DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. In patients with CHD or multiple risk factors for CHD, Alnavas can be started simultaneously with diet.
Alnavas is an inhibitor of HMG-CoA reductase indicated as an adjunct therapy to diet to:
Limitations of Use
Alnavas has not been studied in Fredrickson Types I and V dyslipidemias.
1.1 Prevention of Cardiovascular Disease
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, Alnavas is indicated to:
In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, Alnavas is indicated to:
In patients with clinically evident coronary heart disease, Alnavas is indicated to:
Alnavas is indicated:
1.3 Limitations of Use
Alnavas has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
2 DOSAGE AND ADMINISTRATION
Dose range: 10 to 80 mg once daily.
Recommended start dose: 10 or 20 mg once daily (2.1).
Patients requiring large LDL-C reduction (>45%) may start at 40 mg once daily (2.1).
Pediatric starting dose: 10 mg once daily; maximum recommended dose: 20 mg once daily (2.2).
2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
The recommended starting dose of Alnavas is 10 or 20 mg once daily. Patients who require a large reduction in LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of Alnavas is 10 to 80 mg once daily. Alnavas can be administered as a single dose at any time of the day, with or without food. The starting dose and maintenance doses of Alnavas should be individualized according to patient characteristics such as goal of therapy and response (see current NCEP Guidelines). After initiation and/or upon titration of Alnavas, lipid levels should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
The recommended starting dose of Alnavas is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy [see current NCEP Pediatric Panel Guidelines, Clinical Pharmacology (12) , and Indications and Usage (1.2) ]. Adjustments should be made at intervals of 4 weeks or more.
2.3 Homozygous Familial Hypercholesterolemia
The dosage of Alnavas in patients with homozygous FH is 10 to 80 mg daily. Alnavas should be used as an adjunct to other lipid-lowering treatments in these patients or if such treatments are unavailable.
2.4 Concomitant Lipid-Lowering Therapy
Alnavas may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7) ].
2.5 Dosage in Patients With Renal Impairment
Renal disease does not affect the plasma concentrations nor LDL-C reduction of Alnavas; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle, Clinical Pharmacology, Pharmacokinetics (12.3) ].
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, or a Combination of Ritonavir plus Saquinavir or Lopinavir plus Ritonavir
In patients taking cyclosporine, therapy should be limited to Alnavas 10 mg once daily. In patients taking clarithromycin, itraconazole, or in patients with HIV taking a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, for doses of Alnavas exceeding 20 mg, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of Alnavas is employed [see Warnings and Precautions, Skeletal Muscle (5.1), Drug Interactions (7) ].
3 DOSAGE FORMS AND STRENGTHS
White, elliptical, film-coated tablets containing 10, 20, 40, and 80 mg Alnavas calcium.
10, 20, 40, and 80 mg tablets (3).
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels.
Women who are pregnant or may become pregnant (4.3).
Nursing mothers (4.4).
Hypersensitivity to any component of this medication (4.2).
4.1 Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
4.2 Hypersensitivity to any component of this medication
Women who are pregnant or may become pregnant. Alnavas may cause fetal harm when administered to a pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of Alnavas use during pregnancy; however in rare reports, congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, Alnavas revealed no evidence of teratogenicity. Alnavas SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, Alnavas should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations ].
4.4 Nursing mothers
It is not known whether Alnavas is excreted into human milk; however a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require Alnavas treatment should not breastfeed their infants [see Use in Specific Populations (8.3) ].
5 WARNINGS AND PRECAUTIONS
Skeletal muscle effects : Risks increase when higher doses are used concomitantly with cyclosporine, fibrates, and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, HIV protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. In cases of myopathy or rhabdomyolysis, therapy should be temporarily withheld or discontinued (5.1).
Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminases can occur. Monitor liver enzymes before and during treatment (5.2).
A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the Alnavas 80 mg group vs. placebo (5.5).
5.1 Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Alnavas and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Alnavas, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of Alnavas with certain drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Alnavas therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, combination of ritonavir plus saquinavir or lopinavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with Alnavas and fibric acid derivatives, erythromycin, clarithromycin, a combination of ritonavir plus saquinavir or lopinavir plus ritonavir, immunosuppressive drugs, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or 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. Lower starting and maintenance doses of Alnavas should be considered when taken concomitantly with the aforementioned drugs (see Drug Interactions (7) ). Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.6), Drug Interactions (7) , Clinical Pharmacology (12.3) ].
