): Impotence in male patients, interstitial cystitis[Ref]

Ocular

Hydrochlorothiazide:
Rare (less than 0.1%): Acute transient myopia, acute angle-closure glaucoma[Ref]

Hepatic

Hydrochlorothiazide:
Frequency not reported: Interstitial nephritis[Ref]

Some side effects of Accuretic may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Hydrochlorothiazide / quinapril Pregnancy Warnings

-Use is contraindicated. (AU, UK) -This drug should not be used in pregnancy unless the benefit outweighs the risk to the fetus. (US) AU TGA pregnancy category: D US FDA pregnancy category: D Comments: -Adequate methods of contraception should be encouraged. -If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

-Data have shown an association between major congenital malformations and the use of ACE inhibitors during the first trimester. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. -Mothers whose embryos and fetuses are exposed to an ACE inhibitor during the first trimester should be informed of the risks. When pregnancy is detected or expected, this should be discontinued as soon as possible. -Cases of neonatal thrombocytopenia associated with antepartum administration of thiazide diuretics have been reported. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

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