Zivast-L

Atorvastatin:

• Pharmacological action
• Pharmacokinetics
• Why is Zivast-L prescribed?
• Dosage and administration
• Zivast-L (Atorvastatin) side effects, adverse reactions
• Zivast-L contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Zivast-L drug interactions
• Zivast-L in case of emergency / overdose
• Zivast-L (Atorvastatin) reviews

Pharmacological action

Zivast-L is a lipid-lowering drugs of the statin group. An inhibition of HMG-CoA reductase leads to a series of sequential reactions that result in reduced intracellular cholesterol content and it is a compensatory increase in activity of LDL receptors and thus accelerate the catabolism of LDL cholesterol.

The lipid-lowering effect of statins is associated with lower levels of total cholesterol by LDL-C. The reduction in LDL cholesterol is dose-dependent and is not linear, but exponential. The inhibitory effect of Zivast-L (Atorvastatin) on HMG-CoA reductase by about 70% determined by the activity of its circulating metabolites.

Statins do not affect the activity of lipoprotein lipase and hepatic, no significant effect on the synthesis and catabolism of free fatty acids, so their effect on triglycerides and again vicariously through their main effects on reducing LDL-C.

In addition to lipid-lowering actions, statins have beneficial effects in endothelial dysfunction (pre-clinical sign of early atherosclerosis) in the vascular wall, the state of atheroma, improves blood rheology, have antioxidant, antiproliferative properties.

Zivast-L (Atorvastatin) lowers cholesterol levels in patients with homozygous familial hypercholesterolemia, which is usually not amenable to therapy with lipid-lowering agents.

Pharmacokinetics

Zivast-L (Atorvastatin) is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability is low (about 12%) due to first-pass clearance in gastrointestinal mucosa and / or due to the "first pass" through the liver, predominantly in the scene. Zivast-L (Atorvastatin) is metabolized with the participation of isoenzyme CYP3A4 to form a number of substances which are inhibitors of HMG-CoA reductase inhibitors.

T_1/2 from plasma is about 14 hours, although the T_1/2 inhibitor activity of HMG-CoA reductase is approximately 20-30 hours, due to the involvement of active metabolites.

The plasma protein binding is 98%.

Zivast-L (Atorvastatin) is excreted in the form of metabolites mainly in the bile.

Why is Zivast-L prescribed?

Primary hypercholesterolemia in ineffectiveness of diet, combined hypercholesterolemia and hypertriglyceridemia, heterozygous and homozygous familial hypercholesterolemia with the ineffectiveness of diet.

Dosage and administration

The treatment by Zivast-L is with a standard diet for patients with hypercholesterolemia. The dose is determined individually, depending on the initial cholesterol levels. This medication is taken orally. The initial dose is usually 10 mg 1 time / day. The effect is manifested within 2 weeks, and the maximum effect is for 4 weeks. If necessary, the dose can be gradually increased every 4 weeks or more. The maximum daily dose is 80 mg.

Zivast-L (Atorvastatin) side effects, adverse reactions

Digestive system: constipation, flatulence, dyspepsia, abdominal pain, nausea, diarrhea.

CNS and peripheral nervous system: headache, insomnia.

Other: asthenia, myalgia.

Zivast-L contraindications

Liver disease in the active phase, increasing the serum transaminase activity more than 3 times of unknown origin, pregnancy, lactation (breastfeeding), hypersensitivity to Zivast-L (Atorvastatin). Women of reproductive age not using reliable contraception.

Using during pregnancy and breastfeeding

Zivast-L is contraindicated during pregnancy and lactation (breastfeeding).

It is not known whether Zivast-L (Atorvastatin) is allocated in breast milk. Given the potential for adverse effects in infants, if necessary to use this drug during lactation it should decide on the termination of breastfeeding.

Women of reproductive age during treatment should use adequate contraceptive methods. Zivast-L (Atorvastatin) may be used in women of childbearing age only if the probability of pregnancy is very low, and the patient informed about the possible risk of treatment for the fetus.

Category of the fetus by FDA - X.

