Lipid Metabolism Regulator
Action And Clinical Pharmacology: Lovastatin is a cholesterol-lowering agent isolated from a strain of A. terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding b-hydroxyacid form. This principal metabolite is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.
Lovastatin reduces cholesterol production by the liver and induces some changes in cholesterol transport and disposition in the blood and tissues. The mechanism(s) of this effect is believed to involve both reduction of the synthesis of low density lipoprotein (LDL), and an increase in LDL catabolism as a result of induction of the hepatic LDL receptors.
Lovastatin has complex pharmacokinetic characteristics.
Pharmacokinetics: Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding b-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the b-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
Following an oral dose of 4-labeled lovastatin to man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable. In a single dose study in 4 hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on between-subject variability, was approximately 40% for the area under the curve of total inhibitory activity in the general circulation.
Both lovastatin and its b-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
The major active metabolites present in human plasma are the b-hydroxyacid of lovastatin, its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic dose range is 20 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady-state between the second and third days of therapy and were about 1.5 times those following a single dose. When lovastatin was given under fasting conditions, plasma concentrations of both active and total inhibitors were on average about two-thirds those found when lovastatin was administered immediately after a standard test meal.
In a study of patients with severe renal insufficiency (creatinine clearance 0.167 to 0.5 mL/s [10 to 30 mL/min]), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately 2-fold higher than those in healthy volunteers.
Indications And Clinical Uses: As an adjunct to diet, at least equivalent to the American Heart Association (AHA) Step 1 diet, for the reduction of elevated total and Low Density Lipoprotein Cholesterol (LDL-C) levels in patients with primary hypercholesterolemia (Types IIa and IIb),* when the response to diet and other nonpharmacological measures alone has been inadequate.
*A disorder of lipid metabolism characterized by elevated serum cholesterol levels in association with normal triglyceride levels (Type IIa) or with increased triglyceride levels (Type IIb).
After establishing that the elevation in plasma lipids represents a primary disorder not due to secondary conditions such as poorly-controlled diabetes mellitus, hypothyroidism, the nephrotic syndrome, liver disease, or dysproteinemias, it should be determined that patients for whom treatment with lovastatin is being considered have an elevated LDL-C level as the cause for an elevated total serum cholesterol. This may be particularly relevant for patients with total triglycerides over 4.52 mmol/L (400 mg/dL) or with markedly elevated High Density Lipoprotein Cholesterol (HDL-C) values, where non-LDL lipoprotein fractions may contribute significantly to total cholesterol levels without apparent increase in cardiovascular risk. In general, LDL-C may be estimated according to the following equation:
When total triglycerides are greater than 4.52 mmol/L (400 mg/dL) this equation is not applicable. In such patients, LDL-C may be obtained by ultra-centrifugation.
Lovastatin was also found to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL-cholesterol to target levels. In 2 trials including this type of patients, i.e., in a secondary prevention intervention, lovastatin monotherapy was shown to slow the progression of coronary atherosclerosis as evaluated by computerized quantitative coronary angiography (QCA). This effect, however, was not accompanied by an improvement in the clinical endpoints (death, fatal/nonfatal myocardial infarction, hospitalization for unstable angina, and coronary revascularization procedure [PTCA and CABG]) within the 2 to 2 1/2 years’ period of treatment. These trials, however, were not designed to demonstrate a reduction in the risk of coronary morbidity and mortality.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In a trial including hyperlipidemic patients with early, asymptomatic carotid lesions and without known coronary artery disease, the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone. The predictive value of changes in the carotid vasculature for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs 14) and a significant reduction in all-cause mortality (1 vs 8). This trial should be viewed as supportive and complementary to the others mentioned above. However, it was not powered to demonstrate a reduction in the risk of coronary morbidity and mortality. A larger trial of longer duration is needed to clarify the effect of lovastatin in monotherapy on clinical events (see Warnings).
Contra-Indications: Hypersensitivity to any component of this medication. Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy and Lactation (see also Precautions).
Manufacturers’ Warnings In Clinical States: The effect of lovastatin-induced changes in lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity or mortality or total mortality has not been established.
