Zocor

simvastatin

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

Indications and Usage for Zocor

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 indicated 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 coronary heart disease (CHD) or at high risk of CHD, Zocor1 can be started simultaneously with diet.

1

Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Copyright © 1999-2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved

Reductions in Risk of CHD Mortality and Cardiovascular Events

In patients at high risk of coronary events because of existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, Zocor is indicated to:

• Reduce the risk of total mortality by reducing CHD deaths.


• Reduce the risk of non-fatal myocardial infarction and stroke.


• Reduce the need for coronary and non-coronary revascularization procedures.

Hyperlipidemia

Zocor is indicated to:

• Reduce elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).


• Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).


• Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III hyperlipidemia).


• Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)

Zocor is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10-17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:

1. LDL cholesterol remains ≥190 mg/dL; or


2. LDL cholesterol remains ≥160 mg/dL and

• There is a positive family history of premature cardiovascular disease (CVD) or


• Two or more other CVD risk factors are present in the adolescent patient.

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

Limitations of Use

Zocor has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

Zocor Dosage and Administration

Recommended Dosing

 The usual dosage range is 5 to 40 mg/day. In patients with CHD or at high risk of CHD, Zocor can be started simultaneously with diet. The recommended usual starting dose is 10 or 20 mg once a day in the evening. For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.

Restricted Dosing for 80 mg

 Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 80-mg dose of Zocor should be restricted to patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Warnings and Precautions (5.1)].

 Patients who are currently tolerating the 80-mg dose of Zocor who need to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin should be switched to an alternative statin with less potential for the drug-drug interaction.

 Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 80-mg dose of Zocor, patients unable to achieve their LDL-C goal utilizing the 40-mg dose of Zocor should not be titrated to the 80-mg dose, but should be placed on alternative LDL-C-lowering treatment(s) that provides greater LDL-C lowering.

Coadministration with Other Drugs

 Patients taking Verapamil or Diltiazem

•  The dose of Zocor should not exceed 10 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

 Patients taking Amiodarone, Amlodipine or Ranolazine

•  The dose of Zocor should not exceed 20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

Patients with Homozygous Familial Hypercholesterolemia

 The recommended dosage is 40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. Zocor should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Adolescents (10-17 years of age) with Heterozygous Familial Hypercholesterolemia

The recommended usual starting dose is 10 mg once a day in the evening. The recommended dosing range is 10 to 40 mg/day; the maximum recommended dose is 40 mg/day. Doses should be individualized according to the recommended goal of therapy [see NCEP Pediatric Panel Guidelines2 and Clinical Studies (14.2)]. Adjustments should be made at intervals of 4 weeks or more.

2

National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.

Patients with Renal Impairment

Because Zocor does not undergo significant renal excretion, modification of dosage should not be necessary in patients with mild to moderate renal impairment. However, caution should be exercised when Zocor is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing Products

 Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known. It is also unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings and Precautions (5.1).]

Dosage Forms and Strengths

• Tablets Zocor 5 mg are buff, oval, film-coated tablets, coded MSD 726 on one side and Zocor 5 on the other.


• Tablets Zocor 10 mg are peach, oval, film-coated tablets, coded MSD 735 on one side and plain on the other.


• Tablets Zocor 20 mg are tan, oval, film-coated tablets, coded MSD 740 on one side and plain on the other.


• Tablets Zocor 40 mg are brick red, oval, film-coated tablets, coded MSD 749 on one side and plain on the other.


• Tablets Zocor 80 mg are brick red, capsule-shaped, film-coated tablets, coded 543 on one side and 80 on the other.

Contraindications

Zocor is contraindicated in the following conditions:

•  Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone) [see Warnings and Precautions (5.1)].


•  Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions (5.1)].


• Hypersensitivity to any component of this medication [see Adverse Reactions (6.2)].


• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions (5.2)].


• Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Zocor may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the 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 use with Zocor during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Zocor should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, Zocor should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].


• Nursing mothers. It is not known whether simvastatin 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 treatment with Zocor should not breastfeed their infants [see Use in Specific Populations (8.3)].

Warnings and Precautions

Myopathy/Rhabdomyolysis

 Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment.

 The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with Zocor, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded.

 In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with Zocor (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

 The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 80-mg dose of Zocor should be used only in patients who have been taking simvastatin 80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 80 mg (2.2)]. If, however, a patient who is currently tolerating the 80-mg dose of Zocor needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately. [See Warnings and Precautions (5.2).]

 All patients starting therapy with simvastatin, or whose dose of simvastatin is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness. Simvastatin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with simvastatin or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy.

 Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients merit closer monitoring. Zocor therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Zocor therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

 The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, the antidepressant nefazodone, or large quantities of grapefruit juice (>1 quart daily). Combination of these drugs with simvastatin is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7.1).] In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the simvastatin dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if voriconazole must be used concomitantly with simvastatin. [See Drug Interactions (7.1).]

 The combined use of simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications (4) and Drug Interactions (7.1 and 7.2)].

 Caution should be used when prescribing other fibrates with simvastatin, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered [see Drug Interactions (7.2)].

 Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine [see Drug Interactions (7.7)].

 The benefits of the combined use of simvastatin with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (other fibrates or ≥1 g/day of niacin), amiodarone, verapamil, diltiazem, amlodipine, or ranolazine [see Drug Interactions (7.3) and Table 3 in Clinical Pharmacology (12.3)].

 Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind, randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin 40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with simvastatin in doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration of simvastatin with lipid-modifying doses of niacin-containing products observed in Chinese patients applies to other Asian patients [see Drug Interactions (7.4)].

Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2.3), Drug Interactions (7), Clinical Pharmacology (12.3)].