Special instructions

Prior to and during treatment with Zivast-L (Atorvastatin), especially if symptoms of liver damage, it is necessary to monitor liver function tests. With an increase in transaminase levels it should be monitored their activity up to normalization. If AST or ALT more than 3 times the norm persists, we recommend reducing the dose or withdrawal of Zivast-L (Atorvastatin).

When prompted during the treatment of symptoms of myopathy it should determine the activity of creatine kinase. If a significant increase in CK levels is preserved, it is recommended to reduce the dose of Zivast-L (Atorvastatin) or to cancel taking it.

The risk of myopathy during the treatment with Zivast-L (Atorvastatin) increased, while the use of cyclosporine, fibrates, erythromycin, antifungal agents belonging to azoles, and niacin.

There is a likelihood of the following side effects, but not in all cases, a clear link with taking Zivast-L (Atorvastatin): muscle cramps, myositis, myopathy, paresthesia, peripheral neuropathy, pancreatitis, hepatitis, cholestatic jaundice, anorexia, vomiting, alopecia, pruritus, rash, impotence, hyperglycemia and hypoglycemia.

The children experience of Zivast-L (Atorvastatin) using at a dose of 80 mg / day is restricted.

With careful use Zivast-L (Atorvastatin) in patients with chronic alcoholism.

Zivast-L drug interactions

When this drug applied simultaneously with:

- digoxin slightly increased concentration of digoxin in plasma.

- itraconazole greatly increases the concentration of Zivast-L (Atorvastatin) in plasma, apparently due to inhibition of itraconazole its metabolism in the liver that occurs with the participation of isoenzyme CYP3A4; increased risk of myopathy.

- colestipol may decrease the concentration of Zivast-L (Atorvastatin) in plasma, with lipid-lowering effect is enhanced.

- antacids containing magnesium hydroxide and aluminum hydroxide, reduce the concentration of Zivast-L (Atorvastatin) by approximately 35%.

- cyclosporine, fibrates (including gemfibrozil), azole antifungals derivatives, nicotinic acid increases the risk of myopathy.

- erythromycin, clarithromycin moderately increased concentrations of Zivast-L (Atorvastatin) in plasma, increases the risk of myopathy.

- ethinyl estradiol, norethisterone (norethindrone) slightly increases the concentration of ethinyl estradiol, norethisterone and (norethindrone) in blood plasma.

- protease inhibitors increases the concentration of Zivast-L (Atorvastatin) in plasma, as protease inhibitors are inhibitors of the CYP3A4 isoenzyme.

Diltiazem, verapamil, isradipine inhibit isoenzyme CYP3A4, which participates in the metabolism of Zivast-L (Atorvastatin) Sanis Health, so that while the use of these calcium channel blockers may increase the concentration of Zivast-L (Atorvastatin) in plasma and increased risk of myopathy.

Zivast-L in case of emergency / overdose

Treatment: symptomatic and supportive therapy. There is no specific antidote. Hemodialysis is ineffective.

Losartan:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Patient information
• Zivast-L (Losartan) reviews

INDICATIONS AND USAGE

Hypertension

Zivast-L Potassium Tablets, USP is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics.

Hypertensive Patients with Left Ventricular Hypertrophy

Zivast-L (Losartan) Potassium Tablets USP is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. (See PRECAUTIONS , Race and CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race .)

Nephropathy in Type 2 Diabetic Patients

Zivast-L (Losartan) potassium is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥ 300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Zivast-L (Losartan) potassium reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation) (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects ).

CONTRAINDICATIONS

Zivast-L (Losartan) Potassium Tablets USP is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, Zivast-L potassium tablets should be discontinued as soon as possible.

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 renal function; oligohydramnios in this setting has been associated with 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.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Zivast-L (Losartan) potassium tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Zivast-L (Losartan) potassium tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Zivast-L (Losartan) potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of Zivast-L (Losartan) and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Hypotension - Volume-Depleted Patients

In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with Zivast-L (Losartan) potassium. These conditions should be corrected prior to administration of Zivast-L (Losartan) potassium tablets, or a lower starting dose should be used (see DOSAGE AND ADMINISTRATION ).

PRECAUTIONS

General

Hypersensitivity: Angioedema.