Hepatic Effects: In the initial controlled clinical trials performed in 695 patients, marked persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.6% of adult patients who received lovastatin for at least 1 year (see Adverse Effects and Laboratory Tests). When the drug was interrupted or discontinued in these patients, the transaminase levels fell slowly to pretreatment levels. The increases usually appeared 3 to 12 months after the start of therapy with lovastatin. In most cases they were not associated with jaundice or other clinical signs or symptoms (see Precautions, Drug Interactions and Adverse Effects, Postmarketing Experience).
In a 48-week Expanded Clinical Evaluation of Lovastatin (EXCEL study) performed in 8 245 patients suffering from moderate hypercholesterolemia, the incidence of marked (more than 3 times the upper limit of normal) increases in serum transaminases on successive testing was 0.1% in patients receiving a placebo and 0.1% at 20 mg/day, 0.9% at 40 mg/day and 1.5% at 80 mg/day in patients administered lovastatin. A significant lovastatin dose-related trend was noted for confirmed serum transaminase elevation >3 times the ULN.
It is recommended that liver function tests be performed at baseline and periodically thereafter in all patients. Particular attention should be paid to patients who develop elevated serum transaminase levels, and in these patients, measurements should be repeated promptly and then performed more frequently.
If the transaminase levels show evidence of progression, particularly if they rise to 3 times the upper limit of normal and are persistent, the drug should be discontinued.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver disease or unexplained serum transaminase elevations are contraindications to the use of lovastatin; if such condition develops during therapy, the drug should be discontinued.
Moderate elevations of serum transaminases (less than 3 times the upper limit of normal) have been reported following therapy with lovastatin (see Adverse Effects). These changes were not specific to lovastatin and were also observed with comparative lipid metabolism regulators. They generally appeared within the first 3 months after initiation of therapy, were often transient and were not accompanied by any other symptoms. They did not necessitate interruption of treatment.
Muscle Effects: CPK: Transient elevations of creatine phosphokinase (CPK) levels are commonly seen in lovastatin-treated patients but have usually been of no clinical significance.
Myalgia and muscle cramps have also been associated with lovastatin therapy.
Myopathy has occurred rarely and should be considered in any patient with diffuse myalgias, muscle tenderness and/or weakness and/or marked elevation of creatine phosphokinase (10 times the upper limit of normal). There have been reports of severe rhabdomyolysis that precipitated acute renal failure. Therapy with lovastatin should be discontinued if marked elevation of CPK levels occurs, or if myopathy is diagnosed or suspected.
In the EXCEL study comparing lovastatin to placebo in 8 245 patients, myopathy (defined as a CPK elevation >10 times the ULN with associated muscle symptoms) occurred in 1 patient in the lovastatin 40 mg/day group (0.1%) and in 4 patients in the 80 mg/day group (0.2%).
The EXCEL study, however, excluded patients with factors known to be associated with an increased risk of myopathy, including rhabdomyolysis.
These factors include pre-existing renal insufficiency (usually as a consequence of long-standing diabetes), concomitant therapy with cyclosporine, gemfibrozil, or lipid-lowering doses of niacin, and erythromycin (see Precautions, Drug Interactions).
Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin.
In the initial clinical trials, about 30% of patients on immunosuppressive therapy, including cyclosporine, developed myopathy within a year after starting therapy with lovastatin. The corresponding incidence figures for concomitant therapy with gemfibrozil and niacin were approximately 5% and 2% respectively. Most of these patients were taking lovastatin 40 to 80 mg/day. In 7 subsequent reports, 148 cyclosporine-treated transplant patients (105 cardiac and 43 renal) received concurrent lovastatin 10 to 60 mg/day (the vast majority receiving 20 mg/day) for periods of 3 to 41 months with 1 reported case of rhabdomyolysis (0.6%) and 1 case of significant CPK elevations.
Therefore, the benefits and risks of using lovastatin concomitantly with immunosuppressive drugs, erythromycin, fibrates or lipid-lowering doses of niacin should be carefully considered. In patients receiving lovastatin without these concomitant therapies, the incidence of myopathy was approximately 0.1%.