TABLE 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis

Interacting Agents	Prescribing Recommendations
Itraconazole  Ketoconazole  Posaconazole  Erythromycin  Clarithromycin  Telithromycin  HIV protease inhibitors  Nefazodone  Gemfibrozil  Cyclosporine  Danazol	Contraindicated with simvastatin
Verapamil  Diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone  Amlodipine  Ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Liver Dysfunction

Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical studies. When drug treatment was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms. There was no evidence of hypersensitivity.

In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.1)], the number of patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group (n=2,221) and 5 in the placebo group (n=2,223). Of the 1,986 simvastatin treated patients in 4S with normal liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study. Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.

In 2 controlled clinical studies in 1,105 patients, the 12-month incidence of persistent hepatic transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40- and 80-mg dose, respectively. No patients developed persistent liver function abnormalities following the initial 6 months of treatment at a given dose.

 It is recommended that liver function tests be performed before the initiation of treatment, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Zocor, promptly interrupt therapy. If an alternate etiology is not found do not restart Zocor. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].

The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are contraindications to the use of simvastatin.

As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases have been reported following therapy with simvastatin. These changes appeared soon after initiation of therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not require interruption of treatment.

Endocrine Function

 Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Zocor.

Adverse Reactions

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%). The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were: upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).

Scandinavian Simvastatin Survival Study

In 4S involving 4,444 (age range 35-71 years, 19% women, 100% Caucasians) treated with 20-40 mg/day of Zocor (n=2,221) or placebo (n=2,223) over a median of 5.4 years, adverse reactions reported in ≥2% of patients and at a rate greater than placebo are shown in Table 2.

TABLE 2: Adverse Reactions Reported Regardless of Causality by ≥2% of Patients Treated with Zocor and Greater than Placebo in 4S

	Zocor (N = 2,221) %	Placebo (N = 2,223) %
Body as a Whole     Edema/swelling     Abdominal pain	2.7 5.9	2.3 5.8
Cardiovascular System Disorders     Atrial fibrillation	5.7	5.1
Digestive System Disorders     Constipation     Gastritis	2.2 4.9	1.6 3.9
Endocrine Disorders     Diabetes mellitus	4.2	3.6
Musculoskeletal Disorders     Myalgia	3.7	3.2
Nervous System / Psychiatric Disorders     Headache     Insomnia     Vertigo	2.5 4.0 4.5	2.1 3.8 4.2
Respiratory System Disorders     Bronchitis     Sinusitis	6.6 2.3	6.3 1.8
Skin / Skin Appendage Disorders     Eczema	4.5	3.0
Urogenital System Disorders     Infection, urinary tract	3.2	3.1

Heart Protection Study

In the Heart Protection Study (HPS), involving 20,536 patients (age range 40-80 years, 25% women, 97% Caucasians, 3% other races) treated with Zocor 40 mg/day (n=10,269) or placebo (n=10,267) over a mean of 5 years, only serious adverse reactions and discontinuations due to any adverse reactions were recorded. Discontinuation rates due to adverse reactions were 4.8% in patients treated with Zocor compared with 5.1% in patients treated with placebo. The incidence of myopathy/rhabdomyolysis was <0.1% in patients treated with Zocor.

Other Clinical Studies

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with Zocor (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded.

Other adverse reactions reported in clinical trials were: diarrhea, rash, dyspepsia, flatulence, and asthenia.

Laboratory Tests

Marked persistent increases of hepatic transaminases have been noted [see Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have also been reported. About 5% of patients had elevations of CK levels of 3 or more times the normal value on one or more occasions. This was attributable to the noncardiac fraction of CK. [See Warnings and Precautions (5.1).]

Adolescent Patients (ages 10-17 years)

In a 48-week, controlled study in adolescent boys and girls who were at least 1 year post-menarche, 10-17 years of age (43.4% female, 97.7% Caucasians, 1.7% Hispanics, 0.6% Multiracial) with heterozygous familial hypercholesterolemia (n=175), treated with placebo or Zocor (10-40 mg daily), the most common adverse reactions observed in both groups were upper respiratory infection, headache, abdominal pain, and nausea [see Use in Specific Populations (8.4) and Clinical Studies (14.2)].

Post-Marketing Experience

Because the below reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following additional adverse reactions have been identified during postapproval use of simvastatin: pruritus, alopecia, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails), dizziness, muscle cramps, myalgia, pancreatitis, paresthesia, peripheral neuropathy, vomiting, anemia, erectile dysfunction, interstitial lung disease, rhabdomyolysis, hepatitis/jaundice, fatal and non-fatal hepatic failure, and depression.

An apparent hypersensitivity syndrome has been reported rarely which has included some of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.

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).

Drug Interactions

Strong CYP3A4 Inhibitors, cyclosporine, or danazol

Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentration of simvastatin. It is recommended that dose adjustment of simvastatin be considered during concomitant use of voriconazole and simvastatin to reduce the risk of myopathy, including rhabdomyolysis. [see Warnings and Precautions (5.1)]

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated. [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

Gemfibrozil: Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)]. 

Other fibrates: Caution should be used when prescribing with simvastatin [see Warnings and Precautions (5.1)].

Amiodarone, Ranolazine, or Calcium Channel Blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1), and Table 3 in Clinical Pharmacology (12.3)].

Niacin

Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]

Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated [see Clinical Pharmacology (12.3)].

Coumarin Anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting simvastatin and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of simvastatin is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing simvastatin with colchicine.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X [See Contraindications (4).]

Zocor is contraindicated in women who are or may become pregnant. 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 use with Zocor during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Zocor may cause fetal harm when administered to a pregnant woman. If Zocor is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review3 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.

Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 3 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.

Women of childbearing potential, who require treatment with Zocor for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of Zocor should be considered. If pregnancy occurs, Zocor should be immediately discontinued.

3

Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.

Nursing Mothers

It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in this class is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking simvastatin should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother [see Contraindications (4)].

Pediatric Use

Safety and effectiveness of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial in adolescent boys and in girls who were at least 1 year post-menarche. Patients treated with simvastatin had an adverse reaction profile similar to that of patients treated with placebo. Doses greater than 40 mg have not been studied in this population. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. [See Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Studies (14.2).] Adolescent females should be counseled on appropriate contraceptive methods while on simvastatin therapy [see Contraindications (4) and Use in Specific Populations (8.1)]. Simvastatin has not been studied in patients younger than 10 years of age, nor in pre-menarchal girls.

Geriatric Use

Of the 2,423 patients who received Zocor in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received Zocor, 363 (15%) and 5,366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) 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 individuals cannot be ruled out. Since advanced age (≥65 years) is a predisposing factor for myopathy, Zocor should be prescribed with caution in the elderly. [See Clinical Pharmacology (12.3).]

A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1,021 (23%) of 4,444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and Zocor significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4,891 patients 65-69 years and 5,806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies (14.1)]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.

Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, Zocor should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).]

Renal Impairment

Caution should be exercised when Zocor is administered to patients with severe renal impairment. [See Dosage and Administration (2.6).]

Hepatic Impairment

Zocor is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Warnings and Precautions (5.2)].

Overdosage

Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with Zocor have been reported; t

Prednisolone Gastro-resistant tablets

Prednisolone

Gastro-resistant tablets

Prednisolone Leaflet – Headlines

• 
  Prednisolone is a steroid medicine, prescribed for many different conditions, including serious illnesses.


• 
  You need to take it regularly to get the maximum benefit.


• 
  Don’t stop taking this medicine without talking to your doctor – you may need to reduce the dose gradually.


• 
  Prednisolone can cause side effects in some people (read Section 4 Possible Side Effects below). Some problems such as mood changes (feeling depressed, or ‘high’), or stomach problems can happen straight away. If you feel unwell in any way, keep taking your tablets, but see your doctor straight away.


• 
  Some side effects only happen after weeks or months. These include weakness of arms and legs, developing a rounder face (read Section 4 Possible Side Effects for more information)


• 
  If you take it for more than 3 weeks, you will get a blue ‘steroid card’: always keep it with you and show it to any doctor or nurse treating you.


• 
  Keep away from people who have chicken-pox or shingles, if you have never had them. They could affect you severely. If you do come into contact with chicken-pox or shingles, see your doctor straight away.

Now read the rest of this leaflet. It includes other important information on the safe and effective use of this medicine that might be especially important for you. This leaflet was last updated on 29th May 2009.

Read all of this leaflet carefully before you start taking this medicine

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet please tell your doctor or pharmacist.

The information in this leaflet has been divided into the following sections:

• 
  1. What Prednisolone is and what it is taken for
  


• 
  2. Check before you take Prednisolone
  


• 
  3. How to take Prednisolone
  


• 
  4. Possible side effects
  


• 
  5. How to store Prednisolone
  


• 
  6. Further information
  

What Prednisolone is and what it is taken for

Prednisolone belongs to a group of medicines called steroids. Their full name is corticosteroids. These corticosteroids occur naturally in the body, and help to maintain health and well-being. Boosting your body with extra corticosteroid (such as prednisolone) is an effective way to treat various illnesses involving inflammation in the body. Prednisolone reduces this inflammation, which could otherwise go on making your condition worse. You must take this medicine regularly to get maximum benefit from it.

Prednisolone is used in a wide range of inflammatory and auto-immune conditions including:

• allergies, including severe allergic reactions


• inflammation affecting the:
  
  
  • lungs, including asthma
  • blood vessels and heart
  • bowel or kidneys
  • muscles and joints, including rheumatoid arthritis
  • eye or nervous system


• skin conditions


• some infections


• some cancers, including leukaemia, lymphoma and myeloma


• to prevent organ rejection after a transplant.

Also:

• to boost steroid levels when the body is not making enough natural steroid on its own.


• to treat high calcium levels.

Check before you take Prednisolone

Check with your doctor first

• 
  If you have ever had severe depression or manic-depression (bipolar disorder). This includes having had depression before while taking steroid medicines like prednisolone.


• 
  If any of your close family has had these illnesses.

If either of these applies to you, talk to a doctor before taking prednisolone.

Do not take Prednisolone if you:

• are allergic (hypersensitive) to prednisolone or any of the ingredients of prednisolone (see Section 6 Further Information)


• are suffering from a serious infection which is not being treated


• are suffering from a herpes infection of the eye.

Take special care with Prednisolone

Before you take prednisolone tell your doctor if you:

• suffer from or have ever been treated for tuberculosis (TB)


• have high blood pressure


• have a heart condition


• have liver or kidney problems


• suffer from diabetes or diabetes runs in your family


• have osteoporosis (thinning of the bone), particularly if you are past the menopause (the change of life).


• suffer from epilepsy (fits)


• suffer from stomach ulcers


• have taken prednisolone (or other steroids) before and had muscular problems (steroid myopathy)


• are receiving treatment for a condition called myasthenia gravis (a rare muscle weakness disorder)


• have ever had blood clots, (for example, deep vein thrombosis [DVT], or, thromboembolism)


• are planning to have a vaccination.


• have Cushing’s disease. (A hormone disorder which can cause symptoms including gaining weight very quickly, especially on the trunk and face, thinning of the skin and sweating).


• suffer from hypothyroidism (an underactive thyroid gland which can cause tiredness or weight gain)


• have Duchenne’s muscular dystrophy.

If any of the above applies to you, or if you are not sure, speak to your doctor or pharmacist before you take prednisolone.

Taking other medicines

Tell your doctor or pharmacist if you are taking or have recently taken any of the following medicines as they may interfere with prednisolone:

• antivirals such as ritonavir which can be used to treat HIV infection


• antifungals such as ketoconazole and amphotericin which are used to treat fungal infections


• antibiotics such as erythromycin and rifamycin which are used to treat bacterial infections


• antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin and primidone which are used to treat epilepsy


• antiarthritis drugs


• oestrogens, for example in the contraceptive pill or HRT


• thiazide diuretics (“water tablets”) for example bendroflumethiazide used for water retention or high blood pressure


• medicines to treat high blood pressure


• anticoagulants for example warfarin which is used to thin the blood


• carbenoxolone which is used for ulcers


• salbutamol, formoterol, bambuterol, fenoteral, ritodrine, salmeterol and terbutaline used to


• drugs for diabetes including insulin


• ciclosporin which is used to treat rheumatic disease, skin complaints or after a transplant


• cardiac glycosides for example digoxin which is used to help strengthen a weak heart


• non-steroidal anti-inflammatory drugs (NSAIDs) for example aspirin, ibuprofen and indometacin used for pain relief or to treat rheumatic disease.


• mifepristone, used to induce labour or abortion.


• cytotoxic drugs for example methotrexate which is used to treat cancer


• vaccinations: You must tell your doctor or nurse that you are taking a steroid before you are given any vaccinations. Steroids affect your immune response and you must not be given any live vaccines.


• somatropin which is a growth hormone


• acetazolamide which is used in the treatment of glaucoma and epilepsy


• loop diuretics for example furosemide which is used to treat heart failure


• theophylline which is used for asthma and chronic obstructive pulmonary disease (COPD)

Please tell your doctor or pharmacist if you are taking or have recently taken/used any other medicines, including medicines obtained without a prescription.

Taking with food and drink

Prednisolone should be swallowed with water. You can take prednisolone before or after a meal.

Pregnancy and breast-feeding

If you are pregnant or trying to become pregnant, you must tell your doctor before you start the treatment.

If you are breast-feeding you must tell your doctor before you start the treatment. Your doctor will want to examine your baby during your time of treatment. Small amounts of steroids are present in breast milk.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

If you feel dizzy or tired after taking prednisolone do not drive or operate machinery until these effects have worn off.

Important information about some of the ingredients of Prednisolone

Prednisolone contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

How to take Prednisolone

Always take Prednisolone exactly as your doctor has told you to. You should check with your doctor or pharmacist if you are not sure.

Different illnesses require different doses of prednisolone. Depending on your illness your daily dose may be between 5 and 60 mg. In some cases you may be instructed to take it every other day. Your doctor will decide when and how to treat you with prednisolone.

Once your condition starts to get better, your doctor may change your dosage to a lower one. Your doctor may also reduce your dosage before stopping treatment completely. This may depend on your illness, your dosage and how long you have been taking this medicine. In all cases you should be careful to follow any changes.

Stopping taking Prednisolone: It is important to discuss your treatment with your doctor before stopping treatment. Sudden stopping of treatment can cause the following symptoms: fever, painful muscles and joints, inflammation of the eyes and nasal passages, painful and itchy skin lumps, loss of weight.

Treatment of children: The use of steroids can slow down normal growth of children and adolescents. In order to lessen this effect the tablets are often taken in a single dose every other day.

Treatment of the elderly: When steroids are taken by elderly patients some of the unwanted side effects can be more serious especially brittle bone disease, diabetes, high blood pressure, infections and thinning of the skin.

Whilst you are taking Prednisolone, if any of the following occur tell your doctor straight away:

• 
  Infections: If you think you might have an infection. You are more likely to develop illnesses due to infection whilst you are taking prednisolone. Also any existing infections may become worse. This is especially so during periods of stress. Certain infections can be serious if not controlled.


• 
  Chicken-pox and Shingles: If you, anyone in your family or regular contacts catches chicken-pox or shingles. This is because you may become very ill if you get chicken-pox whilst taking prednisolone. You should avoid contact with people who have chicken-pox or shingles whilst taking prednisolone and for up to 3 months after you have stopped taking prednisolone. Do not stop taking prednisolone.


• 
  Measles: If you, anyone in your family or regular contacts catches measles. You should avoid contact with people who have measles.

Your doctor will give you a steroid treatment card. You must carry it with you at all times. You should show your steroid treatment card to anyone who is giving you treatment such as a doctor, nurse or dentist.

Mental problems while taking Prednisolone

Mental health problems can happen while taking steroids like prednisolone (see also Section 4 Possible side effects).

• These illnesses can be serious.


• Usually they start within a few days or weeks of starting the medicine.


• They are more likely to happen at high doses.


• Most of these problems go away if the dose is lowered or the medicine is stopped. However, if problems do happen they might need treatment.

Talk to a doctor if you (or someone taking this medicine), show any signs of mental problems. This is particularly important if you are depressed, or might be thinking about suicide. In a few cases, mental problems have happened when doses are being lowered or stopped.

What to do if you take more Prednisolone than you should

If you accidentally take too many prednisolone tablets or someone else takes any of your medicine, you should tell your doctor at once or contact your nearest accident and emergency department. Show any left-over medicines or the empty packet to the doctor.

If you forget to take Prednisolone

Do not worry. If you forget to take a dose, take it as soon as possible, unless it is almost time to take the next dose. Do not take a double dose. Then go on as before.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible side effects

Do not worry. Like all medicines, prednisolone can cause side effects, although not everyone gets them.

Serious effects: tell a doctor straight away

Steroids including prednisolone can cause serious mental health problems. These are common in both adults and children. They can affect about 5 in every 100 people taking medicines like prednisolone.

• Feeling depressed, including thinking about suicide.


• Feeling high (mania) or moods that go up and down.


• Feeling anxious, having problems sleeping, difficulty in thinking or being confused and losing your memory.


• Feeling, seeing or hearing things which do not exist. Having strange and frightening thoughts, changing how you act or having feelings of being alone.

If you notice any of these problems talk to a doctor straight away.

Other side effects you may experience:

• allergic reaction


• tiredness


• increased number of white blood cells


• blood clotting


• nausea and vomiting


• high blood pressure


• heart problems which can cause shortness of breath


• convulsions


• dizziness


• headache raised pressure in the brain (which can cause headaches, nausea and vomiting)


• thinning of the skin


• bruising


• stretch marks


• patches of skin reddening


• itching


• rash


• hives


• acne


• extra hair growth


• slow healing of wounds


• increased sweating


• hiding or altering reactions to skin tests such as for tuberculosis


• reduction of growth in babies, children and adolescents


• absence or irregularity of menstrual periods


• face becomes very round


• weight gain


• carbohydrate imbalance in diabetes


• euphoria (feeling high)


• feeling of dependency on treatment


• depression


• pressure on the nerve to the eye (sometimes in children after stopping treatment)


• worsening of schizophrenia


• worsening of epilepsy


• increased pressure in the eyeball (glaucoma)


• whitening or clouding of the lens


• pressure on the nerve to the eye, thinning of the tissues of the eye (sclera and cornea)


• bulging eyes


• worsening of viral or fungal infections of the eye


• risk of contracting infection is increased


• existing infections can worsen


• signs of infection can be masked


• previous infections, such as tuberculosis (TB) may be re-activated (flare up).


• muscle wasting of the upper arms and legs


• muscle pain


• brittle bone disease or wasting of the bones


• bone fractures


• tendon rupture


• indigestion


• feeling sick


• stomach ulcers with bleeding or perforation


• bloating


• ulcers in the gullet (oesophagus) which may cause discomfort on swallowing


• candidiasis (thrush)


• abdominal (stomach) pain


• increased appetite which may result in weight gain


• diarrhoea


• water and salt retention


• high blood pressure (hypertension)


• a change in the levels of some hormones, mineral balance or protein in blood tests


• inflammation of the pancreas.

If any of the side effects gets worse, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Prednisolone

Keep out of the reach and sight of children.

Do not take prednisolone after the expiry date which is stated on the packaging. The expiry date refers to the last day of that month.

Store below 25°C. Keep your medicine in a dry place.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist on how to dispose of medicines no longer required. These measures will help protect the environment.

Further information

What is in Prednisolone?

The active ingredient in this medicine is prednisolone.

The other ingredients are: calcium carbonate, lactose, magnesium stearate, maize starch, polyvinyl alcohol, titanium dioxide (E171), purified talc, lecithin, xanthan gum (E415), polyvinyl acetate phthalate, polyethylene glycol, sodium hydrogen carbonate, triethyl citrate, purified stearic acid, sodium alginate (E401), colloidal silicon dioxide, methylcellulose (E461), sodium carboxymethyl cellulose, beeswax (E901), carnauba wax (E903), polysorbate 20 (E432) and sorbic acid (E200).

The Prednisolone 5 mg tablet also contains carmine (E120) and indigo carmine aluminium lake (E132).

The Prednisolone 2.5 mg tablet contains iron oxide (E172).

What Prednisolone looks like and contents of the pack

Prednisolone tablets come in two strengths.

Prednisolone 2.5 mg is a brown tablet.

Prednisolone 5 mg is a maroon tablet.

They are gastro-resistant tablets.

Prednisolone tablets come in packs of 30 or 100 tablets.

Marketing Authorisation Holder and Manufacturer

The product licence holder is:

Alliance Generics

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

UK

Prednisolone is manufactured by:

Recipharm Stockholm AB

Lagervägen 7

SE-136 50 Haninge

Sweden

The information in this leaflet applies only to prednisolone. If you have any questions or you are not sure about anything, ask your doctor or a pharmacist.

This leaflet was last approved in: 29th May 2009

Alliance and associated devices are registered Trademarks of Alliance Pharmaceuticals Ltd

© Alliance Pharmaceuticals Ltd 2009.

Liothyronine

Dosage Form: injection
Liothyronine SODIUM INJECTION (T3)

Rx Only

DESCRIPTION

Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, levothyroxine) sodium or triiodothyronine (T3, Liothyronine) sodium or both. T4 andT3 are produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. T4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T3 contains three atoms of iodine and is formed by the coupling of one molecule of DIT with one molecule of monoiodotyrosine (MIT). Both hormones are stored in the thyroid colloid as thyroglobulin and released into the circulation. The major source of T3 has been shown to be peripheral deiodination of T4. T3 is bound less firmly than T4 in the serum, enters peripheral tissues more readily, and binds to specific nuclear receptor(s) to initiate hormonal, metabolic effects. T4 is the prohormone which is deiodinated to T3 for hormone activity.

Thyroid hormone preparations belong to two categories: (1) natural hormonal preparations derived from animal thyroid, and (2) synthetic preparations. Natural preparations include desiccated thyroid and thyroglobulin. Desiccated thyroid is derived from domesticated animals that are used for food by man (either beef or hog thyroid), and thyroglobulin is derived from thyroid glands of the hog.

Liothyronine sodium injection (T3) contains Liothyronine (L-triiodothyronine or L-T3), a synthetic form of a natural thyroid hormone, as the sodium salt.

The structural and empirical formulas and molecular weight of Liothyronine sodium are given below.

In euthyroid patients, 25 mcg of Liothyronine is equivalent to approximately 1 grain of desiccated thyroid or thyroglobulin and 0.1 mg of L-thyroxine.

Each mL of Liothyronine sodium injection (T3) in amber glass vials contains, in sterile non-pyrogenic aqueous solution, Liothyronine sodium equivalent to 10 mcg of Liothyronine; alcohol, 6.8% by volume; anhydrous citric acid, 0.175 mg; ammonia, 2.19 mg, as ammonium hydroxide; Water for Injection, USP.

CLINICAL PHARMACOLOGY

Thyroid hormones enhance oxygen consumption by most tissues of the body and increase the basal metabolic rate and the metabolism of carbohydrates, lipids and proteins. In vitro studies indicate that T3 increases aerobic mitochondrial function, thereby increasing the rates of synthesis and utilization of myocardial high-energy phosphates. This, in turn, stimulates myosin ATPase and reduces tissue lactic acidosis. Thus, thyroid hormones exert a profound influence on virtually every organ system in the body and are of particular importance in the development of the central nervous system.

While the source of levothyroxine (T4) and some triiodothyronine (T3) is via secretion from the thyroid gland, it is now well-established that approximately 80% of circulating T3 arises predominantly by way of the extrathyroidal conversion of T4. The membrane-bound enzyme responsible for this reaction is iodothyronine 5’-deiodinase. Activity of the enzyme is greatest in the liver and kidney. A second pathway of T4 to T3 conversion occurs via a PTU-insensitive 5’-deiodinase located primarily in the pituitary and central nervous system.

The prohormone T4 must be converted to T3 in the body before it can exert biological effects. During periods of illness or stress, this conversion is often inhibited and can be diverted to the inactive reverse T3 (rT3) moiety. Therefore, correction of the hypothyroid condition in patients with myxedema coma is facilitated by the parenteral administration of triiodothyronine (T3). T3 is bound much less firmly to serum binding proteins and therefore penetrates into the cells much more rapidly than T4. Also, the binding of T3 to a nuclear thyroid hormone receptor seems to initiate most effects of thyroid hormone in tissues. Although most thyroid hormone analogs, both natural and synthetic, will bind to this protein, the affinity of T3 for this receptor is roughly 10-fold higher than that of T4. Thus, T3 is the biologically active thyroid hormone.

Pharmacodynamics

The clinical features of myxedema coma include depression of the cardiovascular, respiratory, gastrointestinal and central nervous systems, impaired diuresis, and hypothermia. Administration of thyroid hormones reverses or attenuates these conditions. Thyroid hormones increase heart rate, ventricular contractility and cardiac output, as well as decrease total systemic vascular resistance. They also increase the rate and depth of respiration, motility of the gastrointestinal tract, rapidity of cerebration, and vasodilatation. Thyroid hormones correct hypothermia by markedly increasing the basal metabolic rate, as well as the number and activity of mitochondria in almost all cells of the body.

Pharmacokinetics

Since Liothyronine sodium (T3) is not firmly bound to serum protein, it is readily available to body tissues.

Liothyronine sodium has a rapid cutoff of activity which permits quick dosage adjustment and facilitates control of the effects of overdosage, should they occur.

The higher affinity of levothyroxine (T4) as compared to triiodothyronine (T3) for both thyroid-binding globulin and thyroid-binding prealbumin partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity. T4 is deiodinated to T3.

A single dose of Liothyronine sodium administered intravenously produces a detectable metabolic response in as little as two to four hours and a maximum therapeutic response within two days. However, no pharmacokinetic studies have been performed with intravenous Liothyronine (T3) in myxedema coma or precoma patients.

INDICATIONS AND USAGE

Liothyronine sodium injection (T3) is indicated in the treatment of myxedema coma/precoma.

Liothyronine sodium injection (T3) can be used in patients allergic to desiccated thyroid or thyroid extract derived from pork or beef.

CONTRAINDICATIONS

Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as yet uncorrected adrenal cortical insufficiency or untreated thyrotoxicosis. Thyroid hormone preparations are also generally contraindicated in patients with hypersensitivity to any of the active or extraneous constituents of these preparations; however, there is no well-documented evidence in the literature of true allergic or idiosyncratic reactions to thyroid hormone.

Concomitant use of Liothyronine sodium injection (T3) and artificial rewarming of patients is contraindicated. (See PRECAUTIONS.)

BOXED WARNING

Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction.  Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.

WARNINGS

The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is unjustified and has been shown to be ineffective. Neither is their use justified for the treatment of male or female infertility unless this condition is accompanied by hypothyroidism.

Thyroid hormones should be used with great caution in a number of circumstances where the integrity of the cardiovascular system, particularly the coronary arteries, is suspect. These include patients with angina pectoris or the elderly, in whom there is a greater likelihood of occult cardiac disease. Therefore, in patients with compromised cardiac function, use thyroid hormones in conjunction with careful cardiac monitoring. Although the specific dosage of Liothyronine sodium injection (T3) depends upon individual circumstances, in patients with known or suspected cardiovascular disease the extremely rapid onset of action of Liothyronine sodium injection (T3) may warrant initiating therapy at a dose of 10 mcg to 20 mcg. (See DOSAGE AND ADMINISTRATION.)

Myxedematous patients are very sensitive to thyroid hormones; dosage should be started at a low level and increased gradually as acute changes may precipitate adverse cardiovascular events.

Severe and prolonged hypothyroidism can lead to a decreased level of adrenocortical activity commensurate with the lowered metabolic state. When thyroid replacement therapy is administered, the metabolism increases at a greater rate than adrenocortical activity. This can precipitate adrenocortical insufficiency. Therefore, in severe and prolonged hypothyroidism, supplemental adrenocortical steroids may be necessary.

In rare instances, the administration of thyroid hormone may precipitate a hyperthyroid state or may aggravate existing hyperthyroidism.

Extreme caution is advised when administering thyroid hormones with digitalis or vasopressors. (See PRECAUTIONS-Drug Interactions.)

Fluid therapy should be administered with great care to prevent cardiac decompensation. (See PRECAUTIONS-Adjunctive Therapy.)

PRECAUTIONS

General

Thyroid hormone therapy in patients with concomitant diabetes mellitus (see PRECAUTIONS-Drug Interactions, Insulin or Oral Hypoglycemics) regarding interaction and dose adjustment with insulin) or insipidus or adrenal cortical insufficiency may aggravate the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required.

The therapy of myxedema coma requires simultaneous administration of glucocorticoids. (See PRECAUTIONS-Adjunctive Therapy).

Hypothyroidism decreases and hyperthyroidism increases the sensitivity to anticoagulants. Prothrombin time should be closely monitored in thyroid-treated patients on anticoagulants and dosage of the latter agents adjusted on the basis of frequent prothrombin time determinations.

Oral therapy should be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication. If L-thyroxine rather than Liothyronine sodium is used in initiating oral therapy, the physician should bear in mind that there is a delay of several days in the onset of L-thyroxine activity and that intravenous therapy should be discontinued gradually.

Adjunctive Therapy

Many investigators recommend that corticosteroids be administered routinely in the initial emergency treatment of all patients with myxedema coma. Patients with pituitary myxedema should receive adrenocortical hormone replacement therapy at or before the start of Liothyronine sodium injection (T3) therapy. Similarly, patients with primary myxedema may also require adrenocortical hormone replacement therapy since a rapid return to normal body metabolism from a severely hypothyroid state may result in acute adrenocortical insufficiency and shock.

In considering the need to elevate blood pressure, it should be kept in mind that tissue metabolic requirements are markedly reduced in the hypothyroid patient. Because arrhythmias and circulatory collapse have infrequently occurred following the concomitant administration of thyroid hormones and vasopressor therapies, use caution when administering these therapies concomitantly. (See PRECAUTIONS-Drug Interactions, Vasopressors.)

Hyponatremia is frequently present in myxedema coma, but usually resolves without specific therapy as the metabolic status of the patient is improved with thyroid hormone treatment. Fluid therapy should be administered with great care to prevent cardiac decompensation. In addition, some patients with myxedema have inappropriate secretion of ADH and are susceptible to water intoxication.

In some patients, respiratory depression has been a significant factor in the development or persistence of the comatose state. Decreased oxygen saturation and elevated CO2 levels respond quickly to artificial respiration.

Infection is often present in myxedema coma and should be looked for and treated appropriately.

Concomitant use of Liothyronine sodium injection (T3) and artificial rewarming of patients is contraindicated. Although patients in myxedema coma are often hypothermic, most investigators believe that artificial rewarming is of little value or may be harmful. The peripheral vasodilation produced by external heat serves to further decrease circulation to vital internal organs and to increase shock if present. It has been reported that the administration of Liothyronine sodium will restore a normal body temperature in 24 to 48 hours if heat loss is prevented by keeping the patient covered with blankets in a warm room.

Laboratory Tests

Treatment of patients with thyroid hormones requires the periodic assessment of thyroid status by means of appropriate laboratory tests besides the full clinical evaluation. Serum T3 and TSH levels should be monitored to assess dosage adequacy and biologic effectiveness.

Drug Interactions

Oral Anticoagulants:

Thyroid hormones appear to increase catabolism of vitamin K-dependent clotting factors. If oral anticoagulants are also being given, compensatory increases in clotting factor synthesis are impaired. Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when thyroid is started. If a patient is truly hypothyroid, it is likely that a reduction in anticoagulant dosage will be required. No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance thyroid replacement therapy.

Insulin or Oral Hypoglycemics:

Initiating thyroid replacement therapy may cause increases in insulin or oral hypoglycemic requirements. The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient. Patients receiving insulin or oral hypoglycemics should be closely watched during initiation of thyroid replacement therapy.

Estrogen, Oral Contraceptives:

Estrogens tend to increase serum thyroxine-binding globulin (TBG). In a patient with a nonfunctioning thyroid gland who is receiving thyroid replacement therapy, free levothyroxine may be decreased when estrogens are started thus increasing thyroid requirements. However, if the patient’s thyroid gland has sufficient function, the decreased free thyroxine will result in a compensatory increase in thyroxine output by the thyroid. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroid dose if estrogens or estrogen-containing oral contraceptives are given.

Tricyclic Antidepressants:

Use of thyroid products with imipramine and other tricyclic antidepressants may increase receptor sensitivity and enhance antidepressant activity; transient cardiac arrhythmias have been observed. Thyroid hormone activity may also be enhanced.

Digitalis:

Thyroid preparations may potentiate the toxic effects of digitalis. Thyroid hormonal replacement increases metabolic rate, which requires an increase in digitalis dosage.

Ketamine:

When administered to patients on a thyroid preparation, this parenteral anesthetic may cause hypertension and tachycardia. Use with caution and be prepared to treat hypertension, if necessary.

Vasopressors:

Thyroid hormones increase the adrenergic effect of catecholamines such as epinephrine and norepinephrine. Therefore, use of vasopressors in patients receiving thyroid hormone preparations may increase the risk of precipitating coronary insufficiency, especially in patients with coronary artery disease. Therefore, use caution when administering vasopressors with Liothyronine (T3).

DRUG & OR LABORATORY TEST INTERACTIONS

The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations and the numerous preparations containing salicylates.

1. Changes in TBG concentration should be taken into consideration in the interpretation of T4 and T3 values. In such cases, the unbound (free) hormone should be measured. Pregnancy, estrogens and estrogen-containing oral contraceptives increase TBG concentrations. TBG may also be increased during infectious hepatitis. Decreases in TBG concentrations are observed in nephrosis, acromegaly and after androgen or corticosteroid therapy. Familial hyper- or hypothyroxine-binding globulinemias have been described. The incidence of TBG deficiency approximates 1 in 9000. The binding of thyroxine by thyroxine-binding prealbumin (TBPA) is inhibited by salicylates.
   
   


2. Medicinal or dietary iodine interferes with all in vivo tests of radioiodine uptake, producing low uptakes which may not be reflective of a true decrease in hormone synthesis.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients on thyroid for established indications should not discontinue therapy. No confirmatory long-term studies in animals have been performed to evaluate carcinogenic potential, mutagenicity, or impairment of fertility in either males or females.

Pregnancy

Pregnancy Category A: Thyroid hormones do not readily cross the placental barrier. The clinical experience to date does not indicate any adverse effect on fetuses when thyroid hormones are administered to pregnant women. On the basis of current knowledge, thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy.

Nursing Mothers

Minimal amounts of thyroid hormones are excreted in human milk. Thyroid hormones are not associated with serious adverse reactions and do not have a known tumorigenic potential. However, caution should be exercised when thyroid hormones are administered to a nursing woman.