See ADVERSE REACTIONS , Post-Marketing Experience.

Impaired Hepatic Function

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of Zivast-L in cirrhotic patients, a lower dose should be considered for patients with impaired liver function (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY , Pharmacokinetics ).

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with Zivast-L (Losartan) potassium; in some patients, these changes in renal function were reversible upon discontinuation of therapy.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Zivast-L (Losartan) potassium.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with Zivast-L (Losartan) potassium; in some patients, these effects were reversible upon discontinuation of therapy.

Electrolyte Imbalance

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with Zivast-L potassium as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see ADVERSE REACTIONS ).

Information for Patients

Pregnancy: Female patients of childbearing age should be told about the consequences of second-and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.

Potassium Supplements: A patient receiving Zivast-L (Losartan) potassium tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician (see PRECAUTIONS , Drug Interactions ).

Drug Interactions: No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of Zivast-L (Losartan) and its active metabolite. (See CLINICAL PHARMACOLOGY , Drug Interactions .) In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of Zivast-L (Losartan) to the active metabolite after intravenous administration of Zivast-L (Losartan), and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased Zivast-L (Losartan) concentration. The pharmacodynamic consequences of concomitant use of Zivast-L (Losartan) and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize Zivast-L (Losartan) to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of Zivast-L (Losartan) to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Lithium: As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) including Selective Cyclooxygenase-2 Inhibitors(COX-2Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function co-administration of NSAIDS, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including Zivast-L (Losartan)) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Zivast-L (Losartan) and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Zivast-L (Losartan) may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Dual blockade of the renin-angiotensin-aldosterone system: Dual blockade of the renin-angiotensin-aldosterone system is associated with increased risk of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure). Closely monitor blood pressure, renal function, and electrolytes in patients on Zivast-L (Losartan) Potassium Tablets and ACE inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Zivast-L potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for Zivast-L (Losartan) and its pharmacologically active metabolite that were approximately 160- and 90-times (rats) and 30- and 15-times (mice) the exposure of a 50 kg human given 100 mg per day.

Zivast-L (Losartan) potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of Zivast-L (Losartan) potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for Zivast-L (Losartan) and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNING , Fetal/Neonatal Morbidity and Mortality .

Nursing Mothers

It is not known whether Zivast-L is excreted in human milk, but significant levels of Zivast-L (Losartan) and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Antihypertensive effects of Zivast-L (Losartan) potassium have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data on the effect of Zivast-L (Losartan) potassium on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m² (see CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects and DOSAGE AND ADMINISTRATION).

Geriatric Use

Of the total number of patients receiving Zivast-L potassium in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Race

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on Zivast-L (Losartan) potassium. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of Zivast-L (Losartan) potassium on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients. (See CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects ; Reduction in the Risk of Stroke .)

ADVERSE REACTIONS

Hypertension

Zivast-L potassium has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year. In general, treatment with Zivast-L (Losartan) potassium was well-tolerated. The overall incidence of adverse experiences reported with Zivast-L (Losartan) potassium was similar to placebo.

In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 2.3 percent of patients treated with Zivast-L (Losartan) potassium and 3.7 percent of patients given placebo.

The following table of adverse events is based on four 6- to 12-week, placebo-controlled trials involving over 1000 patients on various doses (10-150 mg) of Zivast-L (Losartan) and over 300 patients given placebo. All doses of Zivast-L (Losartan) are grouped because none of the adverse events appeared to have a dose-related frequency. The adverse experiences reported in ≥1% of patients treated with Zivast-L (Losartan) potassium and more commonly than placebo are shown in the table below.

The following adverse events were also reported at a rate of 1% or greater in patients treated with Zivast-L (Losartan), but were as, or more frequent, in the placebo group: asthenia/fatigue, edema/swelling, abdominal pain, chest pain, nausea, headache, pharyngitis, diarrhea, dyspepsia, myalgia, insomnia, cough, sinus disorder.

Adverse events occurred at about the same rates in men and women, older and younger patients, and Black and non-Black patients.

A patient with known hypersensitivity to aspirin and penicillin, when treated with Zivast-L (Losartan) potassium, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.

