Niaspanâ. Prolonged-Release Tablets MECRK. Composition

Transcription

1 Niaspanâ Prolonged-Release Tablets MECRK Composition Niaspan? 375 mg Prolonged-Release Tablets: Each prolonged-release tablet contains 375 mg nicotinic acid as active ingredients. Niaspan? 500 mg Prolonged-Release Tablets: Each prolonged-release tablet contains 500 mg nicotinic acid as active ingredients. Niaspan? 750 mg Prolonged-Release Tablets: Each prolongedrelease tablet contains 750 mg nicotinic acid as active ingredients. Niaspan? 1000 mg Prolonged-Release Tablets: Each prolonged-release tablet contains 1000 mg nicotinic acid as active ingredients. Pharmacodynamic properties Nicotinic acid is a water-soluble B-complex vitamin which is naturally occuring constituent of foods. The human body is not entirely dependent on dietary sources of nicotinic acid, since it may also be synthesised from tryptophan. Nicotinic acid functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. Nicotinic acid (but not nicotinamide) in gram doses reduces total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), and increases high-density lipoprotein cholesterol (HDL-C). The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of the underlying lipid abnormality. The increase in total HDL-C is associated with a shift in the distribution of HDL subfractions (as defined by ultra-centrifugation), with an increase in the HDL2:HDL3 ratio; and an increase in apolipoprotein A1 (Apo A1) content. Nicotinic acid treatment also decreases serum levels of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions, and of lipoprotein a, (Lp(a)), a variant form of LDL independently associated with coronary risk. In addition, nicotinic acid has been shown to cause favourable transformations in LDL particle size subclass distribution, converting the pattern B phenotype ( characterised by a predominance of triglyceride-rich, small dense LDL) to pattern A (characterised by a predominance of large bouyant LDL) or the intermediate AB phenotype. Pattern B LDL phenotype is one manifestation of what has been termed the atherogenic Lipoprotein Profile (ALP), a Mendelian dominant inherited condition which also includes low levels of HDL-C, raised triglyceride, and insulin resistance. The mechanism by which nicotinic acid alters lipid profiles has not been well defined. It may involve several actions including inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity, which may increase the rate of chylomicrom triglyceride removal from plasma. Nicotinic acid decreases the rate of hepatic synthesis of VLDL and LDL, and does not appear to affect faecal excretion of fats, sterols, or bile acids. Pharmacokinetic Properties Absorption Nicotinic acid is rapidly and extensively absorbed when administered orally (at least 60-76% of dose). To maximise bioavailability and reduce the risk of gastrointestinal upset, administration of Niaspan with low-fat meal or snack is recommended. Single-dose bioavailability studies have demonstrated that Niaspan tablet strengths are not interchangeable. Distribution Studies using radiolabelled nicotinic acid in mice show that nicotinic acid and its metabolites concentrate in the liver, kidney and adipose tissue. Metabolism The pharmacokinetic profile of nicotinic acid complicated due to rapid and extensive first-pass metabolism which is species and dose-rate specific. In humans, one pathway (Pathway 1) is through a simple conjugation stepwith glycine to form nicotinuric acid (NUA). NUA is then excreted in the urine, although there may be a small amount of reversible metabolism back to nicotinic acid. There is evidence to suggest that nicotinic acid metabolism along this pathway leads to flush. The other pathway (pathway 2)

2 results in the formation of nicotinamide adenine dinucleotide (NAD). A predominance of metabolism down pathway 2 may lead to hepatotoxicity. It is unclear whether nicotinamide is formed as a precursor to, or following he synsthesis of, NAD. Nicotinamid is further metabolised to at least N-methylnicotinamide (MNA) and nicotinamide N-oxide (NNO). MNA is further metabolised to two other compounds, N-methyl-2-pyridone-5-carboxamide (2PY) and N-methyl- 4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans. At the doses used to treat hyperlipidaemia, these metabolic pathways are saturable, which explains the non-linear relationship between nicotinic acid dose and plasma concentrations following multiple dose Niaspan administration (as detailed below; mean steadystate parameters for plasma nicotinic acid). The absorption rate from Niaspan is controlled to balance the metabolism along these two pathways to minimise flush and the risk of hepatotoxicity. Niaspan? Nicotinic acid Dose/day Given as Peak concentration Time to peak (hr) 1000 mg 2x500 mg (?