Alnavas therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
5.2 Liver Dysfunction
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations in serum transaminases occurred in 0.7% of patients who received Alnavas in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of Alnavas.
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Liver enzyme changes generally occur in the first 3 months of treatment with Alnavas. Patients who develop increased transaminase levels should be monitored until the abnormalities resolve. Should an increase in ALT or AST of >3 times ULN persist, reduction of dose or withdrawal of Alnavas is recommended.
Alnavas should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of Alnavas [see Contraindications (4.1) ].
5.3 Endocrine Function
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that Alnavas does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
5.4 CNS Toxicity
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0–24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
5.5 Use in Patients with Recent Stroke or TIA
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where Alnavas 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the Alnavas 80 mg group compared to placebo (55, 2.3% Alnavas vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the Alnavas and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the Alnavas group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the Alnavas group [see Adverse Reactions (6.1) ].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see Warnings and Precautions ]
Liver enzyme abnormalities [see Warnings and Precautions (5.2) ]
The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with Alnavas in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (1-800-438-1985 and www.pfizer.com) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trial Adverse Experiences
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In the Alnavas placebo-controlled clinical trial database of 16,066 patients (8755 Alnavas vs. 7311 placebo; age range 10–93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on Alnavas and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with Alnavas that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).
The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with Alnavas in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with Alnavas (n=8755), from seventeen placebo-controlled trials.
Other adverse reactions reported in placebo-controlled studies include:
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
In ASCOT [see Clinical Studies (14.1) ] involving 10,305 participants (age range 40–80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with Alnavas 10 mg daily (n=5,168) or placebo (n=5,137), the safety and tolerability profile of the group treated with Alnavas was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.
Collaborative Alnavas Diabetes Study (CARDS)
In CARDS [see Clinical Studies (14.1) ] involving 2,838 subjects (age range 39–77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1.0% other) with type 2 diabetes treated with Alnavas 10 mg daily (n=1,428) or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.
Treating to New Targets Study (TNT)
In TNT [see Clinical Studies (14.1) ] involving 10,001 subjects (age range 29–78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1.0% Asians, 2.0% other) with clinically evident CHD treated with Alnavas 10 mg daily (n=5006) or Alnavas 80 mg daily (n=4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose Alnavas group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥3 × ULN twice within 4–10 days) occurred in 62 (1.3%) individuals with Alnavas 80 mg and in nine (0.2%) individuals with Alnavas 10 mg. Elevations of CK (≥ 10 × ULN) were low overall, but were higher in the high-dose Alnavas treatment group (13, 0.3%) compared to the low-dose Alnavas group (6, 0.1%).
Incremental Decrease in Endpoints through Aggressive Lipid Lowering Study (IDEAL)
In IDEAL [see Clinical Studies (14.1) ] involving 8,888 subjects (age range 26–80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with Alnavas 80 mg/day (n=4439) or simvastatin 20–40 mg daily (n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In SPARCL involving 4731 subjects (age range 21–92 years, 40% women; 93.3% Caucasians, 3.0% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with Alnavas 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 × ULN twice within 4–10 days) in the Alnavas group (0.9%) compared to placebo (0.1%). Elevations of CK (>10 × ULN) were rare, but were higher in the Alnavas group (0.1%) compared to placebo (0.0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the Alnavas group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions (5.5) ].
In a post-hoc analysis, Alnavas 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 Alnavas vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the Alnavas group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) Alnavas vs. 2 (4%) placebo].
There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the Alnavas 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the Alnavas 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the Alnavas 80 mg group (5.0%) than in the placebo group (4.0%).
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Alnavas. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions associated with Alnavas therapy reported since market introduction, that are not listed above, regardless of causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes, rhabdomyolysis, fatigue, tendon rupture, hepatic failure, dizziness, memory impairment, depression, and peripheral neuropathy.
6.3 Pediatric Patients (ages 10–17 years)
In a 26-week controlled study in boys and postmenarchal girls (n=140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of Alnavas 10 to 20 mg daily was generally similar to that of placebo [see Clinical Studies (14.6) and Use in Special Populations, Pediatric Use (8.4) ].
7 DRUG INTERACTIONS
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3) ].
