Somatuline Depot

lanreotide acetate

Dosage Form: injection
FULL PRESCRIBING INFORMATION

Indications and Usage for Somatuline Depot

Somatuline Depot (lanreotide) Injection 60 mg, 90 mg and 120 mg is indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.

The goal of treatment in acromegaly is to reduce growth hormone (GH) and insulin growth factor-1 (IGF-1) levels to normal.

Somatuline Depot Dosage and Administration

Patients should begin treatment with Somatuline Depot 90 mg given via the deep subcutaneous route, at 4 week intervals for 3 months.

After 3 months dosage may be adjusted as follows:

• GH >1 to ≤ 2.5 ng/mL, IGF-1 normal and clinical symptoms controlled: maintain Somatuline Depot dose at 90 mg every 4 weeks.


• GH > 2.5 ng/mL, IGF-1 elevated and/or clinical symptoms uncontrolled, increase Somatuline Depot dose to 120 mg every 4 weeks.


• GH ≤ 1 ng/mL, IGF-1 normal and clinical symptoms controlled: reduce Somatuline Depot dose to 60 mg every 4 weeks.

Thereafter, the dose should be adjusted according to the response of the patient as judged by a reduction in serum GH and /or IGF-1 levels; and/or changes in symptoms of acromegaly.

 Patients who are controlled on Somatuline Depot 60 mg or 90 mg may be considered for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks. GH and IGF-1 levels should be obtained 6 weeks after this change in dosing regimen to evaluate persistence of patient response.

 Continued monitoring of patients response with dose adjustments for biochemical and clinical symptom control, as necessary, is recommended.

Somatuline Depot should be injected via the deep subcutaneous route in the superior external quadrant of the buttock. The skin should not be folded and the needle should be inserted perpendicular to the skin, rapidly and to its full length. The injection site should alternate between the right and left side.

The starting dose in patients with moderate and severe renal or moderate and severe hepatic impairment should be 60 mg via the deep subcutaneous route, at 4 week intervals for 3 months followed by dose adjustment as described above [see Clinical Pharmacology (12.3)].

Dosage Forms and Strengths

60, 90 and 120 mg sterile, single-use, pre-filled syringes. The pre-filled syringes contain a white to pale yellow, semi-solid formulation.

Contraindications

None

Warnings and Precautions

Cholelithiasis and Gallbladder Sludge

Lanreotide may reduce gallbladder motility and lead to gallstone formation therefore, patients may need to be monitored periodically [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

Hyperglycemia and Hypoglycemia

Pharmacological studies in animals and humans show that lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Hence, patients treated with Somatuline Depot may experience hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when lanreotide treatment is initiated, or when the dose is altered, and antidiabetic treatment should be adjusted accordingly [see Adverse Reactions (6.1)].

Thyroid function Abnormalities

Slight decreases in thyroid function have been seen during treatment with lanreotide in acromegalic patients, though clinical hypothyroidism is rare (<1%). Thyroid function tests are recommended where clinically indicated.

Cardiovascular Abnormalities

The most common overall cardiac adverse reactions observed in three pooled Somatuline Depot Cardiac Studies in patients with acromegaly were sinus bradycardia (12/217, 5.5%), bradycardia (6/217, 2.8%) and hypertension (12/217, 5.5%) [see Adverse Reactions (6.1)].

In patients without underlying cardiac disease, lanreotide may lead to a decrease in heart rate without necessarily reaching the threshold of bradycardia. In patients suffering from cardiac disorders prior to lanreotide treatment, sinus bradycardia may occur. Care should be taken when initiating treatment with lanreotide in patients with bradycardia.

Drug Interactions

The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs.

Lanreotide may decrease the relative bioavailability of cyclosporine. Concomitant administration of Somatuline Depot and cyclosporine may necessitate the adjustment of cyclosporine dose to maintain therapeutic levels [see Drug Interactions (7.2)].

Monitoring: Laboratory Tests

Serum GH and IGF-1 levels are useful markers of the disease and the effectiveness of treatment [see Dosage and Administration (2)].

Adverse Reactions

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

Clinical Studies Experience

The data described below reflect exposure to Somatuline Depot in 416 acromegalic patients in seven studies. One study was a fixed-dose pharmacokinetic study. The other six studies were open-label or extension studies, one had a placebo controlled run-in period and another had an active control. The population was mainly Caucasian (329/353, 93%) with a median age of 53.0 years of age (range 19-84 years). Fifty-four subjects (13%) were age 66-74 and eighteen subjects (4.3%) were ≥ 75 years of age. Patients were evenly matched for gender (205 males and 211 females). The median average monthly dose was 91.2 mg (e.g., 90 mg injected via the deep subcutaneous route every 4 weeks) over 385 days with a median cumulative dose of 1290 mg. Of the patients reporting acromegaly severity at baseline (N=265), serum GH levels were < 10 ng/mL for 69% (183/265) of the patients and ≥ 10 ng/mL for 31% (82/265) of the patients.

The most commonly reported adverse reactions reported by > 5% of patients who received Somatuline Depot (N=416) in the overall pooled safety studies in acromegaly patients were gastrointestinal disorders (diarrhea, abdominal pain, nausea, constipation, flatulence, vomiting, loose stools), cholelithiasis and injection site reactions.

Tables 1 and 2 present adverse reaction data from clinical studies with Somatuline Depot in acromegalic patients. The tables include data from a single clinical study and pooled data from seven clinical studies.

Adverse Reactions in Parallel Fixed-Dose Phase of Study 1:

The incidence of treatment-emergent adverse reactions for Somatuline Depot 60 mg, 90 mg, and 120 mg by dose as reported during the first 4 months (fixed-dose phase) of Study 1 [see Clinical Studies (14)], are provided in Table 1.

Table 1 Adverse Reactions at an Incidence > 5% Lanreotide Overall and Occurring at Higher Rate in Drug than Placebo: Placebo-Controlled and Fixed-Dose Phase of Study 1 by Dose

	Placebo-Controlled Double-Blind Phase Weeks 0 to 4		Fixed-Dose Phase Double-Blind + Single-Blind Weeks 0 to 20
Body System   Preferred Term	Placebo (N=25) N (%)	Lanreotide Overall (N=83) N (%)	Lanreotide 60 mg (N=34) N (%)	Lanreotide 90 mg (N=36) N (%)	Lanreotide 120 mg (N=37) N (%)	Lanreotide Overall (N=107) N (%)
A patient is counted only once for each body system and preferred term.
Dictionary = WHOART.
Gastrointestinal System Disorders	1 (4%)	30 (36%)	12 (35%)	21 (58%)	27 (73%)	60 (56%)
Diarrhea	0	26 (31%)	9 (26%)	15 (42%)	24 (65%)	48 (45%)
Abdominal pain	1 (4%)	6 (7%)	3 (9%)	6 (17%)	7 (19%)	16 (15%)
Flatulence	0	5 (6%)	0 (0%)	3 (8%)	5 (14%)	8 (7%)
Application Site Disorders	0 (0%)	5 (6%)	3 (9%)	4 (11%)	8 (22%)	15 (14%)
(Injection site mass/ pain/ reaction/ inflammation)
Liver and Biliary System Disorders	1 (4%)	3 (4%)	9 (26%)	7 (19%)	4 (11%)	20 (19%)
Cholelithiasis	0	2 (2%)	5 (15%)	6 (17%)	3 (8%)	14 (13%)
Heart Rate & Rhythm Disorders	0	8 (10%)	7 (21%)	2 (6%)	5 (14%)	14 (13%)
Bradycardia	0	7 (8%)	6 (18%)	2 (6%)	2 (5%)	10 (9%)
Red Blood Cell Disorders	0	6 (7%)	2 (6%)	5 (14%)	2 (5%)	9 (8%)
Anemia	0	6 (7%)	2 (6%)	5 (14%)	2 (5%)	9 (8%)
Metabolic & Nutritional Disorders	3 (12%)	13 (16%)	8 (24%)	9 (25%)	4 (11%)	21 (20%)
Weight decrease	0	7 (8%)	3 (9%)	4 (11%)	2 (5%)	9 (8%)

In Study 1, the adverse reactions of diarrhea, abdominal pain and flatulence increased in incidence with increasing dose of Somatuline Depot.