In 6 patients with cardiac transplants taking immunosuppressive therapy including cyclosporine, concomitantly with lovastatin 20 mg/day, the average plasma level of active metabolites derived from lovastatin was elevated to approximately 4 times the expected levels. In this group the therapeutic response also appeared to be proportionately higher, relative to the dosage used.
Because of an apparent relationship between increased plasma levels of active metabolites derived from lovastatin and myopathy, the daily dosage in patients taking immunosuppressants should not exceed 20 mg/day (see Dosage). Even at this dosage, the benefits and risks of using lovastatin in patients taking immunosuppressants should be carefully considered.
Rhabdomyolysis with renal failure has been reported in a renal transpant patient receiving cyclosporine and lovastatin shortly after a dose increase in the systemic antifungal agent itraconazole. Another transplant patient on cyclosporine and a different HMG-CoA reductase inhibitor experienced muscle weakness accompanied by marked elevation of CPK following the initiation of systemic itraconazole therapy. The HMG-CoA reductase inhibitors and the azole derivative antifungal agents inhibit cholesterol biosynthesis at different points in the biosynthetic pathway. In patients receiving cyclosporine, lovastatin should be temporarily discontinued if systemic azole derivative antifungal therapy is required; patients not taking cyclosporine should be carefully monitored if systemic azole derivative antifungal therapy is required.
Interruption of therapy with lovastatin should be considered in any patient with an acute, serious condition, suggestive of a myopathy or having a risk factor predisposing to the development of renal failure or rhabdomyolysis, such as severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine or electrolyte disorders and uncontrolled seizures.
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
Precautions: General: Before instituting therapy with lovastatin, an attempt should be made to control hypercholesterolemia with appropriate diet, exercise, weight reduction in overweight and obese patients, and to treat other underlying medical problems (see Indications). The patient should be advised to inform subsequent physicians of the prior use of lovastatin or any other lipid metabolism regulator.
Homozygous Familial Hypercholesterolemia (FH): Lovastatin is not effective or is less effective in patients with rare homozygous familial hypercholesterolemia because these patients have no or very low levels of LDL receptor activity. Lovastatin appears to be more likely to raise serum transaminases (see Adverse Effects) in these homozygous patients.
Effect on the Lens: Current long-term data from clinical trials do not indicate an adverse effect of lovastatin on the human lens.
Effect on Lipoprotein(a) [Lp(a)]: In some patients the beneficial effect of lowered total cholesterol and LDL cholesterol levels may be partly blunted by a concomitant increase in the Lp(a) levels. Until further experience is obtained from controlled clinical trials, it is suggested, where feasible, that Lp(a) measurements be carried out in patients placed on therapy with lovastatin.
Effect on CoQ10 Levels (Ubiquinone): A significant decrease in plasma CoQ10 levels in patients treated with lovastatin and other statins has been observed in short-term clinical trials. The clinical significance of a potential long-term statin-induced deficiency of CoQ10 has not yet been established.
Hypersensitivity: Although to date hypersensitivity syndrome has not been described as such, in few instances eosinophilia and skin eruptions appear to be associated with lovastatin treatment. If hypersensitivity is suspected, lovastatin should be discontinued.
Pregnancy: Lovastatin is contraindicated during pregnancy.
Atherosclerosis is a chronic process and the discontinuation of lipid metabolism regulators during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Moreover, cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as lovastatin to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, lovastatin may cause fetal harm when administered to a pregnant woman.
A few reports have been received of congenital anomalies in infants whose mothers were treated during a critical period of pregnancy with HMG-CoA reductase inhibitors including lovastatin.
Lovastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, it should be discontinued and the patient apprised of the potential hazard to the fetus.
Lactation: It is not known whether lovastatin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lovastatin, women taking the drug should not nurse their infants (see Contraindications).
Children: Limited experience is available in children. However, safety and effectiveness in children have not been established.
Geriatrics: In patients over 60 years, efficacy appeared similar to that seen in the population as a whole, with no apparent increase in the frequency of clinical or laboratory adverse findings.
