Novina

Novina is a cholesterol-lowering agent that belongs to a class of medications known as statins. It was derived from microbial transformation of mevastatin, the first statin discovered. It is a ring-opened dihydroxyacid with a 6’-hydroxyl group that does not require in vivo activation. Novina is one of the lower potency statins; however, its increased hydrophilicity is thought to confer advantages such as minimal penetration through lipophilic membranes of peripheral cells, increased selectivity for hepatic tissues, and a reduction in side effects compared with lovastatin and simvastatin.

For the reduction of increased cholesterol levels in the blood (primary hypercholesterolaemia) with or without increased triglycerides (combined hypercholesterolaemia and hypertriglyceridaemia, if the hypercholesterolaemia is prevalent). If an adequate reduction of cholesterol cannot be achieved by a diet with reduced fat and cholesterol consumption and/or low-calorie foods and other measures (eg, physical activity).

Primary prevention of myocardial infarction and death due to coronary heart disease in patients with hypercholesterolaemia or combined hypercholesterolaemia, in particular in patients with the following risk factors: Men, between 45 and 54 years with diet-resistant low-density lipoprotein (LDL) values persistently >4 mmol/L (155 mg/dL), who have vascular disease in their history, or slight changes in resting ECG, or who have diabetes mellitus, or are smokers; men, between 55 and 65 years with diet-resistant LDL values persistently >4 mmol/L (155 mg/dL), who have slight changes in resting ECG or vascular disease in their history, or a high-density lipoprotein (HDL) value <1.1 mmol/L (43 mg/dL), or a family history of sudden cardiac death, or have diabetes, or high blood pressure, or are smokers.

Secondary prevention of cardiovascular events (repeat of myocardial infarction, need for reconstructive surgery on the cardiac vessels, ischaemic strokes, transient ischaemic attacks) in patients (between 21 and 75 years) with previous myocardial infarction (3-20 months before) and an LDL cholesterol level >125 mg/dL.

Note: It has not been established in investigations whether the effects achieved with 40 mg Novina in patients following myocardial infarction would also be seen in: Elderly patients >75 years; patients with recent myocardial infarction (in the past 3 months); patients with severe heart failure (LV-EF<25% or clinical NYHA class III or IV).

Treatment with Novina is part of a therapeutic regimen which aims to reduce the increased risk of vascular sclerosis because of hypercholesterolaemia. Novina should be taken together with dietary measures ie, decreased intake of saturated fatty acids and cholesterol.

There is no clinical experience with Novina in the treatment of markedly increased triglyceride levels in the blood with raised cholesterol levels at the same time (hyperlipoproteinaemia).

Only limited effects can be expected in the treatment of the rare metabolic disorder characterized by an increase in cholesterol levels (homozygotic familial hypercholesterolaemia). There is no clinical experience with Novina.

Novina is in a group of drugs called HMG CoA reductase inhibitors, or "statins." Novina reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).

Novina is used to lower cholesterol and triglycerides (types of fat) in the blood.

Novina is also used to lower the risk of stroke, heart attack, and other heart complications in people with diabetes, coronary heart disease, or other risk factors

Novina is used in adults and children who are at least 8 years old.

Novina may also be used for purposes not listed in this medication guide.

General Dosing Information

The patient should be placed on a standard cholesterol-lowering diet before receiving Novina and should continue on this diet during treatment with Novina.

Adult Patients

The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. Novina can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

Patients with Renal Impairment

​In patients with severe renal impairment, a starting dose of 10 mg Novina daily is recommended. Although the Novina 10 mg tablets are no longer available, Novina 10 mg tablets are available.

Pediatric Patients

Children (Ages 8 to 13 Years, Inclusive)

The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.

Adolescents (Ages 14 to 18 Years)

The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.

Children and adolescents treated with Novina should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.

Concomitant Lipid-Altering Therapy

Novina may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and Novina, Novina should be given either 1 hour or more before or at least 4 hours following the resin.