Adverse Reactions in Long-Term Clinical Trials:

Table 2 provides the most common adverse reactions that occurred in 416 acromegalic patients treated with Somatuline Depot in seven studies. The analysis of safety compares adverse reaction rates of patients at baseline from the two efficacy studies, to the overall pooled data from seven studies. Patients with elevated GH and IGF-1 levels were either naive to somatostatin analog therapy or had undergone a 3-month washout [see Clinical Studies (14)].

Table 2 Adverse Reactions at an Incidence > 5.0% in Overall Group Reported in Clinical Studies

System Organ Class	Number and Percentage of Patients
	Studies 1 & 2		Overall Pooled Data
	(N = 170)		(N = 416)
	N	%	N	%
Dictionary - MedDRA 7.1
Patients with any Adverse Reactions	157	92	356	86
Gastrointestinal disorders	121	71	235	57
Diarrhea	81	48	155	37
Abdominal pain	34	20	79	19
Nausea	15	9	46	11
Constipation	9	5	33	8
Flatulence	12	7	30	7
Vomiting	8	5	28	7
Loose stools	16	9	23	6
Hepatobiliary disorders	53	31	99	24
Cholelithiasis	45	27	85	20
General disorders and administration site conditions	51	30	91	22
(Injection site pain /mass / induration /nodule /pruritus)	28	17	37	9
Musculoskeletal and connective tissue disorders	44	26	70	17
Arthralgia	17	10	30	7
Nervous system disorders	34	20	80	19
Headache	9	5	30	7

In addition to the adverse reactions listed in Table 2, the following reactions were also seen:

• Sinus bradycardia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (13) of patients in the overall pooled studies.


• Hypertension occurred in 7% (11) of patients in the pooled Study 1 and 2 and in 5% (20) of patients in the overall pooled studies.


• Anemia occurred in 7% (12) of patients in the pooled Study 1 and 2 and in 3% (14) of patients in the overall pooled studies.

Gastrointestinal Adverse Reactions

In the pooled clinical studies of Somatuline Depot therapy, a variety of gastrointestinal reactions occurred, the majority of which were mild to moderate in severity. One percent of acromegalic patients treated with Somatuline Depot in the pooled clinical studies discontinued treatment because of gastrointestinal reactions.

Pancreatitis was reported in < 1% of patients.

Gallbladder Adverse Reactions

In clinical studies involving 416 acromegalic patients treated with Somatuline Depot, cholelithiasis and gallbladder sludge were reported in 20% of the patients. Among 167 acromegalic patients treated with Somatuline Depot who underwent routine evaluation with gallbladder ultrasound, 17.4% had gallstones at baseline. New cholelithiasis was reported in 12.0% of patients. Cholelithiasis may be related to dose or duration of exposure [see Cholelithiasis and Gallbladder Sludge (5.1)].

Injection Site Reactions

In the pooled clinical studies, injection site pain (4.1%) and injection site mass (1.7%) were the most frequently reported local adverse drug reactions that occurred with the administration of Somatuline Depot. In a specific analysis 20 of 413 patients (4.8%) presented indurations at the injection site. Injection site adverse reactions were more commonly reported soon after the start of treatment and were less commonly reported as treatment continued. Such adverse reactions were usually mild or moderate but did lead to withdrawal from clinical studies in two subjects.

Glucose Metabolism Adverse Reactions

In the clinical studies in acromegalic patients treated with Somatuline Depot, adverse reactions of dysglycemia (hypoglycemia, hyperglycemia, diabetes) were reported by 14% (47/332) of patients and were considered related to study drug in 7% (24/332) of patients [see Hyperglycemia and Hypoglycemia (5.2)].

Cardiac Adverse Reactions

In the pooled clinical studies, sinus bradycardia (3.1%) was the most frequently observed heart rate and rhythm disorder. All other cardiac adverse drug reactions were observed in < 1% of patients. The relationship of these events to Somatuline Depot could not be established because many of these patients had underlying cardiac disease [see Cardiovascular Abnormalities (5.4)].

A comparative echocardiography study of lanreotide and another somatostatin analog demonstrated no difference in the development of new or worsening valvular regurgitation between the two treatments over one year. The occurrence of clinically significant mitral regurgitation (i.e., moderate or severe in intensity) or of clinically significant aortic regurgitation (i.e., at least mild in intensity) was low in both groups of patients throughout the study.

Other Adverse Reactions

For the most commonly occurring adverse reactions in the pooled analysis, diarrhea, abdominal pain and cholelithiasis, there was no apparent trend for increasing incidence with age. GI disorders and renal and urinary disorders were more common in patients with documented hepatic impairment; however, the incidence of cholelithiasis was similar between groups.

Laboratory investigations of acromegalic patients treated with Somatuline Depot in clinical studies show that the percentage of patients with putative antibodies at any time point after treatment is low (<1% to 4% of patients in specific studies whose antibodies were tested). The antibodies did not appear to affect the efficacy or safety of Somatuline Depot.

Postmarketing Experience

As adverse reactions experienced post approval use 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.

The profile of reported adverse reactions for Somatuline Depot was consistent with that observed for treatment-related adverse reactions in the clinical studies. Those reported most frequently being gastrointestinal disorders (abdominal pain and diarrhea) and general disorders and administration site conditions (injection site reactions). Occasional cases of pancreatitis have also been observed.

Drug Interactions

Insulin and Oral Hypoglycemic Drugs

Lanreotide, like somatostatin and other somatostatin analogs, inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when lanreotide treatment is initiated or when the dose is altered and antidiabetic treatment should be adjusted accordingly.

Cyclosporine

Concomitant administration of cyclosporine with lanreotide may decrease the relative bioavailability of cyclosporine and, therefore, may necessitate adjustment of cyclosporine dose to maintain therapeutic levels.

Other Concomitant Drug Therapy

The pharmacological gastrointestinal effects of Somatuline Depot may reduce the intestinal absorption of concomitant drugs. Limited published data indicate that concomitant administration of a somatostatin analog and bromocriptine may increase the availability of bromocriptine.

Concomitant administration of bradycardia inducing drugs (e.g. beta-blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Dose adjustments of concomitant medication may be necessary.

Vitamin K absorption was not affected when concomitantly administered with lanreotide.

Drug Metabolism Interactions

The limited published data available indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that lanreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine, terfenadine) should therefore be used with caution. Drugs metabolized by the liver may be metabolized more slowly during lanreotide treatment and dose reductions of the concomitantly administered medications should be considered.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

Lanreotide has been shown to have an embryocidal effect in rats and rabbits. There are no adequate and well controlled studies in pregnant women. Somatuline Depot should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Reproductive studies in pregnant rats given 30 mg/kg by subcutaneous injection every 2 weeks (5-times the human dose based on body surface area comparisons) resulted in decreased embryo/fetal survival. Studies in pregnant rabbits given subcutaneous injections of 0.45 mg/kg/day, 2-times the human therapeutic exposures at the maximum recommended dose of 120 mg based on comparisons of relative body surface area shows decreased fetal survival and increased fetal skeletal/soft tissue abnormalities.