Impaired Renal Function: Because lovastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with moderate renal insufficiency.
Endocrine Function: HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Clinical studies with lovastatin have shown that this agent does not reduce plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. However, the effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate number of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown.
Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone, or cimetidine) that may decrease the levels of endogenous steroid hormones.
Drug Interactions: Concomitant Therapy with other Lipid Metabolism Regulators: Combined drug therapy should be approached with caution as information from controlled studies is limited.
Bile Acid Sequestrants: Preliminary evidence suggests that the cholesterol-lowering effects of lovastatin and the bile acid sequestrant, cholestyramine, are additive.
When lovastatin is used concurrently with cholestyramine or any other resin, an interval of at least 2 hours should be maintained between the two drugs, since the absorption of lovastatin may be impaired by the resin.
Gemfibrozil, Fenofibrate and Niacin: Myopathy, including rhabdomyolysis, has occurred in patients who were receiving coadministration of lovastatin with fibric acid derivatives and niacin, particularly in subjects with pre-existing renal insufficiency (see Warnings).
Erythromycin: See Warnings, Muscle Effects.
Angiotensin-Converting Enzyme Inhibitors: Hyperkalemia associated with myositis (myalgia and elevated CPK) has been reported in the case of a single patient with insulin-dependent diabetes mellitus and mild renal insufficiency who received lovastatin concomitantly with an angiotensin-converting enzyme inhibitor (lisinopril).
Coumarin Anticoagulants: Clinically evident bleeding and/or increased prothrombin time have been reported occasionally in patients taking coumarin anticoagulants concomitantly with lovastatin. Careful monitoring of prothrombin time is therefore recommended in such cases.
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.
Beta-Adrenergic Blocking Drugs: In healthy volunteers, the coadministration of propranolol and lovastatin resulted in a slight decrease of the AUC of lovastatin and its metabolites as well as in a significant decrease of the Cmax for the lovastatin metabolites.
The clinical interpretation of this phenomenon is difficult as it may indicate a greater uptake of lovastatin by the liver.
There was no clinically relevant interaction reported in patients who have been receiving lovastatin concomitantly with beta-adrenergic blocking agents.
Antipyrine: Antipyrine was used as a model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P450 system). Lovastatin had no effect on the pharmacokinetics of antipyrine.
Other Concomitant Therapy: Caution should be exercised with concomitant use of immunosuppressants and itraconazole (see Warnings).
Although specific interaction studies were not performed, in clinical studies, lovastatin was used concomitantly with calcium-channel blockers (such as verapamil HCI, nifedipine and diltiazem HCl) and a number of diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs), hypoglycemic drugs (chlorpropamide, glipizide, glyburide, insulin), without evidence of clinically significant adverse interactions.
Drug/Laboratory Test Interactions : Lovastatin may elevate creatine phosphokinase and transaminase levels (see Adverse Effects, Laboratory Tests). In the differential diagnosis of chest pain in a patient on therapy with lovastatin, cardiac and noncardiac fractions of these enzymes should be determined.
Adverse Reactions: Lovastatin was compared to placebo in 8 245 patients with hypercholesterolemia (total cholesterol 6.2 to 7.8 mmol/L) in a randomized, double-blind, parallel, 48-week Expanded Clinical Evaluation of Lovastatin (EXCEL study).
Other clinical adverse reactions reported as possibly, probably or definitely drug-related in 0.5 to 1% of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different.
Body as a whole: chest pain.
Gastrointestinal: acid regurgitation, dry mouth, vomiting.
Musculoskeletal: leg pain, shoulder pain, arthralgia.
Nervous System/Psychiatric: insomnia, paresthesia.
Skin: alopecia, pruritus.
Special Senses: eye irritation.
No significant difference was found among the different treatment group including placebo in the incidence of serious clinical adverse experiences including death due to CHD, nonfatal myocardial infarction, cancer, and deaths due to all causes. This study was not designed or powered to evaluate the incidence of these serious clinical adverse experiences. The EXCEL study included a minority of patients at risk of or with coronary artery disease; however, its findings cannot be extrapolated in this respect to other segments of the high-risk population.
