A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Vytorin Side Effects, and Drug Interactions - Ezetimibe / Simvastatin
Vytorin Side Effects, and Drug Interactions - Ezetimibe / Simvastatin
SIDE EFFECTS
VYTORIN has been evaluated for safety in more than 3800 patients
in clinical trials. VYTORIN was generally well tolerated.
Table 5 summarizes the frequency of clinical adverse experiences
reported in ³2% of patients treated with VYTORIN
(n=1236) and at an incidence greater than placebo regardless of causality assessment
from three similarly designed, placebo-controlled trials.
|
Table 5* Clinical Adverse Events Occurring in ³2%
of Patients Treated with VYTORIN and at an Incidence Greater than Placebo,
Regardless of Causality
|
|
Body System/Organ Class
Adverse Event
|
Placebo (%)
|
Ezetimibe 10 mg (%)
|
Simvastatin** (%)
|
VYTORIN** (%)
|
| |
n=311
|
n=302
|
n=1234
|
n=1236
|
|
Body as a whole – general disorders
|
|
Headache
|
6.4
|
6.0
|
5.9
|
6.8
|
|
Infection and infestations
|
|
Influenza
|
1.0
|
1.0
|
1.9
|
2.6
|
|
Upper respiratory tract infection
|
2.6
|
5.0
|
5.0
|
3.9
|
|
Musculoskeletal and connective tissue disorders
|
|
Myalgia
|
2.9
|
2.3
|
2.6
|
3.5
|
|
Pain in extremity
|
1.3
|
3.0
|
2.0
|
2.3
|
| |
|
|
|
|
|
*Includes two placebo-controlled combination studies
in which the active ingredients equivalent to VYTORIN were coadministered
and one placebo-controlled study in which VYTORIN was administered.
|
|
**All doses.
|
Ezetimibe
Other adverse experiences reported with ezetimibe in placebo-controlled
studies, regardless of causality assessment: Body as a whole – general disorders:
fatigue; Gastrointestinal system disorders: abdominal pain, diarrhea;
Infection and infestations: infection viral, pharyngitis, sinusitis;
Musculoskeletal system disorders: arthralgia, back pain; Respiratory
system disorders: coughing.
Post-marketing Experience
The following adverse reactions have been reported in post-marketing
experience, regardless of causality assessment:
Hypersensitivity reactions, including angioedema and rash;
pancreatitis; nausea; cholelithiasis; cholecystitis.
Simvastatin
Other adverse experiences reported with simvastatin in placebo-controlled
clinical studies, regardless of causality assessment: Body as a whole – general
disorders: asthenia; Eye disorders: cataract;
Gastrointestinal system disorders: abdominal pain, constipation,
diarrhea, dyspepsia, flatulence, nausea;
Skin and subcutaneous tissue disorders: eczema, pruritus,
rash.
The following effects have been reported with other HMG-CoA
reductase inhibitors. Not all the effects listed below have necessarily been
associated with simvastatin therapy.
Musculoskeletal system disorders: muscle cramps, myalgia,
myopathy, rhabdomyolysis, arthralgias.
Nervous system disorders: dysfunction of certain cranial
nerves (including alteration of taste, impairment of extra-ocular movement,
facial paresis), tremor, dizziness, memory loss, paresthesia, peripheral neuropathy,
peripheral nerve palsy, psychic disturbances.
Ear and labyrinth disorders: vertigo.
Psychiatric disorders: anxiety, insomnia, depression,
loss of libido.
Hypersensitivity Reactions: An apparent hypersensitivity
syndrome has been reported rarely which 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.
Gastrointestinal system disorders: pancreatitis, vomiting.
Hepatobiliary disorders: hepatitis, including chronic
active hepatitis, cholestatic jaundice, fatty change in liver, and, rarely,
cirrhosis, fulminant hepatic necrosis, and hepatoma.
Metabolism and nutrition disorders: anorexia.
Skin and subcutaneous tissue disorders: alopecia, pruritus.
A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous
membranes, changes to hair/nails) have been reported.
Reproductive system and breast disorders: gynecomastia,
erectile dysfunction. Eye disorders: progression of cataracts (lens opacities),
ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline
phosphatase, g-glutamyl transpeptidase, and bilirubin;
thyroid function abnormalities.
Laboratory Tests
Marked persistent increases of serum transaminases have been
noted (see WARNINGS, Liver Enzymes).
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. Muscle pain or dysfunction usually was not
reported (see WARNINGS, Myopathy/Rhabdomyolysis).
Concomitant Lipid-Lowering Therapy
In controlled clinical studies in which simvastatin was administered
concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant
treatment were observed. The adverse reactions that occurred were limited to
those reported previously with simvastatin or cholestyramine.