Nursing Mothers

It is not known whether lanreotide is excreted in human milk. Many drugs are excreted in human milk. As a result of serious adverse reactions in animals and potential in nursing infants from Somatuline, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly patients compared with younger patients, and the 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. It is not necessary to alter the starting dose in elderly patients as expected lanreotide serum concentrations in the elderly are well within the range of serum concentrations safely tolerated in healthy young subjects. Similarly, it is not necessary to alter the titration or maintenance doses of Somatuline Depot as dose selection is based on therapeutic response [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Renal Impairment

Lanreotide has been studied in patients with end-stage renal function on dialysis, but has not been studied in patients with mild, moderate and severe renal impairment. It is recommended that patients with moderate and severe renal impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Hepatic Impairment

It is recommended that patients with moderate and severe hepatic impairment receive a starting dose of lanreotide of 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Overdosage

If overdose occurs, symptomatic management is indicated.

There are no confirmed postmarketing cases of overdose with lanreotide that were serious or led to an adverse reaction.

Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at phone number 1-800-222-1222.

Somatuline Depot Description

Somatuline Depot (lanreotide) Injection 60, 90 and 120 mg is a prolonged-release formulation for deep subcutaneous injection containing the drug substance lanreotide acetate, a synthetic octapeptide with a biological activity similar to naturally occurring somatostatin, and water for injection.

Somatuline Depot is available as sterile, ready-to-use, pre-filled syringes containing lanreotide supersaturated bulk solution of 24.6% w/w lanreotide base.

Each syringe contains:	Somatuline Depot 60 mg	Somatuline Depot 90 mg	Somatuline Depot 120 mg
Lanreotide acetate	79.8 mg	116.4 mg	155.5 mg
Water for injection	186.2mg	271.6 mg	363 mg

Lanreotide acetate is a synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Lanreotide acetate is chemically known as [cyclo S - S] - 3 - (2 - naphthyl) - D - alanyl - L - cysteinyl - L - tyrosyl - D - tryptophyl - L - lysyl - L - valyl - L - cysteinyl - L - threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is:

For appearance of the formulation, see Dosage Forms and Strengths (3).

Somatuline Depot - Clinical Pharmacology

Mechanism of Action

Lanreotide, the active component of Somatuline Depot is an octapeptide analog of natural somatostatin. The mechanism of action of lanreotide is believed to be similar to that of natural somatostatin.

Pharmacodynamics

Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3, and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for GH inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions.

The primary pharmacodynamic effect of lanreotide is a reduction of GH and/or IGF-1 levels enabling normalization of levels in acromegalic patients [see Clinical Studies (14)]. In acromegalic patients, lanreotide reduces GH levels in a dose-dependent way. After a single injection of Somatuline Depot, plasma GH levels fall rapidly and are maintained for at least 28 days.

Lanreotide inhibits the basal secretion of motilin, gastric inhibitory peptide and pancreatic polypeptide, but has no significant effect on the secretion of secretin. Lanreotide inhibits post-prandial secretion of pancreatic polypeptide, gastrin and cholecystokinin (CCK). In healthy subjects, lanreotide produces a reduction and a delay in post-prandial insulin secretion, resulting in transient, mild glucose intolerance.

Lanreotide inhibits meal-stimulated pancreatic secretions, and reduces duodenal bicarbonate and amylase concentrations, and produces a transient reduction in gastric acidity.

Lanreotide has been shown to inhibit gallbladder contractility and bile secretion in healthy subjects [see Warnings and Precautions (5)].

In healthy subjects, lanreotide inhibits meal-induced increases in superior mesenteric artery and portal venous blood flow, but has no effect on basal or meal-stimulated renal blood flow. Lanreotide has no effect on renal plasma flow or renal vascular resistance. However, a transient decrease in glomerular filtration rate (GFR) and filtration fraction has been observed after a single injection of lanreotide.

In healthy subjects, non-significant reductions in glucagon levels were seen after lanreotide administration. In diabetic non-acromegalic subjects receiving a continuous infusion (21 day) of lanreotide, serum glucose concentrations were temporarily decreased by 20-30% after the start and end of the infusion. Serum glucose concentrations returned to normal levels within 24 hours. A significant decrease in insulin concentrations was recorded between baseline and Day 1 only [see Warnings and Precautions (5)].

Lanreotide inhibits the nocturnal increase in thyroid-stimulating hormone (TSH) seen in healthy subjects. Lanreotide reduces prolactin levels in acromegalic patients treated on a long-term basis.

Pharmacokinetics

Somatuline Depot is thought to form a drug depot at the injection site due to the interaction of the formulation with physiological fluids. The most likely mechanism of drug release is a passive diffusion of the precipitated drug from the depot towards the surrounding tissues, followed by the absorption to the blood stream.

After a single deep, subcutaneous administration, the mean absolute bioavailability of Somatuline Depot in healthy subjects was 73.4, 69.0 and 78.4%, for the 60, 90 and 120 mg doses, respectively. Mean Cmax values ranged from 4.3 to 8.4 ng/mL during the first day. Single-dose linearity was demonstrated with respect to AUC and Cmax, and showed high inter-subject variability. Somatuline Depot showed sustained release of lanreotide with a half-life of 23 to 30 days. Mean serum concentrations were > 1 ng/mL throughout 28 days at 90 mg and 120 mg and > 0.9 ng/mL with 60 mg.

In a repeat-dose administration pharmacokinetics (PK) study in acromegalic patients, rapid initial release was seen giving peak levels during the first day after administration. At doses of Somatuline Depot between 60 and 120 mg linear pharmacokinetics were observed in acromegalic patients. At steady state mean Cmax values were 3.8 ± 0.5, 5.7 ± 1.7 and 7.7 ± 2.5 ng/mL increasing linearly with dose. The mean accumulation ratio index was 2.7 which is in line with the range of values for the half life of Somatuline Depot. The steady-state trough serum lanreotide concentrations in patients receiving Somatuline Depot every 28 days were 1.8 ± 0.3; 2.5 ± 0.9 and 3.8 ± 1.0 ng/mL at 60, 90 and 120 mg doses respectively. A limited initial burst effect and a low peak to trough fluctuation (81% to 108%) of the serum concentration at the plateau was observed.

For the same doses, similar values were obtained in clinical studies after at least four administrations (2.3 ± 0.9, 3.2 ± 1.1 and 4.0 ± 1.4 ng/mL, respectively).

Pharmacokinetic data from studies evaluating extended dosing use of Somatuline Depot 120 mg demonstrated mean steady state, Cmin values between 1.6 and 2.3 ng/mL for the 8 and 6 week treatment interval, respectively.

Specific Populations

Somatuline Depot has not been studied in specific populations. The pharmacokinetics of lanreotide in renal impaired, hepatic impaired and geriatric subjects were evaluated after IV administration of lanreotide immediate release formulation (IRF) at 7 mcg/kg dose.

Renal Impairment

An approximate 2-fold decrease in total serum clearance of lanreotide, with a consequent 2-fold increase in half-life and AUC was observed. Patients with moderate to severe renal impairment should begin treatment with Somatuline Depot 60 mg. Caution should be exercised when considering patients with moderate or severe renal impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks.

Geriatric

Studies in healthy elderly subjects showed an 85% increase in half-life and a 65% increase in mean residence time (MRT) of lanreotide compared to those seen in healthy young subjects; however, there was no change in either AUC or Cmax of lanreotide in elderly as compared to healthy young subjects.