Geriatric Use

Clinical studies of Liothyronine sodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Pediatric Use

There is limited experience with Liothyronine sodium injection (T3) in the pediatric population. Safety and effectiveness in pediatric patients have not been established.

ADVERSE REACTIONS

The most frequently reported adverse events were arrhythmia (6% of patients) and tachycardia (3%). Cardiopulmonary arrest, hypotension and myocardial infarction occurred in approximately 2% of patients. The following events occurred in approximately 1% or fewer of patients: angina, congestive heart failure, fever, hypertension, phlebitis and twitching.

In rare instances, allergic skin reactions have been reported with Liothyronine sodium tablets.

OVERDOSAGE

Signs and Symptoms: Headache, irritability, nervousness, tremor, sweating, increased bowel motility and menstrual irregularities. Angina pectoris, arrhythmia, tachycardia, acute myocardial infarction or congestive heart failure may be induced or aggravated. Shock may also develop if there is untreated pituitary or adrenocortical failure. Massive overdosage may result in symptoms resembling thyroid storm.

Treatment of Overdosage: Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary- thyroid axis function is restored in six to eight weeks after cessation of therapy following thyroid suppression.

Treatment is symptomatic and supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Beta-adrenergic antagonists have been used advantageously in the treatment of increased sympathetic activity. Measures to control fever, hypoglycemia or fluid loss should be instituted if needed.

DOSAGE AND ADMINISTRATION

Adults

Myxedema coma is usually precipitated in the hypothyroid patient of long standing by intercurrent illness or drugs such as sedatives and anesthetics and should be considered a medical emergency. Therapy should be directed at the correction of electrolyte disturbances, possible infection, or other intercurrent illness in addition to the administration of intravenous Liothyronine (T3). Simultaneous glucocorticosteroids are required.

Liothyronine sodium injection (T3) is for intravenous administration only. It should not be given intramuscularly or subcutaneously.

• Prompt administration of an adequate dose of intravenous Liothyronine (T3) is important in determining clinical outcome.


• Initial and subsequent doses of Liothyronine sodium injection (T3) should be based on continuous monitoring of the patient’s clinical status and response to therapy.


• Liothyronine sodium injection (T3) should normally be administered at least four hours-and not more than 12 hours-apart.


• Administration of at least 65 mcg/day of intravenous Liothyronine (T3) in the initial days of therapy was associated with lower mortality.


• There is limited clinical experience with intravenous Liothyronine (T3) at total daily doses exceeding 100 mcg/day.

No controlled clinical studies have been done with Liothyronine sodium injection (T3). The following dosing guidelines have been derived from data analysis of myxedema coma/precoma case reports collected by SmithKline Beecham Pharmaceuticals since 1963 and from scientific literature since 1956.

An initial intravenous Liothyronine sodium injection (T3) dose ranging from 25 mcg to 50 mcg is recommended in the emergency treatment of myxedema coma/precoma in adults. In patients with known or suspected cardiovascular disease, an initial dose of 10 mcg to 20 mcg is suggested (see WARNINGS). However, both the initial dose and subsequent doses should be determined on the basis of continuous monitoring of the patient’s clinical condition and response to Liothyronine sodium injection (T3) therapy. Normally at least four hours should be allowed between doses to adequately assess therapeutic response and no more than 12 hours should elapse between doses to avoid fluctuations in hormone levels. Caution should be exercised in adjusting the dose due to the potential of large changes to precipitate adverse cardiovascular events. Review of the myxedema case reports indicates decreased mortality in patients receiving at least 65 mcg/day in the initial days of treatment. However, there is limited clinical experience at total daily doses above 100 mcg. See PRECAUTIONS-Drug Interactions for potential interactions between thyroid hormones and digitalis and vasopressors.

Pediatric Use

There is limited experience with Liothyronine sodium injection (T3) in the pediatric population. Safety and effectiveness in pediatric patients have not been established.

Switching to Oral Therapy

Oral therapy should be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication. When switching a patient to Liothyronine sodium tablets from Liothyronine sodium injection (T3), discontinue Liothyronine sodium injection (T3), initiate oral therapy at a low dosage, and increase gradually according to the patient’s response.

If L-thyroxine rather then Liothyronine sodium is used in initiating oral therapy, the physician should bear in mind that there is a delay of several days in the onset of L-thyroxine activity and that intravenous therapy should be discontinued gradually.

HOW SUPPLIED

Liothyronine sodium injection (T3) is supplied in a single vial carton containing a 1mL vial at a concentration of 10 mcg/1mL (base). NDC number 39822-0151-1.

Storage and Handling

Store between 2°C – 8°C (36°F – 46°F).

Manufactured for:

X-GEN Pharmaceuticals, Inc

Big Flats, NY 14814

USA

LS-PI-02

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 39822-0151-1

Liothyronine Injection

10 mcg/1mL (Base activity)

For Intravenous Use

Rx Only

1 Vial

X-GEN Pharmaceuticals, Inc

NDC 39822-0151-1

Liothyronine Injection

10 mcg/1mL (Base activity)

For Intravenous Use

Rx Only

1 Vial

X-GEN Pharmaceuticals, Inc

Liothyronine SODIUM  Liothyronine sodium  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 39822-0151 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Liothyronine SODIUM (Liothyronine) Liothyronine SODIUM 10 ug  in 1 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 39822-0151-1 1 VIAL In 1 CARTON contains a VIAL 1 1 mL In 1 VIAL This package is contained within the CARTON (39822-0151-1)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076923	08/17/2005

Labeler - X-GEN Pharmaceuticals, Inc. (790169531)

Registrant - X-GEN Pharmaceuticals, Inc. (790169531)

Establishment
Name	Address	ID/FEI	Operations
PharmaForce, Inc.		113894740	ANALYSIS, MANUFACTURE

Revised: 12/2009X-GEN Pharmaceuticals, Inc.

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