7.1 Strong Inhibitors of CYP 3A4
Alnavas is metabolized by cytochrome P450 3A4. Concomitant administration of Alnavas with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of Alnavas. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
7.2 Grapefruit Juice
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of Alnavas, especially with excessive grapefruit juice consumption.
Alnavas and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of Alnavas. Alnavas AUC was significantly increased with concomitant administration of Alnavas 10 mg and cyclosporine 5.2 mg/kg/day compared to that of Alnavas alone [see Clinical Pharmacology (12.3) ]. In cases where co-administration of Alnavas with cyclosporine is necessary, the dose of Alnavas should not exceed 10 mg [see Warnings and Precautions, Skeletal Muscle (5.1) ].
7.4 Rifampin or other Inducers of Cytochrome P450 3A4
Concomitant administration of Alnavas with inducers of cytochrome P450 3A4 can lead to variable reductions in plasma concentrations of Alnavas. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of Alnavas with rifampin is recommended, as delayed administration of Alnavas after administration of rifampin has been associated with a significant reduction in Alnavas plasma concentrations.
When multiple doses of Alnavas and digoxin were coadministered, steady state plasma digoxin concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
7.6 Oral Contraceptives
Co-administration of Alnavas and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology ]. These increases should be considered when selecting an oral contraceptive for a woman taking Alnavas.
Alnavas had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category X
Alnavas is contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of Alnavas use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified.
Alnavas crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Alnavas was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2) [see Contraindications, Pregnancy (4.3) ].
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human AUC at 80 mg/day.
Statins may cause fetal harm when administered to a pregnant woman. Alnavas should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the woman becomes pregnant while taking Alnavas, it should be discontinued immediately and the patient advised again as to the potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.
8.3 Nursing Mothers
It is not known whether Alnavas is excreted in human milk, but a small amount of another drug in this class does pass into breast milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk. Animal breast milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and because statins have a potential to cause serious adverse reactions in nursing infants, women requiring Alnavas treatment should be advised not to nurse their infants [see Contraindications ].
8.4 Pediatric Use
Safety and effectiveness in patients 10–17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of 6 months' duration in adolescent boys and postmenarchal girls. Patients treated with Alnavas had an adverse experience profile generally similar to that of patients treated with placebo. The most common adverse experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in boys or on menstrual cycle length in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10–17 years) (6.3) ; and Dosage and Administration, Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10–17 years of age) (2.2) ]. Adolescent females should be counseled on appropriate contraceptive methods while on Alnavas therapy [see Contraindications, Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1) ]. Alnavas has not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.
Clinical efficacy with doses up to 80 mg/day for 1 year have been evaluated in an uncontrolled study of patients with homozygous FH including 8 pediatric patients [see Clinical Studies, Homozygous Familial Hypercholesterolemia (14.5) ].
8.5 Geriatric Use
Of the 39,828 patients who received Alnavas in clinical studies, 15,813 were ≥65 years old and 2,800 (7%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, Alnavas should be prescribed with caution in the elderly.
8.6 Hepatic Impairment
Alnavas is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Pharmacokinetics (12.3) ].
There is no specific treatment for Alnavas overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance Alnavas clearance.
Alnavas is a synthetic lipid-lowering agent. Alnavas is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Alnavas calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of Alnavas calcium is (C33H34 FN2O5)2Ca-3H2O and its molecular weight is 1209.42. Its structural formula is:
Alnavas calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Alnavas calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely soluble in methanol.
Alnavas Tablets for oral administration contain 10, 20, 40, or 80 mg Alnavas and the following inactive ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Alnavas is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL, IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased cardiovascular risk.
In animal models, Alnavas lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; Alnavas also reduces LDL production and the number of LDL particles. Alnavas reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.
Alnavas reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Alnavas also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Alnavas reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Alnavas reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.
Alnavas, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and Administration (2) ].
Absorption: Alnavas is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to Alnavas dose. The absolute bioavailability of Alnavas (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether Alnavas is given with or without food. Plasma Alnavas concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2) ].
Distribution: Mean volume of distribution of Alnavas is approximately 381 liters. Alnavas is ≥98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, Alnavas is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations, Nursing Mothers (8.3) ].