Hepatic Impairment

In subjects with moderate to severe hepatic impairment, a 30% reduction in clearance of lanreotide was observed. Patients with moderate to severe hepatic impairment should begin treatment with Somatuline Depot 60 mg. Caution should be exercised when considering patients with moderate or severe hepatic impairment for an extended dosing interval of Somatuline Depot 120 mg every 6 or 8 weeks.

In studies evaluating excretion, <5% of lanreotide was excreted in urine and less than 0.5% was recovered unchanged in feces, indicative of some biliary excretion.

Nonclinical Toxicology

Carcinogenicity, Mutagenicity, Impairment of Fertility

Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given daily subcutaneous doses of lanreotide acetate at 0.5, 1.5, 5, 10 and 30 mg/kg for 104 weeks. Cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the high dose of 30 mg/kg/day. Fibrosarcomas in both genders and malignant fibrous histiocytomas were observed in males at 30mg/kg/day resulting in exposures 3-times higher than the clinical therapeutic exposure at the maximum therapeutic dose of 120 mg given by monthly subcutaneous injection based on the AUC values. Rats were given daily subcutaneous doses of lanreotide acetate at 0.1, 0.2, and 0.5 mg/kg for 104 weeks. Increased cutaneous and subcutaneous tumors of fibrous connective tissues at the injection sites were observed at the dose of 0.5mg/kg/day resulting in exposures less than the clinical therapeutic exposure at 120 mg given by monthly subcutaneous injection. The increased incidence of injection site tumors in rodents is likely related to the increased dosing frequency (daily) in animals compared to monthly dosing in humans and therefore may not be clinically relevant.

Lanreotide was not genotoxic in tests for gene mutations in a bacterial mutagenicity (Ames) assay, or mouse lymphoma cell assay with or without metabolic activation. Lanreotide was not genotoxic in tests for the detection of chromosomal aberrations in a human lymphocyte and in vivo mouse micronucleus assay.

Subcutaneous dosing (30mg/kg/2 wks) before mating and continuing into gestation in rats at doses 5 times the human clinical exposure (120 mg every 4 weeks) based on mg/m2 had reduced fertility. Gestation length was statistically significantly increased suggesting some delay in parturition at 3 times human exposure. The reduction in fertility in non-acromegalic animals is likely related to the pharmacologic activity (decreased growth hormone secretion) of lanreotide acetate.

Clinical Studies

The effect of Somatuline Depot on reducing GH and IGF-levels and control of symptoms in patients with acromegaly was studied in two long-term, multiple-dose, randomized multicenter studies.

Study 1

This one-year study included a 4-week double-blind, placebo-controlled phase, a 16-week single-blind, fixed-dose phase, and a 32-week open-label dose-titration phase. Patients with active acromegaly based on biochemical tests and medical history entered a 12-week washout period if there was previous treatment with a somatostatin analog or a dopaminergic agonist.

Upon entry, patients were randomly allocated to receive a single deep subcutaneous injection of Somatuline Depot 60, 90 or 120 mg or placebo. Four weeks later, patients entered a fixed-dose phase where they received 4 injections of Somatuline Depot followed by a dose-titration phase of 8 injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at 4-week intervals. During the dose-titration phase of the study, the dose was titrated twice (every fourth injection), as needed, according to individual GH and IGF-1 levels.

A total of 108 patients (51 males, 57 females) were enrolled in the initial placebo-controlled phase of the study. Half (54/108) of the patients had never been treated with a somatostatin analog or dopamine agonist, or had stopped treatment for at least 3 months prior to their participation in the study and were required to have a mean GH level > 5 ng/mL at their first visit. The other half of the patients had received prior treatment with a somatostatin analog or a dopamine agonist before study entry and at study entry were to have a mean GH concentration >3 ng/mL and at least a 100% increase in mean GH concentration after washout of medication.

One hundred and seven (107) patients completed the placebo-controlled phase, 105 patients completed the fixed-dose phase and 99 patients completed the dose-titration phase. Patients not completing withdrew due to adverse events (5) or lack of efficacy (4).

In the double-blind phase of study 1, a total of 52 (63%) of the 83 lanreotide-treated patients had a > 50% decrease in mean GH from baseline to Week 4 including 52%, 44% and 90% of patients in the 60, 90 and 120 mg groups, respectively, compared to placebo (0%, 0/25). In the fixed-dose phase at Week 16, 72% of all 107 lanreotide-treated patients had a decrease from baseline in mean GH of > 50% including 68% (23/34), 64% (23/36) and 84% (31/37) of patients in the 60, 90 and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained for the duration of the study (see Table 3).

Table 3 Overall Efficacy Results Based on GH and IGF-1 Levels by Treatment Phase in Study 1

		Baseline N=107	Before Titration 1 (16 weeks) N=107	Before Titration 2 (32 weeks) N=105	Last Value Available* N=107
GH
* Last Observation Carried Forward † Age-adjusted, ‡ n=105, § n=102,
≤5.0 ng/mL	Number of Responders (%)	20 (19%)	72 (67%)	76 (72%)	74 (69%)
≤2.5 ng/mL	Number of Responders (%)	0 (0%)	52 (49%)	59 (56%)	55 (51%)
≤1.0 ng/mL	Number of Responders (%)	0 (0%)	15 (14%)	18 (17%)	17 (16%)
Median GH	ng/mL	10.27	2.53	2.20	2.43
GH Reduction	Median % Reduction	--	75.5	78.2	75.5
IGF-1
Normal†	Number of Responders (%)	9 (8%)	58 (54%)	57 (54%)	62 (58%)
Median IGF-1	ng/mL

Codeine/Diphenhydramine/Phenylephrine Solution

Pronunciation: KOE-deen/DYE-fen-HYE-dra-meen/FEN-il-EF-rin
Generic Name: Codeine/Diphenhydramine/Phenylephrine
Brand Name: Examples include Airacof and Endal CD

Codeine/Diphenhydramine/Phenylephrine Solution is used for:

Relieving symptoms of sinus congestion, runny nose, sneezing, and cough caused by colds, upper respiratory infections, and allergies. It may also be used for other conditions as determined by your doctor.

Codeine/Diphenhydramine/Phenylephrine Solution is a decongestant, antihistamine, and cough suppressant combination. It works by constricting blood vessels and reducing swelling in the nasal passages. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing. The cough suppressant works in the brain to help decrease the cough reflex to reduce a dry cough.

Do NOT use Codeine/Diphenhydramine/Phenylephrine Solution if:

• you are allergic to any ingredient in Codeine/Diphenhydramine/Phenylephrine Solution


• you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, severe heart problems, stomach ulcer, narrow-angle glaucoma, or difficulty urinating, or you are having an asthma attack


• you take sodium oxybate (GHB) or you have taken furazolidone or a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) within the last 14 days

Contact your doctor or health care provider right away if any of these apply to you.