/ml) mg 2x750 mg mg 2x1000 mg Nicotinamide does not have hypolipidaemic activity; the activity of the other metabolites is unknown. Elimination Nicotinic acid and its metabolites are rapidly eliminated in the urine. Following single and multiple doses, approximately 60-76% of the dose administered as Niaspan was recovered in the urine as nicotinic acid and metabolites; up to 12 % was recovered as unchanged nicotinic acid after multiple dosing. The ratio of metabolites recovered in the urine was dependent on the dose administered. Gender differences Steady state plasma concentrations of nicotinic acid and metabolites after administration of Niaspan are generally higher in women than in men, with the magnitude of difference varying with dose and metabolite. Recovery of nicotinic acid and metabolites in urine, however, is generally similar for men and women, indicating the absorption is similar for both genders. The gender differences observed in plasma levels of nicotinic acid and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution. Data from clinical trials suggest that women have a greater hypolipidaemic response than men at equivalent doses of Niaspan. Indication As an adjunct to exercise and diet for the reduction of elevated TC, LDL-C, Apo B and TG levels, and increase HDL-C in patients with primary hypercholesterolaemia (heterozygous familial and nonfamilial) and mixed dyslipidaemia (Frederickson Types IIa and IIb) when response to diet is inadequate. Dosage and Administration Niaspan should be taken at bedtime, after a low-fat snack, and doses should be individualised according to the patient s response. Single-dose bioavailability studies have demonstrated that Niaspan tablet strengths are not interchangeble. Initial dose Therapy with Niaspan must be initiated by gradually escalating the dose in order to reduce the incidence and severity f side effects which may occur during early therapy. The recommended dose escalation is shown below. Week(s) Dosage Daily nicotinic acid dose 1 Niaspan 375 mg 1 tablet at bedtime 375 mg INITIAL 2 Niaspan 500 mg 1 tablet at bedtime 500 mg TITRATION STARTER PACK TITRATION SCHEDULE 3 Niaspan 750 mg 1 tablet at bedtime 750 mg 4-7 Niaspan 500 mg 2 tablets at bedtime 1000 mg.. Niaspan 750 mg 2 tablets at bedtime 1500 mg Niaspan 1000 mg 2 tablets at bedtime 200 mg After week 7, titrate the dose according to the patient s response and tolerance. If the response to 1000 mg daily is inadequate, increase the dose to 1500 mg daily; the dose may subsequently be increased to 2000 mg daily. The daily dose should not be increased more than 500 mg in a four week period, and doses above 2000 mg daily are not recommended. Women may respond at lower doses than men. Maintenance dose The recommended maintenance dose is 1000mg (two 500mg tablets) to 2000mg (two 1000mg tablets) once daily at bedtime. The daily dosage of Niaspan should not be increased by more than 500 mg in any four-week period. Flushing of the skin may be reduced in frequency or severity by pre-treatment with aspirin (taken 30 minutes prior to Niaspan dose) or non-steroidal anti-inflammatory drugs. Tolerance to this flushing develops

3 rapidly over the course of several weeks. Flushing, pruritus, and gastrointestinal distress are also greatly reduced by slowly increasing the dose of nicotinic acid and avoiding administration on an empty stomach. Equivalent doses of Niaspan should not be substituted for modified release nicotinic acid preparations of immediate-release (crystalline) nicotinic acid. Patients previously receiving other nicotinic acid products should be started with the recommended Niaspan dose escalation schedule, and dose should subsequently be individualised based on patient response. If Niaspan therapy is discontinued for an extended period, re-institution of therapy should include a dose escalation. Niaspan tablets should be taken whole and should not be broken, crushed or chewed before swallowing. Special Warnings and Precautions Warnings Niaspan preparations should not be substituted for equivalent doses of immediate-release (crystalline) nicotinic acid. For patients switching from immediate release nicotinic acid to Niaspan, therapy with Niaspan should be initiated with low doses (i.e. 375 mg qhs) and titrated upwards as required). Liver dysfunction : cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release nicotinic acid products for immediate-release (crystalline) nicotinic acid equivalent doses. Niaspan 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 transaminase elevations are contraindications to the use of Niaspan. Nicotinic acid preparation, like some other