Metabolism: Alnavas is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of Alnavas. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of Alnavas metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of Alnavas in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1) ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Alnavas and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of Alnavas in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of Alnavas is recovered in urine following oral administration.
Geriatric: Plasma concentrations of Alnavas are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations, Geriatric Use (8.5) ].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of Alnavas in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with Alnavas between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of Alnavas; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairment (2.5) , Warnings and Precautions, Skeletal Muscle (5.1) ].
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of Alnavas since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of Alnavas are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1) ].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0–24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0–24) values of approximately 6 times the mean human plasma drug exposure after an 80 mg oral dose.
In vitro, Alnavas was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Alnavas was negative in the in vivo mouse micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of Alnavas for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Alnavas caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.
14 CLINICAL STUDIES
14.1 Prevention of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial, the effect of Alnavas on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients; <130/80 mm Hg for diabetic patients) and allocated to either Alnavas 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.
The effect of 10 mg/day of Alnavas on lipid levels was similar to that seen in previous clinical trials.
Alnavas significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the Alnavas group) or non-fatal MI (108 events in the placebo group vs. 60 events in the Alnavas group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for Alnavas vs. 3.0% for placebo), p=0.0005 ]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of Alnavas was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive.
Figure 1: Effect of Alnavas 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)
Alnavas also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p=0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for Alnavas and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Alnavas Diabetes Study (CARDS), the effect of Alnavas on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40–75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either Alnavas 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.
The effect of Alnavas 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
Alnavas significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the Alnavas group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001). An effect of Alnavas was seen regardless of age, sex, or baseline lipid levels.
Alnavas significantly reduced the risk of stroke by 48% (21 events in the Alnavas group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the Alnavas group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.
There were 61 deaths in the Alnavas group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).
Figure 2: Effect of Alnavas 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS
In the Treating to New Targets Study (TNT), the effect of Alnavas 80 mg/day vs. Alnavas 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label, run-in period with Alnavas 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of Alnavas and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of Alnavas and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of Alnavas.
Treatment with Alnavas 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002. The overall risk reduction was consistent regardless of age (<65, ≥65) or gender.
Figure 3: Effect of Alnavas 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
Of the events that comprised the primary efficacy endpoint, treatment with Alnavas 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 5). Of the predefined secondary endpoints, treatment with Alnavas 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.
There was no significant difference between the treatment groups for all-cause mortality (Table 5). The proportions of subjects who experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the Alnavas 80 mg group than in the Alnavas 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the Alnavas 80 mg group than in the Alnavas 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with Alnavas 80 mg/day was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of Alnavas and 105, 179, 142, 47, and 132 mg/dL during treatment with 20–40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the Alnavas 80 mg/day group vs. 463 (10.4%) in the simvastatin 20–40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p=0.07.
There were no significant differences between the treatment groups for all-cause mortality: 366 (8.2%) in the Alnavas 80 mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The proportions of subjects who experienced CV or non-CV death were similar for the Alnavas 80 mg group and the simvastatin 20–40 mg group.
Figure Figure Figure
14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
Alnavas reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.
Alnavas is effective in a wide variety of patient populations with hyperlipidemia, with and without hypertriglyceridemia, in men and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, Alnavas given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 6.)
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and 75th percentile) percent changes from baseline in HDL-C for Alnavas 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients with hyperlipidemia, Alnavas was compared to other statins. After randomization, patients were treated for 16 weeks with either Alnavas 10 mg per day or a fixed dose of the comparative agent (Table 7).
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 7 is not known. Table 7 does not contain data comparing the effects of Alnavas 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.
The response to Alnavas in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below (Table 8). For the LIPITOR-treated patients, median (min, max) baseline TG level was 565 (267–1502).
The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III) are shown in the table below (Table 9).
14.5 Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of Alnavas. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% ; the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10–17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe hypercholesterolemia, were randomized to Alnavas (n=140) or placebo (n=47) for 26 weeks and then all received Alnavas for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5–385.0 mg/dL) in the Alnavas group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL) in the placebo group. The dosage of Alnavas (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of LIPITOR-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 80 (57.1%).
Alnavas significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week double-blind phase.
The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0–242.0 mg/dL) in the Alnavas group compared to 228.5 mg/dL (range: 152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of Alnavas therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
16 HOW SUPPLIED/STORAGE AND HANDLING
10 mg tablets: coded "PD 155" on one side and "10" on the other.