Before using Codeine/Diphenhydramine/Phenylephrine Solution:

Some medical conditions may interact with Codeine/Diphenhydramine/Phenylephrine Solution. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a recent head injury, severe drowsiness, brain tumor or lesion, or increased pressure in the brain


• if you have a history of adrenal gland problems (eg, adrenal gland tumor); heart problems (eg, heart disease); fast, slow, or irregular heartbeat; high or low blood pressure; liver problems; low blood volume; diabetes; blood vessel problems; stroke; glaucoma or increased pressure in the eye; a blockage of your stomach, bladder, or intestines; recent stomach or bowel surgery or other stomach or bowel problems (eg, constipation, diarrhea caused by antibiotic use, inflammation, ulcers); trouble urinating; an enlarged prostate or other prostate problems; seizures; mental or mood problems (eg, depression); pancreas problems (eg, pancreatitis); or an overactive thyroid


• if you have a history of asthma, sleep apnea, or other breathing problems (eg, slow or irregular breathing), chronic cough, lung problems (eg, chronic bronchitis, emphysema), or chronic obstructive pulmonary disease (COPD), or if your cough occurs with large amounts of mucus


• if you have a history of alcohol abuse, drug abuse, or suicidal thoughts or behavior; or if you are in poor health or are very overweight

Some MEDICINES MAY INTERACT with Codeine/Diphenhydramine/Phenylephrine Solution. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticholinergics (eg, scopolamine) because a serious bowel problem (paralytic ileus) may occur


• Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased


• Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), cimetidine, furazolidone , HIV protease inhibitors (eg, ritonavir), MAOIs (eg, phenelzine), muscle relaxants (eg, cyclobenzaprine), opioid analgesics (eg, hydrocodone), phenothiazines (eg, chlorpromazine), sodium oxybate (GHB), or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Codeine/Diphenhydramine/Phenylephrine Solution's side effects


• Naltrexone, quinidine, or rifamycins (eg, rifampin) because they may decrease Codeine/Diphenhydramine/Phenylephrine Solution's effectiveness


• Bromocriptine or hydantoins (eg, phenytoin) because the risk of their side effects may be increased by Codeine/Diphenhydramine/Phenylephrine Solution


• Guanadrel, guanethidine, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Codeine/Diphenhydramine/Phenylephrine Solution

This may not be a complete list of all interactions that may occur. Ask your health care provider if Codeine/Diphenhydramine/Phenylephrine Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Codeine/Diphenhydramine/Phenylephrine Solution:

Use Codeine/Diphenhydramine/Phenylephrine Solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Codeine/Diphenhydramine/Phenylephrine Solution by mouth with or without food. If stomach upset occurs, take with food to reduce stomach irritation.


• Take Codeine/Diphenhydramine/Phenylephrine Solution with a full glass of water (8 oz/240 mL).


• Drink plenty of water while taking Codeine/Diphenhydramine/Phenylephrine Solution.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Codeine/Diphenhydramine/Phenylephrine Solution, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Codeine/Diphenhydramine/Phenylephrine Solution.

Important safety information:

• Codeine/Diphenhydramine/Phenylephrine Solution may cause drowsiness, dizziness, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Codeine/Diphenhydramine/Phenylephrine Solution with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Codeine/Diphenhydramine/Phenylephrine Solution may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects.


• Do not drink alcohol or use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Codeine/Diphenhydramine/Phenylephrine Solution; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness.


• Do not take diet or appetite control medicines while you take Codeine/Diphenhydramine/Phenylephrine Solution without checking with your doctor.


• Codeine/Diphenhydramine/Phenylephrine Solution has codeine, phenylephrine, and diphenhydramine in it. Before you start any new medicine, check the label to see if it has codeine, phenylephrine, or diphenhydramine in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Do not use Codeine/Diphenhydramine/Phenylephrine Solution for a cough with a lot of mucus. Do not use it for a long-term cough (eg, caused by asthma, emphysema, smoking). However, you may use it for these conditions if your doctor tells you to.


• Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• If your symptoms do not get better within 5 to 7 days or if they get worse, check with your doctor.


• Codeine/Diphenhydramine/Phenylephrine Solution may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Codeine/Diphenhydramine/Phenylephrine Solution. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Codeine/Diphenhydramine/Phenylephrine Solution may interfere with skin allergy tests. If you are scheduled for a skin test, talk to your doctor. You may need to stop taking Codeine/Diphenhydramine/Phenylephrine Solution for a few days before the tests.


• Tell your doctor or dentist that you take Codeine/Diphenhydramine/Phenylephrine Solution before you receive any medical or dental care, emergency care, or surgery.


• Use Codeine/Diphenhydramine/Phenylephrine Solution with caution in the ELDERLY; they may be more sensitive to its effects.


• Caution is advised when using Codeine/Diphenhydramine/Phenylephrine Solution in CHILDREN; they may be more sensitive to its effects, especially excitability.


• Codeine/Diphenhydramine/Phenylephrine Solution should not be used in CHILDREN younger than 6 years old; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is not known if Codeine/Diphenhydramine/Phenylephrine Solution can cause harm to the fetus. If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Codeine/Diphenhydramine/Phenylephrine Solution while you are pregnant. It is not known if Codeine/Diphenhydramine/Phenylephrine Solution is found in breast milk. Do not breast-feed while taking Codeine/Diphenhydramine/Phenylephrine Solution.

Some people who use Codeine/Diphenhydramine/Phenylephrine Solution for a long time may develop a need to continue taking it. People who take high doses are also at risk. This is known as DEPENDENCE or addiction.

If you stop taking Codeine/Diphenhydramine/Phenylephrine Solution suddenly, you may have WITHDRAWAL symptoms. These may include anxiety, irregular heartbeat, irritability, restlessness, trouble sleeping, and unusual sweating.

Possible side effects of Codeine/Diphenhydramine/Phenylephrine Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); confusion; difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; mental or mood changes (eg, irritability); persistent trouble sleeping; restlessness; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; tremor; vision changes or blurred vision.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Codeine/Diphenhydramine/Phenylephrine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include blurred vision; cold and clammy skin; coma; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Codeine/Diphenhydramine/Phenylephrine Solution:

Store Codeine/Diphenhydramine/Phenylephrine Solution at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Codeine/Diphenhydramine/Phenylephrine Solution out of the reach of children and away from pets.

General information:

• If you have any questions about Codeine/Diphenhydramine/Phenylephrine Solution, please talk with your doctor, pharmacist, or other health care provider.


• Codeine/Diphenhydramine/Phenylephrine Solution is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Codeine/Diphenhydramine/Phenylephrine Solution. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Codeine/Diphenhydramine/Phenylephrine resources

• Codeine/Diphenhydramine/Phenylephrine Side Effects (in more detail)
• Codeine/Diphenhydramine/Phenylephrine Use in Pregnancy & Breastfeeding
• Codeine/Diphenhydramine/Phenylephrine Drug Interactions
• Codeine/Diphenhydramine/Phenylephrine Support Group
• 0 Reviews for Codeine/Diphenhydramine/Phenylephrine - Add your own review/rating

Compare Codeine/Diphenhydramine/Phenylephrine with other medications

• Cough and Nasal Congestion

Voltaren Enteric-Coated Tablets

Pronunciation: dye-KLOE-fen-ak
Generic Name: Diclofenac
Brand Name: Voltaren

Voltaren Enteric-Coated Tablets are a nonsteroidal anti-inflammatory drug (NSAID). It may cause an increased risk of serious and sometimes fatal heart and blood vessel problems (eg, a heart attack, stroke). The risk may be greater if you already have heart problems or if you take Voltaren Enteric-Coated Tablets for a long time. Do not use Voltaren Enteric-Coated Tablets right before or after bypass heart surgery.

Voltaren Enteric-Coated Tablets may cause an increased risk of serious and sometimes fatal stomach ulcers and bleeding. Elderly patients may be at greater risk. This may occur without warning signs.

Voltaren Enteric-Coated Tablets are used for:

Treating pain and inflammation caused by certain conditions (eg, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis). It may also be used for other conditions as determined by your doctor.

Voltaren Enteric-Coated Tablets are an NSAID. Exactly how it works is not known. It may block certain substances in the body that are linked to inflammation. NSAIDs treat the symptoms of pain and inflammation. They do not treat the disease that causes those symptoms.