lipid-lowering therapies, have been associated with abnormal liver tests. In three placebo-controlled clinical trials involving titration to final daily Niaspan doses ranging from mg, patients received Niaspan for a mean duration of 17 weeks. No patient with normal serum transaminase levels (AST, ALT) at baseline experienced elevations to more than three times the upper limit of normal (ULN) during treatment with Niaspan. In these studies, fewer than 1% of Niaspan patients discontinued due to transaminase elevations grater than two times the ULN. In a Long-term study of 723 patients treated for a mean duration of 68 weeks, less than 1% of Niaspan treated patients with normal serum transaminase levels at baseline experienced elevations grater than three times the ULN. Among 163 patients in this study receiving Niaspan and an HMG CoA reductase inhibitor (mean treatment duration was 56 weeks) the incidence of elevated liver transaminases > 3 times ULN was < 1%. In placebo-controlled and long-term studies, elevations in transaminases did not appear to be related to treatment duration; elevations in AST levels did appear to be dose-related. Transaminase elevations were reversible upon discontinuation of Niaspan. Liver tests should be performed periodically on all patients during therapy with Niaspan. Special 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 three times the upper limit of normal and are persistent, or if they are associated with symptoms of nausea, fever, and/or malaise, the drug should be discontinued. Skeletal muscle: rare cases of rhabdomyolysis have been associated with concomitant administration of lipid-altering doses (? 1 g/day) of nicotinic acid and HMG-CoA reductase inhibitors. In a long-term study of 163 patients receiving combined therapy with Niaspan and an HMG CoA reductase inhibitor for a mean duration of 56 weeks, no cases of drug-induced myopathy were observed. However, physicians contemplating combined therapy with HMG-CoA reductase inhibitors and Niaspan should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Periodic serum creatine phosphokinase (CPK) and potassium determinations should be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Precautions General : before instituting therapy with Niaspan, an attempt should be made to control

4 hyperlipidaemia with appropriate diet, exercise, and weight reduction in obese patients, and to treat other underlying medical problems. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Niaspan therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a doserelated rise in glucose intolerance, the clinical significance of which is unclear. Diabetic or potentially diabetic patients should be observed closely. Adjustment of diet and/or hypoglycaemic therapy may be necessary. Caution should also be used when Niaspan is used in patients with unstable angina or in the acute phase of myocardial infarction, particularly when such patients are also receiving vasoactive drugs as nitrates, calcium channel blockers, or adrenergic blocking agents. Elevated uric acid levels have occurred with Niaspan therapy, therefore use with caution in patients predisposed to gout. Niaspan has been associated with small but statistically significant dose-related reductions in platelet count (mean of -11% with 2000 mg). In addition, Niaspan has been associated with small but statistically significant increases in prothrombine time (mean of approximately +4%): accordingly patients undergoing surgery should be carefully evaluated. Caution should be observed when Niaspan is administered concomitantly with anti-coagulants; prothrombin time and platelet counts should be monitored closely in such patients. In placebo-controlled trials, Niaspan has been associated with small but statistically significant, dose-related reductions in phosphorous levels (mean of - 13% with 2000 mg). Although these reductions were transient, phosphorous levels should be monitored periodically in patients at risk of hypophosphataemia. Nicotinic acid is rapidly metabolized by the liver, and excreted through the kidneys. Adverse effects Adverse reactions have been mild and transient. In placebo-controlled clinical trials, flushing episodes (ie, warmth, redness, itching and/or tingling) were the most common treatment-emergent adverse events for Niaspan (reported by 88% of patients). In these studies fewer than 6% of Niaspan patients discontinued due to flushing. In comparisons of immediate-release (IR) nicotinic acid and Niaspan, although the number of patients who flushed was similar, fewer flushing episodes were reported by patients who received Niaspan. Following four weeks of maintenance therapy at daily doses of 1500 mg, the incidence of flushing over the four week period averaged 8.56 events per patient for IR nicotinic acid versus 1.88 following Niaspan. In placebo-controlled trials, patients receiving the recommended daily maintenance doses (1000, 1500 and 2000 mg) experienced the following adverse events considered at least remotely related to Niaspan: headache (8-11% at each dose); pain (2-5%); abdominal pain (2-5%); diarrhoea (6-8%); dyspepsia (4-5%); nausea (3-8%); vomiting (2-8%); rhinitis (3-5%); pruritus (<1-3%); and rash (0-5%). A dose-related increase in adverse event frequency was seen only with vomiting. The frequency of this side effect at 2000 mg/day (8%) was the only effect significantly increased versus placebo. In general, the incidence of adverse events was higher in women compared to men. The following adverse events have also been reported during treatment with nicotinic acid product : Cardiovascular : tachycardia, syncope, palpitation, atrial fibrillation and other cardiac arrhythmias; orthostasis; dizziness, hypotension; Gastrointestinal: activation of peptic ulcer and peptic ulceration; jaundice; Skin: hyper-pigmentation; jaundice; acanthosis nigricans; dry skin; Metabolic: decreased glucose tolerance; gout; Eye: toxic amblyopia; cystoid macular oedema; Other: migraine, myalgia. Nervous: insomnia; Body as whole: asthenia, oedem, chills. Clinical chemistry: Elevations in serum transaminases, LDH, fasting glucose, uric acid, total bilirubin, and amylase; reductions in phosphorous; haematology: slight reductions in platelet counts and prolongation of prothrombin time. Overdose Information on acute overdose with Niaspan in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacological effect; severe flushing, nausea/vomiting, diarrhoea, dyspepsia,

5 dizziness, syncope, hypotension, potential cardiac arrhythmias and clinical laboratory abnormalities including elevations in liver function tests. The patient should be carefully observed and given supportive treatment. Insufficient information is available on the dialysis potential of nicotinic acid. Contraindications Niaspan is contraindicated in patients with a known hypersensitivity to nicotinic acid or any component of this medication, significant or unexplained hepatic dysfunction, active peptic ulcer disease, or arterial bleeding. Interactions Nicotinic acid may potentiate the effects of ganglionic blocking agents and vasoactive drugs resulting in postural hypotension. Concomitant aspirin may decrease the metabolic clearance of nicotinic acid. The clinical relevance of this finding is unclear. Concomitant alcohol or hot drinks may increase the side effects of flushing and pruritus and should be avoided around the time of Niaspan ingestion. Nicotinic acid may produce false elevations in some fluorometric determinations of plasma or urinary cathecolamines. Nicotinic acid may also give false-positive reactions with cupric sulphate solution (Benedict s reagent) in urine glucose tests. Use during pregnancy and lactation Pregnancy Female rabbits have been dosed with 0.3 g nicotinic acid per day from pre-conception to lactation, and gave birth to offspring without teratogenic effects. Further specific animal reproduction studies have not been conducted with nicotinic acid or with Niaspan. It is also not known whether nicotinic acid at doses typically used for lipid disorders can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity. If a woman receiving nicotinic acid for primary hypercholesterolaemia (Types IIa or IIb) becomes pregnant, the drug should be discontinued. If a woman being treated with nicotinic acid for hypertriglyceridemia (types IV or V) conceives, the benefits and risks of continued therapy should be assessed on an individual basis. Nursing mothers Nicotinic acid has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants from lipid-altering doses of nicotinic acid, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No studies have been conducted with Niaspan in nursing mothers. Children The safety and efficacy of nicotinic acid therapy in children and adolescent has not been established. Use in children and adolescents is not recommended. Presentation Niaspan 375mg; Niaspan 500mg; Niaspan 750mg; Niaspan 1000mg : Box of 2 x 14 prolonged-release tablets in blisters Box of 2 x 14 prolonged-release tablets in blisters Storage Do not store above 250C. Store in the original package to protect from moisture. Do not use after the expiry date. Keep medicines out of the reach of children. On medical prescription only Harus dengan resep dokter Manufactured by KOS Pharmaceutical, New Jersey USA Imported by PT. Merck Tbk., Jakarta Reg. No. : Niaspan 375mg : Niaspan 500mg : Niaspan 750mg : Niaspan 1000mg :