Laboratory Tests: Marked persistent increases of serum transaminases have been noted (see Warnings).
Other liver function test abnormalities including elevated alkaline phosphatase and bilirubin have been reported. In the EXCEL study, 7.3% of the patients on lovastatin had elevations of CPK levels of at least twice the normal value on one or more occasions compared to 6.2% on placebo.
The EXCEL study, however, excluded patients with factors known to be associated with an increased risk of myopathy (see Warnings, Muscle Effects and Precautions, Drug/Laboratory Test Interactions).
Nervous System: Visual evoked response, nerve conduction measurements and electromyography in over 30 patients showed no evidence of neurotoxic effects of lovastatin.
Effect on the Lens: (See Precautions).
Postmarketing Experience: The following additional side effects have been reported since the drug was marketed: hepatitis, cholestatic jaundice, vomiting, anorexia, paresthesia peripheral neuropathy and psychic disturbances including anxiety, alopecia, erythema multiforme, including Stevens-Johnson’s syndrome; toxic epidermal necrolysis.
An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus-like syndrome, polymyalgia rheumatica, vasculitis, thrombocytopenia, leukopenia, eosinophilia, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, flushing, chills, dyspnea and malaise.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage have been reported; no patients had any specific symptoms and all patients recovered without sequelae. The maximum dosage taken was 5 to 6 g.
In the event of overdosage, treatment should be symptomatic and supportive, liver function should be monitored, and appropriate therapy instituted. Until further experience is obtained, no specific therapy of overdosage can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known.
Dosage And Administration: The patient should be placed on at least an equivalent of the American Heart Association (AHA) Step 1 diet before receiving lovastatin and should continue on this diet during treatment with lovastatin. If appropriate, a program of weight control and physical exercise should be implemented.
Patients with Hypercholesterolemia: The usual starting dose is 20 mg/day given as a single dose with the evening meal. Single daily doses given with the evening meal have been shown to be more effective than the same dose given with the morning meal, perhaps because cholesterol is synthesized mainly at night. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks, to a maximum of 80 mg daily given in single doses or divided doses with the morning and evening meals. Divided doses (i.e., twice daily) tend to be slightly more effective than single daily doses.
Cholesterol levels should be monitored periodically and consideration should be given to reducing the dosage of lovastatin if cholesterol levels fall below the targeted range, such as that recommended by the Second Report of the U.S. National Cholesterol Education Program (NCEP).
Patients with Established Coronary Heart Disease: In the trials involving patients with coronary heart disease and administered lovastatin with (colestipol) or without concomitant therapy, the dosages used were 20 to 80 mg daily, given in single or divided doses. In the 2 trials which utilized lovastatin alone, the dose was reduced if total plasma cholesterol decreased to below 2.85 mmol/L or if LDL-cholesterol decreased to below 2.1 mmol/L, respectively.
Concomitant Therapy: See Precautions, Drug Interactions : Concomitant Therapy with Other Lipid Metabolism Regulators.
In patients taking immunosuppressive drugs concomitantly with lovastatin, the maximum recommended dosage of lovastatin is 20 mg/day (see Warnings, Muscle Effects).
Availability And Storage: 20 mg: Each light blue-colored, octagon-shaped, flat, beveled-edge, scored tablet, engraved with 731/731 on one side and MEVACOR on the other side, contains: lovastatin 20 mg. Nonmedicinal ingredients: butylated hydroxyanisole, indigotine on alumina, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Blister packages of 30, bottles of 500.
40 mg: Each green-colored, octagon-shaped, flat, beveled-edge tablet, engraved with 732 on one side and MEVACOR on the other side, contains: lovastatin 40 mg. Nonmedicinal ingredients: butylated hydroxyanisole, indigotine and quinoline yellow, both on alumina substratum, lactose, magnesium stearate, microcrystalline cellulose and pregelatinized starch. Blister packages of 30, bottles of 250.
Keep container tightly closed and store at 15 to 30°C. Protect from light. (Shown in Product Recognition Section)
MEVACOR® MSD Lovastatin Lipid Metabolism Regulator