Do NOT use Voltaren Enteric-Coated Tablets if:

• you are allergic to any ingredient in Voltaren Enteric-Coated Tablets


• you have had a severe allergic reaction (eg, severe rash, hives, trouble breathing, growths in the nose, dizziness) to aspirin or another NSAID (eg, ibuprofen, celecoxib)


• you have recently had or will be having bypass heart surgery


• you have severe kidney problems


• you are in the last 3 months of pregnancy

Contact your doctor or health care provider right away if any of these apply to you.

Before using Voltaren Enteric-Coated Tablets:

Some medical conditions may interact with Voltaren Enteric-Coated Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of kidney or liver disease, diabetes, or stomach or bowel problems (eg, bleeding, perforation, ulcers)


• if you have a history of swelling or fluid buildup, asthma, growths in the nose (nasal polyps), or mouth inflammation


• if you have high blood pressure, blood disorders (eg, porphyria), bleeding or clotting problems, heart problems (eg, heart failure), blood vessel disease, or if you are at risk of any of these diseases


• if you have poor health, dehydration or low fluid volume, low blood sodium levels, or you drink alcohol or have a history of alcohol abuse

Some MEDICINES MAY INTERACT with Voltaren Enteric-Coated Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Anticoagulants (eg, warfarin), aspirin, clopidogrel, corticosteroids (eg, prednisone), direct factor Xa inhibitors (eg, rivaroxaban), heparin, prasugrel, or selective serotonin reuptake inhibitors (SSRIs) (eg, fluoxetine) because the risk of bleeding, including stomach bleeding, may be increased


• Azole antifungals (eg, itraconazole, voriconazole), bisphosphonates (eg, risedronate), or probenecid because they may increase the risk of Voltaren Enteric-Coated Tablets's side effects


• Rifamycins (eg, rifampin) because they may decrease Voltaren Enteric-Coated Tablets's effectiveness


• Cyclosporine, lithium, methotrexate, other NSAIDs (eg, ibuprofen), quinolones (eg, ciprofloxacin), or tenofovir because the risk of their side effects may be increased by Voltaren Enteric-Coated Tablets


• Angiotensin-converting enzyme (ACE) inhibitors (eg, enalapril) or diuretics (eg, furosemide, hydrochlorothiazide) because their effectiveness may be decreased by Voltaren Enteric-Coated Tablets


• Medicines that may harm the liver (eg, acetaminophen, ketoconazole, isoniazid, certain medicines for HIV infection, certain antibiotics or seizure medicines) because the risk of liver side effects may be increased. Ask your doctor if you are unsure if any of your medicines might harm the liver

This may not be a complete list of all interactions that may occur. Ask your health care provider if Voltaren Enteric-Coated Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Voltaren Enteric-Coated Tablets:

Use Voltaren Enteric-Coated Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Voltaren Enteric-Coated Tablets comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Voltaren Enteric-Coated Tablets refilled.


• Take Voltaren Enteric-Coated Tablets by mouth. It may be taken with food if it upsets your stomach. Taking it with food may not lower the risk of stomach or bowel problems (eg, bleeding, ulcers). Talk with your doctor or pharmacist if you have persistent stomach upset.


• Swallow Voltaren Enteric-Coated Tablets whole. Do not break, crush, or chew before swallowing.


• Take Voltaren Enteric-Coated Tablets with a full glass of water (8 oz/240 mL) as directed by your doctor.


• If you miss a dose of Voltaren Enteric-Coated Tablets and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Voltaren Enteric-Coated Tablets.

Important safety information:

• Voltaren Enteric-Coated Tablets may cause dizziness or drowsiness. These effects may be worse if you take it with alcohol or certain medicines. Use Voltaren Enteric-Coated Tablets with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Serious stomach ulcers or bleeding can occur with the use of Voltaren Enteric-Coated Tablets. Taking it in high doses or for a long time, smoking, or drinking alcohol increases the risk of these side effects. Taking Voltaren Enteric-Coated Tablets with food will NOT reduce the risk of these effects. Contact your doctor or emergency room at once if you develop severe stomach or back pain; black, tarry stools; vomit that looks like blood or coffee grounds; or unusual weight gain or swelling.


• Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor.


• Voltaren Enteric-Coated Tablets are an NSAID. Before you start any new medicine, check the label to see if it has an NSAID (eg, ibuprofen) in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Do not take aspirin while you are using Voltaren Enteric-Coated Tablets unless your doctor tells you to.


• Do not switch between different forms of Voltaren Enteric-Coated Tablets (eg, enteric-coated tablets, immediate-release tablets) unless your doctor tells you to. They may not provide the same amount of medicine to your body.


• Lab tests, including kidney and liver function, blood electrolyte levels, complete blood cell counts, and blood pressure, may be performed while you use Voltaren Enteric-Coated Tablets. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Use Voltaren Enteric-Coated Tablets with caution in the ELDERLY; they may be more sensitive to its effects, especially bleeding and kidney problems.


• Voltaren Enteric-Coated Tablets should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Voltaren Enteric-Coated Tablets may cause harm to the fetus. Do not use it during the last 3 months of pregnancy. If you think you may be pregnant, contact your doctor. You will need to discuss the benefits and risks of using Voltaren Enteric-Coated Tablets while you are pregnant. It is not known if Voltaren Enteric-Coated Tablets are found in breast milk. Do not breast-feed while taking Voltaren Enteric-Coated Tablets.

Possible side effects of Voltaren Enteric-Coated Tablets:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; drowsiness; gas; headache; heartburn; nausea; stomach upset.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; trouble breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody or black, tarry stools; change in the amount of urine produced; chest pain; confusion; depression; fainting; fast or irregular heartbeat; fever, chills, or persistent sore throat; mental or mood changes; numbness of an arm or leg; one-sided weakness; red, swollen, blistered, or peeling skin; ringing in the ears; seizures; severe headache or dizziness; severe or persistent stomach pain or nausea; severe vomiting or diarrhea; shortness of breath; sudden or unexplained weight gain; swelling of the hands, legs, or feet; symptoms of liver problems (eg, dark urine, pale stools, persistent loss of appetite, yellowing of the skin or eyes); unusual bruising or bleeding; unusual joint or muscle pain; unusual tiredness or weakness; vision or speech changes; vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Voltaren side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include decreased urination; loss of consciousness; seizures; severe dizziness or drowsiness; severe nausea, vomiting, or stomach pain; slow or troubled breathing; tremor; unusual bleeding or bruising; vomit that looks like coffee grounds.

Proper storage of Voltaren Enteric-Coated Tablets:

Store Voltaren Enteric-Coated Tablets at room temperature, below 86 degrees F (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Voltaren Enteric-Coated Tablets out of the reach of children and away from pets.

General information:

• If you have any questions about Voltaren Enteric-Coated Tablets, please talk with your doctor, pharmacist, or other health care provider.


• Voltaren Enteric-Coated Tablets are to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Voltaren Enteric-Coated Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Voltaren resources

• Voltaren Side Effects (in more detail)
• Voltaren Use in Pregnancy & Breastfeeding
• Drug Images
• Voltaren Drug Interactions
• Voltaren Support Group
• 60 Reviews for Voltaren - Add your own review/rating

Compare Voltaren with other medications

• Ankylosing Spondylitis
• Aseptic Necrosis
• Back Pain
• Frozen Shoulder
• Muscle Pain
• Osteoarthritis
• Pain
• Period Pain
• Rheumatoid Arthritis
• Sciatica

Pulmolite

Generic Name: technetium tc 99m albumin aggregated (Intravenous route)

tek-NEE-shee-um Tc 99m al-BUE-min AG-re-gay-ted

Commonly used brand name(s)

In the U.S.