Adolescent Patients (ages 10-17 years)
In a 48-week controlled study in adolescent boys and girls
who were at least 1 year post-menarche, 10-17 years of age with heterozygous
familial hypercholesterolemia (n=175), the safety and tolerability profile of
the group treated with simvastatin (10-40 mg daily) was generally similar
to that of the group treated with placebo, with the most common adverse
experiences observed in both groups being upper respiratory infection, headache,
abdominal pain, and nausea (see CLINICAL PHARMACOLOGY,
Special Populations and PRECAUTIONS,
Pediatric Use).
DRUG INTERACTIONS
(See also CLINICAL PHARMACOLOGY,
Drug Interactions)
VYTORIN
CYP3A4 Interactions
Potent inhibitors of CYP3A4 (below) increase the risk of myopathy
by reducing the elimination of the simvastatin component of VYTORIN.
See WARNINGS, Myopathy/Rhabdomyolysis,
and CLINICAL PHARMACOLOGY,
Pharmacokinetics, Drug Interactions.
Itraconazole
Ketoconazole
Erythromycin
Clarithromycin
HIV protease inhibitors
Nefazodone
Cyclosporine
Large quantities of grapefruit juice (>1 quart daily)
Interactions with lipid-lowering drugs that can cause
myopathy when given alone See WARNINGS,
Myopathy/Rhabdomyolysis.
The risk of myopathy is increased by gemfibrozil and to a lesser
extent by other fibrates and niacin (nicotinic acid) (³1
g/day).
Other drug interactions
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis
is increased by concomitant administration of amiodarone or verapamil (see WARNINGS,
Myopathy/Rhabdomyolysis).
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.
Cyclosporine: Caution should be exercised when initiating
VYTORIN in patients treated with cyclosporine due to increased exposure to ezetimibe.
This exposure may be greater in patients with severe renal insufficiency. In
patients treated with cyclosporine, the potential effects of the increased exposure
to ezetimibe from concomitant use should be carefully weighed against the benefits
of alterations in lipid levels provided by ezetimibe. In a pharmacokinetic study
in post-renal transplant patients with mildly impaired or normal renal function
(creatinine clearance of >50 mL/min), concomitant cyclosporine administration
increased the mean AUC and Cmax of total ezetimibe 3.4-fold (range
2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively. In a
separate study, the total ezetimibe exposure increased 12-fold in one renal
transplant patient with severe renal insufficiency receiving multiple medications,
including cyclosporine. (See CLINICAL PHARMACOLOGY,
Drug Interactions and WARNINGS,
Myopathy/Rhabdomyolysis.)
Digoxin: Concomitant administration of a single dose
of digoxin in healthy male volunteers receiving simvastatin resulted in a slight
elevation (less than 0.3 ng/mL) in plasma digoxin concentrations compared to
concomitant administration of placebo and digoxin. 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 PHARMACOLOGY). Coadministration
of VYTORIN with fibrates is not recommended until use in patients is studied.
(See WARNINGS, Myopathy/Rhabdomyolysis.)
Warfarin: 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 insure 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.
Ezetimibe
Fenofibrate: In a pharmacokinetic study, concomitant
fenofibrate administration increased total ezetimibe concentrations approximately
1.5-fold.
Gemfibrozil: In a pharmacokinetic study, concomitant
gemfibrozil administration increased total ezetimibe concentrations approximately
1.7-fold.
Simvastatin
Propranolol: In healthy male volunteers there was a
significant decrease in mean Cmax, but no change in AUC, for simvastatin
total and active inhibitors with concomitant administration of single doses
of simvastatin and propranolol. The clinical relevance of this finding is unclear.
The pharmacokinetics of the enantiomers of propranolol were not affected.
CNS Toxicity
Optic nerve degeneration was seen in clinically normal dogs
treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced
mean plasma drug levels about 12 times higher than the mean plasma drug level
in humans taking 80 mg/day.
A chemically similar drug in this class also produced optic
nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically
normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that
produced mean plasma drug levels about 30 times higher than the mean plasma
drug level in humans taking the highest recommended dose (as measured by total
enzyme inhibitory activity). This same drug also produced vestibulocochlear
Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs
treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma
drug level similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage
and edema, mononuclear cell infiltration of perivascular spaces, perivascular
fibrin deposits and necrosis of small vessels were seen in dogs treated with
simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug
levels that were about 14 times higher than the mean plasma drug levels in humans
taking 80 mg/day. Similar CNS vascular lesions have been observed with several
other drugs of this class.
There were cataracts in female rats after two years of treatment
with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively)
and in dogs after three months at 90 mg/kg/day (19 times) and at two years at
50 mg/kg/day (5 times).
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