Dosage in Patients Taking Cyclosporine

In patients taking immunosuppressive drugs such as cyclosporine concomitantly with Novina, therapy should begin with 10 mg of Novina once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum Novina dose of 20 mg/day. In patients taking cyclosporine, therapy should be limited to 20 mg of Novina once daily. Although the Novina 10 mg tablets are no longer available, Novina 10 mg tablets are available.

Dosage in Patients Taking Clarithromycin

In patients taking clarithromycin, therapy should be limited to 40 mg of Novina once daily.

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What is the most important information I should know about Novina?

You should not take Novina if you are allergic to it, if you are pregnant or breast-feeding, or if you have liver disease.

Stop taking this medication and tell your doctor right away if you become pregnant.

Before taking Novina, tell your doctor if you have ever had liver or kidney disease, diabetes, or a thyroid disorder, or if you drink more than 2 alcoholic beverages daily.

In rare cases, Novina can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Avoid eating foods that are high in fat or cholesterol. Novina will not be as effective in lowering your cholesterol if you do not follow a cholesterol-lowering diet plan.

Avoid drinking alcohol. It can raise triglyceride levels and may increase your risk of liver damage.

There are many other drugs that can increase your risk of serious medical problems if you take them together with Novina. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Novina is only part of a complete program of treatment that also includes diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely.

Use Novina as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Novina by mouth with or without food.
• If you take cholestyramine or colestipol, take them at least 4 hours before or 1 hour after Novina.
• Continue to take Novina even if you feel well. Do not miss any doses.
• If you miss a dose of Novina, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Novina.

Novina is used along with restricted diet regimens to lower excessive fats (cholesterol and triglycerides) in blood and thus reduce the risk of development or progression of heart and blood vessel diseases. It is also used to treat hereditary high blood cholesterol (familial hypercholesterolemia) in children and to reduce increased blood lipid levels in patients receiving immunosuppressive therapy (medications that lower activity of the immune system) following an organ transplant surgery.

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What other drugs will affect Novina?

Immunosuppressive Drugs, Gemfibrozil, Niacin (Nicotinic Acid), Erythromyci Cytochrome P450 3A4 Inhibitor

In vitro and in vivo data indicate that Novina is not metabolized by cytochrome P450 3A4 to a clinically significant extent. This has been shown in studies with known cytochrome P450 3A4 inhibitors. Other examples of cytochrome P450 3A4 inhibitors include ketoconazole, mibefradil, and erythromycin

Diltiaze

Steady-state levels of diltiazem (a known, weak inhibitor of P450 3A4) had no effect on the pharmacokinetics of Novina. In this study, the AUC and Cmax of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 3.6 and 4.3, respectively

Itraconazol

The mean AUC and Cmax for Novina were increased by factors of 1.7 and 2.5, respectively, when given with itraconazole (a potent P450 3A4 inhibitor which also inhibits p-glycoprotein transport) as compared to placebo. The mean half-life was not affected by itraconazole, suggesting that the relatively small increases in Cmax and AUC were due solely to increased bioavailability rather than a decrease in clearance, consistent with inhibition of p-glycoprotein transport by itraconazole. This drug transport system is thought to affect bioavailability and excretion of HMG-CoA reductase inhibitors, including Novina. The AUC and Cmax of another HMG-CoA reductase inhibitor which is known to be metabolized by cytochrome P450 3A4 increased by factors of 19 and 17, respectively, when given with itraconazole

Antipyrin

Since concomitant administration of Novina had no effect on the clearance of antipyrine, interactions with other drugs metabolized via the same hepatic cytochrome isozymes are not expected

Cholestyramine/Colestipo

Concomitant administration resulted in an approximately 40 to 50% decrease in the mean AUC of Novina. However, when Novina was administered 1 hour before or 4 hours after cholestyramine or 1 hour before colestipol and a standard meal, there was no clinically significant decrease in bioavailability or therapeutic effect.

Warfari

Concomitant administration of 40 mg Novina had no clinically significant effect on prothrombin time when administered in a study to normal elderly subjects who were stabilized on warfarin

Cimetidin

The AUC0-12hr for Novina when given with cimetidine was not significantly different from the AUC for Novina when given alone. A significant difference was observed between the AUC's for Novina when given with cimetidine compared to when administered with antacid

Digoxi

In a crossover trial involving 18 healthy male subjects given 20 mg Novina and 0.2 mg digoxin concurrently for 9 days, the bioavailability parameters of digoxin were not affected. The AUC of Novina tended to increase, but the overall bioavailability of Novina plus its metabolites SQ 31,906 and SQ 31,945 was not altered

Cyclosporin

Some investigators have measured cyclosporine levels in patients on Novina (up to 20 mg), and to date, these results indicate no clinically meaningful elevations in cyclosporine levels. In one single-dose study, Novina levels were found to be increased in cardiac transplant patients receiving cyclosporine

Gemfibrozi

In a crossover study in 20 healthy male volunteers given concomitant single doses of Novina and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of Novina. In addition, there was a significant increase in AUC, Cmax, and Tmax for the Novina metabolite SQ 31,906. Combination therapy with Novina and gemfibrozil is generally not recommended.

In interaction studies with aspirin, antacids (1 hour prior to Novina), cimetidine, nicotinic acid, or probucol, no statistically significant differences in bioavailability were seen when Novina (Novina) was administered

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What are the possible side effects of Novina?

Novina is generally well tolerated; adverse reactions have usually been mild and transient. In 4-month-long placebo-controlled trials, 1.7% of Novina-treated patients and 1.2% of placebo-treated patients were discontinued from treatment because of adverse experiences attributed to study drug therapy; this difference was not statistically significant.

Adverse Clinical Events

In the Novina placebo-controlled clinical trials database of 1313 patients (age range 20-76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on Novina and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness.

All adverse clinical events (regardless of causality) reported in ≥2% of Novina-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:

The safety and tolerability of Novina at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of Novina at lower doses except that 4 out of 464 patients taking 80 mg of Novina had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of Novina.

Long-Term Controlled Morbidity and Mortality Trials

In the Novina placebo-controlled clinical trials database of 21,483 patients (age range 24-75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on Novina and 9.3% patients on placebo discontinued due to adverse events regardless of causality.

Adverse event data were pooled from 7 double-blind, placebo-controlled trials (West of Scotland Coronary Prevention Study [WOS]; Cholesterol and Recurrent Events study [CARE]; Long-term Intervention with Novina in Ischemic Disease study [LIPID]; Novina Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Novina, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with Novina 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the Novina group was comparable to that of the placebo group. Patients were exposed to Novina for a mean of 4.0 to 5.1 years in WOS, CARE, and LIPID and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these 7 trials represent 47,613 patient-years of exposure to Novina. All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with Novina in these studies are identified in Table 2.

In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in <2.0% of Novina-treated patients in the long-term trials included the following:

Dermatologic: scalp hair abnormality (including alopecia), urticaria.

Endocrine/Metabolic: sexual dysfunction, libido change.

General: flushing.

Immunologic: allergy, edema head/neck.

Musculoskeletal: muscle weakness.

Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).

Special Senses: taste disturbance.

Postmarketing Experience

In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with Novina, regardless of causality assessment:

Musculoskeletal: myopathy, rhabdomyolysis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.

Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.

There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome).

Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure.

Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).

Renal: urinary abnormality (including dysuria, frequency, nocturia).

Respiratory: dyspnea.

Reproductive: gynecomastia.

Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.

Laboratory Test Abnormalities

Increases in ALT, AST values and CPK have been observed.

Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins.

Pediatric Patients

In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8-18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of Novina was generally similar to that of placebo.