• MPI MAA


• Pulmolite


• Technescan MAA

Available Dosage Forms:

• Kit

Therapeutic Class: Diagnostic Agent, Radiopharmaceutical Imaging

Uses For Pulmolite

Technetium Tc 99m albumin aggregated injection is a radiopharmaceutical. Radiopharmaceuticals are radioactive agents, which may be used to find and treat certain diseases or to study the function of the body's organs.

Technetium Tc 99m albumin aggregated injection is used to help your doctor see an image of your lungs to help evaluate lung problems in children and adults. It is also used to help your doctor see an image of your peritoneovenous [LeVeen] shunt.

This medicine is to be given only by or under the direct supervision of a doctor with specialized training in nuclear medicine.

Before Using Pulmolite

In deciding to use a diagnostic test, any risks of the test must be weighed against the good it will do. This is a decision you and your doctor will make. Also, other things may affect test results. For this test, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Technetium Tc 99m albumin aggregated injection in children.

Geriatric

No information is available on the relationship of age to the effects of technetium Tc 99m albumin aggregated injection in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this diagnostic test. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to human serum albumin, history of or


• Pulmonary hypertension (increased blood pressure in the lungs), severe—Should not be used in patients with these conditions.

• Blood circulation problems or


• Cor pulmonale (serious heart condition)—Use with caution. May make these conditions worse.

• Heart problems (e.g., right-to-left heart shunts)—It is not known if this medicine is safe in patients with this condition.

Proper Use of technetium tc 99m albumin aggregated

This section provides information on the proper use of a number of products that contain technetium tc 99m albumin aggregated. It may not be specific to Pulmolite. Please read with care.

A doctor or other trained health professional will give you or your child this medicine. This medicine is given through a needle placed in one of your veins before you have a scan.

Precautions While Using Pulmolite

It is very important that your doctor check you or your child closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to use it.

While using this medicine, you or your child may be exposed to radiation. Talk with your doctor if you have concerns about this.

Pulmolite Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

Incidence not known

• Confusion


• faintness


• fever and chills


• skin rash or itching


• wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

Vytorin

Dosage Form: tablet
FULL PRESCRIBING INFORMATION

Indications and Usage for Vytorin

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.

Primary Hyperlipidemia

Vytorin® is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia.

Homozygous Familial Hypercholesterolemia (HoFH)

Vytorin is indicated for the reduction of elevated 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.

Limitations of Use

No incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

Vytorin has not been studied in Fredrickson type I, III, IV, and V dyslipidemias.

Vytorin Dosage and Administration

Recommended Dosing

 The usual dosage range is 10/10 mg/day to 10/40 mg/day. The recommended usual starting dose is 10/10 mg/day or 10/20 mg/day. Vytorin should be taken as a single daily dose in the evening, with or without food. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day in the absence of moderate to severe renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m2). After initiation or titration of Vytorin, lipid levels may be analyzed after 2 or more weeks and dosage adjusted, if needed.

Restricted Dosing for 10/80 mg

 Due to the increased risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, use of the 10/80-mg dose of Vytorin should be restricted to patients who have been taking Vytorin 10/80 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 10/80-mg dose of Vytorin 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 or statin-based regimen with less potential for the drug-drug interaction.

 Due to the increased risk of myopathy, including rhabdomyolysis, associated with the 10/80-mg dose of Vytorin, patients unable to achieve their LDL-C goal utilizing the 10/40-mg dose of Vytorin should not be titrated to the 10/80-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 Vytorin should not exceed 10/10 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 Vytorin should not exceed 10/20 mg/day [see Warnings and Precautions (5.1), Drug Interactions (7.3), and Clinical Pharmacology (12.3)].

 Patients taking Bile Acid Sequestrants

•  Dosing of Vytorin should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant [see Drug Interactions (7.5)].

Patients with Homozygous Familial Hypercholesterolemia

 The recommended dosage for patients with homozygous familial hypercholesterolemia is Vytorin 10/40 mg/day in the evening [see Dosage and Administration, Restricted Dosing for 10/80 mg (2.2)]. Vytorin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.

Patients with Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment [see Warnings and Precautions (5.3)].

Patients with Renal Impairment/Chronic Kidney Disease

 In patients with mild renal impairment (estimated GFR ≥60 mL/min/1.73 m2), no dosage adjustment is necessary. In patients with chronic kidney disease and estimated glomerular filtration rate <60 mL/min/1.73 m2, the dose of Vytorin is 10/20 mg/day in the evening. In such patients, higher doses should be used with caution and close monitoring [see Warnings and Precautions (5.1); Clinical Pharmacology (12.3)].

Geriatric Patients

No dosage adjustment is necessary in geriatric patients [see 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 Vytorin doses exceeding 10/20 mg/day coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive Vytorin 10/80 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

• Vytorin® 10/10, (ezetimibe 10 mg/simvastatin 10 mg tablets) are white to off-white capsule-shaped tablets with code "311" on one side.


• Vytorin® 10/20, (ezetimibe 10 mg/simvastatin 20 mg tablets) are white to off-white capsule-shaped tablets with code "312" on one side.


• Vytorin® 10/40, (ezetimibe 10 mg/simvastatin 40 mg tablets) are white to off-white capsule-shaped tablets with code "313" on one side.


• Vytorin® 10/80, (ezetimibe 10 mg/simvastatin 80 mg tablets) are white to off-white capsule-shaped tablets with code "315" on one side.

Contraindications

Vytorin 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 or 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), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Vytorin 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 Vytorin use 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. Vytorin 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, Vytorin 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 Vytorin treatment should not breast-feed 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 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 simvastatin, 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 simvastatin (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 10/80-mg dose of Vytorin should be used only in patients who have been taking Vytorin 10/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [see Dosage and Administration, Restricted Dosing for 10/80 mg (2.2)]. If, however, a patient who is currently tolerating the 10/80-mg dose of Vytorin 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 or statin-based regimen 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)].

 In the Study of Heart and Renal Protection (SHARP), 9270 patients with chronic kidney disease were allocated to receive Vytorin 10/20 mg daily (n=4650) or placebo (n=4620). During a median follow-up period of 4.9 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]) was 0.2% for Vytorin and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK > 40 times ULN) was 0.09% for Vytorin and 0.02% for placebo.

In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates.

 All patients starting therapy with Vytorin or whose dose of Vytorin 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. Vytorin therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin 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 taking Vytorin merit closer monitoring.

 Vytorin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Vytorin 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 that 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 Vytorin is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with Vytorin must be suspended during the course of treatment. [See Contraindications (4) and Drug Interactions (7).] In vitro studies have demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the Vytorin dose may be needed to reduce the risk of myopathy/rhabdomyolysis if voriconazole must be used concomitantly with Vytorin. [See Drug Interactions (7.1).]

 The combined use of Vytorin 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 Vytorin, as these agents can cause myopathy when given alone and the risk is increased when they are co-administered [see Drug Interactions (7.2, 7.7)].

 Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing Vytorin with colchicine [see Drug Interactions (7.9)].

 The benefits of the combined use of Vytorin 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 6 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 or ezetimibe/simvastatin 10/40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used when treating Chinese patients with Vytorin in doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive Vytorin 10/80 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), and 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 Vytorin
Verapamil Diltiazem	Do not exceed 10/10 mg Vytorin daily
Amiodarone Amlodipine Ranolazine	Do not exceed 10/20 mg Vytorin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Liver Enzymes

In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.7% overall for patients treated with Vytorin and appeared to be dose-related with an incidence of 2.6% for patients treated with Vytorin 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with Vytorin 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment.

 In SHARP, 9270 patients with chronic kidney disease were allocated to receive Vytorin 10/20 mg daily (n=4650), or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of consecutive elevations of transaminases (>3 × ULN) was 0.7% for Vytorin and 0.6% for placebo.

 It is recommended that liver function tests be performed before the initiation of treatment with Vytorin, 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 Vytorin, promptly interrupt therapy. If an alternate etiology is not found do not restart Vytorin. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.1)].

Vytorin 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 persistent transaminase elevations are contraindications to the use of Vytorin.

Hepatic Impairment

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, Vytorin is not recommended in these patients. [See Clinical Pharmacology (12.3).]

Endocrine Function

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

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 (5.1)]


• Liver enzyme abnormalities [see Warnings and Precautions (5.2)]

Clinical Trials Experience

Vytorin

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 Vytorin (ezetimibe/simvastatin) placebo-controlled clinical trials database of 1420 patients (age range 20-83 years, 52% women, 87% Caucasians, 3% Blacks, 5% Hispanics, 3% Asians) with a median treatment duration of 27 weeks, 5% of patients on Vytorin and 2.2% of patients on placebo discontinued due to adverse reactions.

The most common adverse reactions in the group treated with Vytorin that led to treatment discontinuation and occurred at a rate greater than placebo were:

• Increased ALT (0.9%)


• Myalgia (0.6%)


• Increased AST (0.4%)


• Back pain (0.4%)

The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in controlled clinical trials were: headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).

Vytorin has been evaluated for safety in more than 10,189 patients in clinical trials.

Table 2 summarizes the frequency of clinical adverse reactions reported in ≥2% of patients treated with Vytorin (n=1420) and at an incidence greater than placebo, regardless of causality assessment, from four placebo-controlled trials.

Table 2*: Clinical Adverse Reactions Occurring in ≥2% of Patients Treated with Vytorin and at an Incidence Greater than Placebo, Regardless of Causality

Body System/Organ Class Adverse Reaction	Placebo (%) n=371	Ezetimibe 10 mg (%) n=302	Simvastatin† (%) n=1234	Vytorin† (%) n=1420
* Includes two placebo-controlled combination studies in which the active ingredients equivalent to Vytorin were coadministered and two placebo-controlled studies in which Vytorin was administered. † All doses.
Body as a whole – general disorders
Headache	5.4	6.0	5.9	5.8
Gastrointestinal system disorders
Diarrhea	2.2	5.0	3.7	2.8
Infections and infestations
Influenza	0.8	1.0	1.9	2.3
Upper respiratory tract infection	2.7	5.0	5.0	3.6
Musculoskeletal and connective tissue disorders
Myalgia	2.4	2.3	2.6	3.6
Pain in extremity	1.3	3.0	2.0	2.3

Study of Heart and Renal Protection

In SHARP, 9270 patients were allocated to Vytorin 10/20 mg daily (n=4650) or placebo (n=4620) for a median follow-up period of 4.9 years. The proportion of patients who permanently discontinued study treatment as a result of either an adverse event or abnormal safety blood result was 10.4% vs. 9.8% among patients allocated to Vytorin and placebo, respectively. Comparing those allocated to Vytorin vs. placebo, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum CK >10 times ULN) was 0.2% vs. 0.1% and the incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) was 0.09% vs. 0.02%, respectively. Consecutive elevations of transaminases (>3 × ULN) occurred in 0.7% vs. 0.6%, respectively. Patients were asked about the occurrence of unexplained muscle pain or weakness at each study visit: 21.5% vs. 20.9% patients ever reported muscle symptoms in the Vytorin and placebo groups, respectively. Cancer was diagnosed during the trial in 9.4% vs. 9.5% of patients assigned to Vytorin and placebo, respectively.

Ezetimibe

Other adverse reactions reported with ezetimibe in placebo-controlled studies, regardless of causality assessment: Musculoskeletal system disorders: arthralgia; Infections and infestations: sinusitis; Body as a whole – general disorders: fatigue.

Simvastatin

In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (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 with simvastatin in placebo-controlled clinical studies, regardless of causality assessment: Cardiac disorders: atrial fibrillation; Ear and labyrinth disorders: vertigo; Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, flatulence, gastritis; Skin and subcutaneous tissue disorders: eczema, rash; Endocrine disorders: diabetes mellitus; Infections and infestations: bronchitis, sinusitis, urinary tract infections; Body as a whole – general disorders: asthenia, edema/swelling; Psychiatric disorders: insomnia.

Laboratory Tests

Marked persistent increases of hepatic serum transaminases have been noted [see Warnings and Precautions (5.2)]. Elevated alkaline phosphatase and γ-glutamyl transpeptidase have been reported. About 5% of patients taking simvastatin 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)].

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 adverse reactions have been reported in post-marketing experience for Vytorin or ezetimibe or simvastatin: pruritus; alopecia; erythema multiforme; a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails); dizziness; muscle cramps; myalgia; arthralgia; pancreatitis; paresthesia; peripheral neuropathy; vomiting; nausea; anemia; erectile dysfunction; interstitial lung disease; myopathy/rhabdomyolysis [see Warnings and Precautions (5.1)]; hepatitis/jaundice; fatal and non-fatal hepatic failure; depression; cholelithiasis; cholecystitis; thrombocytopenia; elevations in liver transaminases; elevated creatine phosphokinase.

Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria have been reported.

In addition, an apparent hypersensitivity syndrome has been reported rarely that has included one or more 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

[See Clinical Pharmacology (12.3).]

Vytorin

Strong CYP3A4 Inhibitors, cyclosporine, or danazol

Strong CYP3A4 inhibitors: The risk of myopathy is increased by reducing the elimination of the simvastatin component of Vytorin. Hence when Vytorin is used with an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of Vytorin. [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 Vytorin 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 Vytorin be considered during concomitant use of voriconazole and Vytorin 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 Vytorin [see Contraindications (4) and Warnings and Precautions (5.1)].

Other fibrates: Caution should be used when prescribing with Vytorin [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 6 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 Vytorin doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive Vytorin 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. [See Warnings and Precautions (5.1).]

Cholestyramine

Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding Vytorin to cholestyramine may be reduced by this interaction.

Digoxin

In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately when Vytorin is initiated.

Fibrates

The safety and effectiveness of Vytorin administered with fibrates have not been established.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Animal Toxicology and/or Pharmacology (13.2)]. Coadministration of Vytorin with fibrates is not recommended until use in patients is studied. [See Warnings and Precautions (5.1).]

Coumarin Anticoagulants

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 a normal volunteer study and in a hypercholesterolemic patient study, 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 Vytorin 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 Vytorin 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.

Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased INR in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications.

The effect of Vytorin on the prothrombin time has not been studied.

Colchicine

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

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X.

[See Contraindications (4).]

Vytorin

Vytorin 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 Vytorin use 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, such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Vytorin may cause fetal harm when administered to a pregnant woman. If Vytorin 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.

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

Ezetimibe

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe coadministered with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in coadministration therapy compared to monotherapy.

Simvastatin

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.

There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review1 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 what would be expected in the general population. The number of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

1

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)].

In rat studies, exposure to ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe or simvastatin are excreted into human breast milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women who are nursing should not take Vytorin [see Contraindications (4)].

Pediatric Use

The effects of ezetimibe coadministered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of a