Superficial peeling of palms and hemolysis were reported in one subject.

In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to Zivast-L (Losartan) or other adverse events that occurred in <1% of patients in clinical studies are listed below. It cannot be determined whether these events were causally related to Zivast-L (Losartan): Body as a Whole: facial edema, fever, orthostatic effects, syncope; Cardiovascular: angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation; Digestive: anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting; Hematologic: anemia; Metabolic: gout; Musculoskeletal: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness; Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, decreased libido, memory impairment, migraine, nervousness, paresthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo; Respiratory: dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion; Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria; Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity; Urogenital: impotence, nocturia, urinary frequency, urinary tract infection.

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of Zivast-L (Losartan) on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to Zivast-L (Losartan) 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown below.

† Demographics = (89% caucasian, 64% female)

†† Demographics = (90% caucasian, 51% female)

These studies demonstrate that the incidence of cough associated with Zivast-L (Losartan) therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of Zivast-L (Losartan) in post-marketing experience.

Pediatric Patients: No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.

Hypertensive Patients with Left Ventricular Hypertrophy

In the LIFE study, adverse events with Zivast-L (Losartan) potassium were similar to those reported previously for patients with hypertension.

Nephropathy in Type 2 Diabetic Patients

In the RENAAL study involving 1513 patients treated with Zivast-L potassium tablets or placebo, the overall incidences of reported adverse experiences were similar for the two groups. Zivast-L (Losartan) potassium tablets was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo (19% for Zivast-L (Losartan) potassium tablets, 24% for placebo). The adverse experiences, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with Zivast-L (Losartan) potassium tablets and occurring more commonly than placebo, on a background of conventional antihypertensive therapy, are shown in the table below.

Post-Marketing Experience

The following additional adverse reactions have been reported in post-marketing experience:

Digestive: Hepatitis (reported rarely).

General Disorders and Administration Site Conditions : Malaise.

Hemic: Thrombocytopenia (reported rarely).

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with Zivast-L (Losartan); some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported. Anaphylactic reactions have been reported.

Metabolic and Nutrition: Hyperkalemia, hyponatremia have been reported with Zivast-L (Losartan).

Musculoskeletal: Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Nervous system disorders: Dysgeusia

Respiratory: Dry cough.

Skin: Erythroderma

Laboratory Test Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Zivast-L (Losartan) potassium.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with Zivast-L (Losartan) potassium alone (see PRECAUTIONS , Impaired Renal Function ).

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred frequently in patients treated with Zivast-L (Losartan) potassium alone, but were rarely of clinical importance. No patients were discontinued due to anemia.

Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with Zivast-L (Losartan) potassium alone, one patient (<0.1%) was discontinued due to these laboratory adverse experiences.

OVERDOSAGE

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m² basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither Zivast-L (Losartan) nor its active metabolite can be removed by hemodialysis.

DOSAGE AND ADMINISTRATION

Adult Hypertensive Patients

Zivast-L potassium tablets may be administered with other antihypertensive agents, and with or without food.

Dosing must be individualized. The usual starting dose of Zivast-L (Losartan) potassium tablets is 50 mg once daily, with 25 mg used in patients with possible depletion of intravascular volume (e.g., patients treated with diuretics) (see WARNINGS , Hypotension - Volume-Depleted Patients ) and patients with a history of hepatic impairment (see PRECAUTIONS , General ). Zivast-L (Losartan) potassium tablets can be administered once or twice daily with total daily doses ranging from 25 mg to 100 mg.

If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The effect of Zivast-L (Losartan) is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Hypertension).

If blood pressure is not controlled by Zivast-L (Losartan) potassium alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Hypertension ).

No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.

Pediatric Hypertensive Patients ≥ 6 years of age

The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total) administered as a tablet or a suspension (see Preparation of Suspension). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects , and WARNINGS , Hypotension - Volume-Depleted Patients .)

Zivast-L (Losartan) potassium is not recommended in pediatric patients <6 years of age or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m² (see CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects , and PRECAUTIONS ).

Preparation of Suspension

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg Zivast-L (Losartan) potassium tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus ** and Ora-Sweet SF **. Add 190 mL of the 50/50 Ora-Plus /Ora-Sweet SF mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

Hypertensive Patients with Left Ventricular Hypertrophy

The usual starting dose is 50 mg of Zivast-L (Losartan) potassium tablets once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Zivast-L (Losartan) potassium should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke ).

Nephropathy in Type 2 Diabetic Patients

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Nephropathy in Type 2 Diabetic Patients). Zivast-L (Losartan) potassium may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).

HOW SUPPLIED

Zivast-L Potassium Tablets USP 25 mg

White, round, biconvex film-coated tablets with “APO” debossed on one side and “LS” over “25” on the other side. Supplied in the following presentations

Bottles of 30 (NDC 60505-3160-3)

Bottles of 90 (NDC 60505-3160-9)

Bottles of 1000 (NDC 60505-3160-8)

Unit dose Blisters of 100 (10x10s) (NDC 60505-3160-0)

Zivast-L (Losartan) Potassium Tablets USP 50 mg

White to off white, round, biconvex, film-coated, scored tablets debossed “APO” on one side and “LS” bisect “50” on the other side. Supplied in the following presentations

Bottles of 30 (NDC 60505-3161-3)

Bottles of 90 (NDC 60505-3161-9)

Bottles of 1000 (NDC 60505-3161-8)

Unit dose Blisters of 100 (10x10s) (NDC 60505-3161-0)

Zivast-L (Losartan) Potassium Tablets USP 100 mg

White, oval, biconvex film-coated tablets with “APO” debossed on one side and “LS100” on the other side. Supplied in the following presentations

Bottles of 30 (NDC 60505-3162-3)

Bottles of 90 (NDC 60505-3162-9)

Bottles of 1000 (NDC 60505-3162-8)

Unit dose Blisters of 100 (10x10s) (NDC 60505-3162-0)

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in a tight, light resistant container.

** Trademark of Paddock Laboratories, Inc

APOTEX CORP.

Zivast-L (Losartan) POTASSIUM TABLETS USP

25 mg, 50 mg and 100 mg

Revised: May 2012

PATIENT INFORMATION

Zivast-L Potassium Tablets USP

25 mg, 50 mg, 100 mg

Read the Patient Information that comes with Zivast-L (Losartan) Potassium Tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your condition and treatment.

What is the most important information I should know about Zivast-L (Losartan) Potassium Tablets?

Do not take Zivast-L (Losartan) Potassium Tablets if you are pregnant or plan to become pregnant. Zivast-L (Losartan) Potassium Tablets can harm your unborn baby causing injury and even death. Stop taking Zivast-L (Losartan) Potassium Tablets if you become pregnant and call your doctor right away. If you plan to become pregnant, talk to your doctor about other treatment options before taking Zivast-L (Losartan) Potassium Tablets.

What is Zivast-L Potassium Tablets?

Zivast-L (Losartan) Potassium Tablets is a prescription medicine called an angiotensin receptor blocker (ARB). It is used:

• Alone or with other blood pressure medicines to lower high blood pressure (hypertension).
• To lower the chance of stroke in patients with high blood pressure and a heart problem called left ventricular hypertrophy. Zivast-L (Losartan) Potassium Tablets may not help Black patients with this problem.
• To slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who have or had high blood pressure.

Zivast-L (Losartan) Potassium Tablets has not been studied in children less than 6 years old or in children with certain kidney problems.

High Blood Pressure (hypertension). Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Zivast-L (Losartan) Potassium Tablets can help your blood vessels relax so your blood pressure is lower.

Left Ventricular Hypertrophy (LVH). is an enlargement of the walls of the left chamber of the heart (the heart’s main pumping chamber). LVH can happen from several things. High blood pressure is the most common cause of LVH.

Type 2 Diabetes with Nephropathy. Type 2 diabetes is a type of diabetes that happens mainly in adults. If you have diabetic nephropathy it means that your kidneys do not work properly because of damage from the diabetes.

Who should not take Zivast-L Potassium Tablets?

• 
  

  Do not take Zivast-L (Losartan) Potassium Tablets if you are allergic to any of the ingredients in Zivast-L (Losartan) Potassium Tablets. See the end of this leaflet for a complete list of ingredients in Zivast-L (Losartan) Potassium Tablets.
  

What should I tell my doctor before taking Zivast-L Potassium Tablets?

Tell your doctor about all of your medical conditions including if you:

• 
  

  Are pregnant or planning to become pregnant. See "What is the most important information I should know about Zivast-L (Losartan) Potassium Tablets?”
  

• 
  

  Are breast-feeding. It is not known if Zivast-L (Losartan) Potassium Tablets passes into your breast milk. You should choose either to take Zivast-L (Losartan) Potassium Tablets or breast-feed, but not both.
  

• 
  

  are vomiting a lot or having a lot of diarrhea
  

• 
  

  have liver problems
  

• 
  

  have kidney problems
  

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Zivast-L Potassium Tablets and certain other medicines may interact with each other. Especially tell your doctor if you are taking:

• 
  

  potassium supplements
  

• 
  

  salt substitutes containing potassium
  

• 
  

  water pills (diuretics)
  

• 
  

  Medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs NSAIDs including COX-2 inhibitors.
  

• other medicines to reduce blood pressure.

How should I take Zivast-L (Losartan) Potassium Tablets?

• 
  

  Take Zivast-L (Losartan) Potassium Tablets exactly as prescribed by your doctor. Your doctor may change your dose if needed.
  

• Zivast-L (Losartan) Potassium Tablets
  

  can be taken with or without food.
  

• 
  

  If you miss a dose, take it as soon as you remember. If it is close to your next dose, donot take the missed dose. Just take the next dose at your regular time.
  

• 
  

  If you take too much Zivast-L (Losartan) Potassium Tablets, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away.
  

What are the possible side effects of Zivast-L Potassium Tablets?

Zivast-L (Losartan) Potassium Tablets may cause the following side effects that may be serious:

• 
  

  Injury or death of unborn babies. See "What is the most important information I should know about Zivast-L (Losartan) Potassium Tablets?”
  

• 
  

  Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat or tongue. Get emergency medical help right away and stop taking Zivast-L (Losartan) Potassium Tablets.
  

• Low blood pressure (hypotension). Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy. Call your doctor right away.
• 
  

  For people who already have kidney problems, you may see a worsening in how well your kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain.
  

The most common side effects of Zivast-L Potassium Tablets in people with high blood pressure are:

• “colds” (upper respiratory infection)
• dizziness
• stuffy nose
• back pain

The most common side effects of Zivast-L (Losartan) Potassium Tablets in people with type 2 diabetes with diabetic kidney disease are:

• diarrhea
• tiredness
• low blood sugar
• chest pain
• high blood potassium
• low blood pressure

Tell your doctor if you get any side effect that bothers you or that won’t go away.

This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist.

How do I store Zivast-L Potassium Tablets?

• 
  

  Store Zivast-L (Losartan) Potassium Tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F), Dispense in a tight; light – resistant container.
  

• 
  

  Keep Zivast-L (Losartan) Potassium Tablets in a tightly closed container that protects the medicine from light.
  

• 
  

  Keep Zivast-L (Losartan) Potassium Tablets and all medicines out of the reach of children.
  

General information about Zivast-L Potassium Tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Zivast-L (Losartan) Potassium Tablets for a condition for which it was not prescribed. Do not give Zivast-L (Losartan) Potassium Tablets to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about Zivast-L (Losartan) Potassium Tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Zivast-L (Losartan) Potassium Tablets that is written for health professionals.

What are the ingredients in Zivast-L Potassium Tablets?

Active ingredients: Zivast-L (Losartan) potassium

Inactive ingredients: Lactose monohydrate, microcrystalline cellulose, pregelatinised starch, magnesium stearate, hypromellose 6 cp, hydroxy propyl cellulose, titanium dioxide and carnauba wax.

Rx only

APOTEX CORP.

Zivast-L (Losartan) POTASSIUM TABLETS USP

25 mg, 50 mg and 100 mg

Revised: May 2012

Zivast-L (Losartan) Potassium 25mg Tablet