NDC 0071-0155-23 bottles of 90
NDC 0071-0155-34 bottles of 5000
NDC 0071-0155-40 10 × 10 unit dose blisters
20 mg tablets: coded "PD 156" on one side and "20" on the other.
NDC 0071-0156-23 bottles of 90
NDC 0071-0156-40 10 × 10 unit dose blisters
NDC 0071-0156-94 bottles of 5000
40 mg tablets: coded "PD 157" on one side and "40" on the other.
NDC 0071-0157-23 bottles of 90
NDC 0071-0157-73 bottles of 500
NDC 0071-0157-88 bottles of 2500
NDC 0071-0157-40 10 × 10 unit dose blisters
80 mg tablets: coded "PD 158" on one side and "80" on the other.
NDC 0071-0158-23 bottles of 90
NDC 0071-0158-73 bottles of 500
NDC 0071-0158-88 bottles of 2500
NDC 0071-0158-92 8 × 8 unit dose blisters
Store at controlled room temperature 20 – 25°C (68 – 77°F).
17 PATIENT COUNSELING INFORMATION
Patients taking Alnavas should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program -recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with Alnavas [see Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking Alnavas.
17.1 Muscle Pain
All patients starting therapy with Alnavas should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription and over the counter, with their healthcare professional.
17.2 Liver Enzymes
It is recommended that liver function tests be performed prior to and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically thereafter.
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Alnavas. Discuss future pregnancy plans with your patients, and discuss when to stop Alnavas if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking Alnavas and call their healthcare professional.
Women who are breastfeeding should be advised to not use Alnavas. Patients who have a lipid disorder and are breastfeeding, should be advised to discuss the options with their healthcare professional.
Pfizer Ireland Pharmaceuticals
Read the Patient Information that comes with Alnavas 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 or treatment.
If you have any questions about Alnavas, ask your doctor or pharmacist.
What is Alnavas?
Alnavas is a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C ("bad" cholesterol) and triglycerides in your blood. It can raise your HDL-C ("good" cholesterol) as well. Alnavas is for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.
Alnavas can lower the risk for heart attack, stroke, certain types of heart surgery, and chest pain in patients who have heart disease or risk factors for heart disease such as:
Alnavas can lower the risk for heart attack or stroke in patients with diabetes and risk factors such as:
Alnavas starts to work in about 2 weeks.
What is Cholesterol?
Cholesterol and triglycerides are fats that are made in your body. They are also found in foods. You need some cholesterol for good health, but too much is not good for you. Cholesterol and triglycerides can clog your blood vessels. It is especially important to lower your cholesterol if you have heart disease, smoke, have diabetes or high blood pressure, are older, or if heart disease starts early in your family.
Who Should Not Take Alnavas?
Do not take Alnavas if you:
Alnavas has not been studied in children under 10 years of age.
Before You Start Alnavas
Tell your doctor if you:
Some medicines should not be taken with Alnavas. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Alnavas and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for:
Know all the medicines you take. Keep a list of them with you to show your doctor and pharmacist.
How Should I Take Alnavas?
What Should I Avoid While Taking Alnavas?
What are the Possible Side Effects of Alnavas?
Alnavas can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or Alnavas is stopped. These serious side effects include:
Call your doctor right away if you have:
In clinical studies, patients reported the following common side effects while taking Alnavas: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been reported with Alnavas:
tiredness, and tendon problems.
Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.
These are not all the side effects of Alnavas. Ask your doctor or pharmacist for a complete list.
How do I store Alnavas
General Information About Alnavas
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Alnavas for a condition for which it was not prescribed. Do not give Alnavas to other people, even if they have the same problem you have. It may harm them.
This leaflet summarizes the most important information about Alnavas. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Alnavas that is written for health professionals. Or you can go to the Alnavas website at www.lipitor.com.
What are the Ingredients in Alnavas?
Active Ingredient: Alnavas calcium
Inactive Ingredients: calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion.
Manufactured by Pfizer Ireland Pharmaceuticals
LAB-0348-4.0 June 2009
Alnavas pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Alnavas available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Alnavas destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Alnavas Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Alnavas pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Alnavas?
Depending on the reaction of the Alnavas after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Alnavas not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Alnavas addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Alnavas, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Alnavas consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology