Approved Drug Label (PDF)
4
Contraindications
Additions
and/revisions underlined:
5
Warnings and Precautions
5.1 Myopathy and Rhabdomyolysis
Additions and/or
revisions underlined:
PRAVACHOL may cause myopathy and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and
rare fatalities have occurred as a result of rhabdomyolysis in
patients treated with statins, including PRAVACHOL. Myopathy, defined as
muscle aching or muscle weakness in conjunction with increases in creatine
phosphokinase (CK) to greater than 10 times the upper limit of normal
(ULN), occurred <0.1% in PRAVACHOL-treated patients in
clinical trials.
Risk Factors for Myopathy
Risk factors for myopathy include age 65 years or
greater, uncontrolled hypothyroidism, renal impairment, concomitant use with
certain other drugs (including other lipid-lowering therapies), and higher
PRAVACHOL dosage [see Drug Interactions
(7.1)].
Steps to
Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
PRAVACHOL is not recommended in patients taking
gemfibrozil [see Drug Interactions (7)]. There
are PRAVACHOL dosage restrictions for patients taking cyclosporin and select
macrolide antibiotics [see Dosage and
Administration (2.5)]. The following drugs when used concomitantly with
PRAVACHOL may also increase the risk of myopathy and rhabdomyolysis: niacin,
fibrates, and colchicine [see Drug
Interactions (7)].
Discontinue PRAVACHOL if markedly elevated CK levels occur or myopathy is diagnosed or
suspected. Muscle symptoms and CK increases may resolve if PRAVACHOL is
discontinued. Temporarily discontinue PRAVACHOL in patients experiencing an
acute or serious condition at
high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock;
severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or
electrolyte disorders; or uncontrolled epilepsy.
Inform patients of the risk of myopathy and
rhabdomyolysis when starting or increasing the PRAVACHOL dosage. Instruct
patients to promptly report any unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever.
5.2 Immune-Mediated Necrotizing Myopathy
Additions and/or revisions underlined:
There have been rare reports of immune-mediated
necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin
use, including reports of recurrence when the same or a different statin was
administered. IMNM is characterized by proximal muscle weakness and
elevated serum creatine kinase that persist despite discontinuation of statin
treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing
necrotizing myopathy; and improvement with immunosuppressive agents. Additional
neuromuscular and serologic testing may be necessary. Treatment with
immunosuppressive agents may be required. Discontinue PRAVACHOL if IMNM is
suspected.
5.3 Hepatic Dysfunction
Additions and/or revisions underlined:
Increases in serum transaminases have been reported
with use of PRAVACHOL [see Adverse
Reactions (6.1)]. In most cases, these changes appeared soon after
initiation, were transient, were not accompanied by symptoms, and resolved or
improved on continued therapy or after a brief interruption in therapy.
Persistent increases to more than three times the ULN in serum transaminases
have occurred in approximately 1% of patients receiving either PRAVACHOL or
placebo in clinical studies. Marked persistent increases of hepatic
transaminases have also occurred with PRAVACHOL. There have been rare postmarketing reports of fatal and non-fatal
hepatic failure in patients taking statins, including PRAVACHOL.
Patients who consume substantial quantities of
alcohol and/or have a history of liver disease may be at increased risk for
hepatic injury.
Consider liver enzyme testing before PRAVACHOL initiation and when
clinically indicated thereafter. PRAVACHOL is contraindicated in patients with
acute liver failure or decompensated cirrhosis [see Contraindications (4)]. If serious hepatic injury with
clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly
discontinue PRAVACHOL.
5.4 Increases in HbA1c and Fasting Serum Glucose Levels
Newly added subsection:
Increases
in HbA1c and fasting serum glucose levels have been reported with statins,
including PRAVACHOL. Optimize lifestyle measures, including regular exercise,
maintaining a healthy body weight, and making healthy food choices.
6
Adverse Reactions
Additions and/or revisions underlined:
The
following important adverse reactions are described below and elsewhere in the
labeling:
- Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]
- Immune-Mediated Necrotizing
Myopathy [see Warnings and
Precautions (5.2)]
- Hepatic Dysfunction [see Warnings and Precautions (5.3)]
- Increases in HbA1c and Fasting
Serum Glucose Levels [see Warnings
and Precautions (5.4)]
6.1 Clinical Trials Experience
Extensive changes; please refer to label
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The
following adverse reactions have been identified during postapproval use of
PRAVACHOL. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their
frequency
or establish a causal relationship to drug exposure.
…
Nervous System: dysfunction of
certain cranial nerves (including alteration of taste, impairment of
extraocular movement, facial paresis), peripheral nerve palsy. Rare
postmarketing reports of cognitive impairment (e.g., memory loss,
forgetfulness, amnesia, memory impairment, confusion) associated with statin
use. Cognitive impairment was generally nonserious, and reversible upon
statin discontinuation, with variable times to symptom onset (1 day to years)
and symptom resolution (median of 3 weeks).
…
Dermatologic: a variety of skin changes (e.g., nodules,
discoloration, dryness of mucous membranes, changes to hair/nails), lichen
planus.
…
7
Drug Interactions
7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with PRAVACHOL
Subsection
title revised
Extensive
changes; please refer to label
7.2 Drug Interactions that Decrease the Efficacy of PRAVACHOL
Newly added subsection
Addition of table; please refer to label
8
Use in Specific Populations
8.1 Pregnancy
Additions and/or revisions underlined:
Risk
Summary
Discontinue
PRAVACHOL
when pregnancy is recognized. Alternatively, consider the ongoing
therapeutic needs of the individual patient. PRAVACHOL decreases synthesis of
cholesterol and possibly other biologically active substances derived from
cholesterol; therefore, PRAVACHOL may cause fetal harm when administered to
pregnant patients based on the mechanism of action [see Clinical Pharmacology (12.1)]. In addition, treatment of
hyperlipidemia is not generally necessary during pregnancy. 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 hyperlipidemia for most patients. Available data from case series and
prospective and retrospective observational cohort studies over decades of use
with statins in pregnant women have not identified a drug-associated risk
of major congenital malformations. Published data from prospective and
retrospective observational cohort studies with PRAVACHOL use in pregnant women
are insufficient to determine if there is a drug-associated risk of
miscarriage (see Data). In animal
reproduction studies, no evidence of fetal malformations was seen in pregnant
rats or rabbits orally administered pravastatin during the period of
organogenesis at doses that resulted in 10 times and 120 times,
respectively, the human exposure at the maximum recommended human dose
(MRHD) of 80 mg/day, based on body surface area (mg/m2). An
imbalance in some fetal skeletal variations, increased offspring
mortality, and developmental delays occurred when pregnant rats were exposed
to 10 times to 12 times the MRHD during organogenesis to parturition (see Data).
The
estimated background risk of major birth defects and miscarriage for the
indicated population is unknown. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2-4% and 15-20%, respectively.
Data
Human Data
A
Medicaid cohort linkage study of 1152 statin-exposed pregnant women compared to
886,996 controls did not find a significant teratogenic effect from maternal
use of statins in the first trimester of pregnancy, after adjusting for
potential cofounders – including maternal age, diabetes mellitus, hypertension,
obesity, and alcohol and tobacco use – using propensity score-based methods.
The relative risk of congenital malformations between the group with statin use
and the group with no statin use in the first trimester was 1.07 (95%
confidence interval 0.85 to 1.37) after controlling for confounders,
particularly pre-existing diabetes mellitus. There were also no statistically
significant increases in any of the organ-specific malformations assessed after
accounting for cofounders. In the majority of pregnancies, statin treatment was
initiated prior to pregnancy and was discontinued at some point in the first
trimester when pregnancy was identified. Study limitations include reliance on
physician coding to define the presence of a malformation, lack of control for
certain confounders such as body mass index, use of prescription dispensing as
verification for the use of a statin, and lack of information on non-live
births.
…
8.2 Lactation
Additions and/or revisions underlined:
Risk Summary
Based on one lactation study in published
literature, pravastatin is present in human milk. There is no available
information on the effects of the drug on the breastfed infant or the effects
of the drug on milk production. Statins, including PRAVACHOL, decrease
cholesterol synthesis and possibly the synthesis of other biologically active
substances derived from cholesterol and may cause harm to the breastfed infant.
Because of the
potential for serious adverse reactions in a breastfed infant, based on the
mechanism of action, advise patients that breastfeeding is not recommended
during treatment with PRAVACHOL [see
Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].
8.4 Pediatric use
Additions and/or revisions underlined:
The safety and effectiveness of PRAVACHOL as an
adjunct to diet to reduce LDL-C have been established in pediatric patients
8 years of age and older with HeFH. Use of PRAVACHOL for this indication is
based on a double-blind, placebo-controlled clinical study in 214
pediatric patients (100 males and 114 females) 8 years of age and older
with HeFH. Doses greater than 40 mg daily have not been studied
in this population.
The safety and effectiveness
of PRAVACHOL have not been established in pediatric patients younger
than 10 years of age with HeFH or in pediatric patients with other types of
hyperlipidemia (other than HeFH).
8.5
Geriatric Use
Additions
and/or revisions underlined:
In
clinical
studies, 4,797 (36.4%) PRAVACHOL-treated patients were aged 65 and older
and 110 (0.8%) were aged 75 and older. No significant differences in efficacy
or safety were observed between geriatric patients and younger
patients.
Mean
pravastatin AUCs are 25%-50% higher in elderly subjects than in healthy young
subjects, but mean maximum plasma concentration (Cmax), time to
maximum plasma concentration (Tmax), and half-life (t½)
values are similar in both age groups and substantial accumulation of
pravastatin would not be expected in the elderly [see Clinical Pharmacology (12.3)].
Advanced
age (?65 years) is a risk factor for PRAVACHOL-associated myopathy and
rhabdomyolysis. Dose selection for an elderly patient should be cautious,
recognizing the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy and the
higher risk of myopathy. Monitor geriatric patients receiving PRAVACHOL for the
increased risk of myopathy [see Warnings
and Precautions (5.1)].
8.6
Renal Impairment
Newly
added subsection:
Renal
impairment is a risk factor for myopathy and rhabdomyolysis. Monitor all
patients with renal impairment for development of myopathy.
In
patients with severe renal impairment, the recommended starting dose is pravastatin
sodium 10 mg once daily. PRAVACHOL is not available in a 10 mg strength. Use
another pravastatin sodium product to intiate dosing in such patients. The
maximum recommended dosage in patients with severe renal impairment is
PRAVACHOL 40 mg once daily. The recommended dosage for patients with mild or
moderate renal impairment is the same as patients with normal renal function. [see Dosage and Administration (2.4),
Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
8.7
Hepatic Impairment
Newly
added subsection:
PRAVACHOL
shows a large inter-subject variability in pharmacokinetics in patients with
liver cirrhosis [Clinical Pharmacology
(12.3)]. PRAVACHOL is contraindicated in patients with acute liver failure
or decompensated cirrhosis [see
Contraindications (4), Warnings and Precautions (5.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
Myopathy and
Rhabdomyolysis
Advise
patients that PRAVACHOL may cause myopathy and rhabdomyolysis. Inform patients
that the risk is increased when taking certain types of medication and they should discuss
all medication, both prescription and over the counter, with their healthcare
provider. Instruct patients to promptly report any unexplained muscle pain,
tenderness or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug
Interactions (7.1)].
Hepatic
Dysfunction
Inform
patients
that PRAVACHOL may cause liver enzyme elevations and possibly
liver failure. Advise patients to promptly report fatigue, anorexia,
right upper abdominal discomfort, dark urine or jaundice [see Warnings and Precautions (5.3)].
Increases in HbA1c
and Fasting Serum Glucose Levels
Inform
patients that increases in HbA1c and fasting serum glucose levels may occur
with PRAVACHOL. Encourage patients to optimize lifestyle measures, including
regular exercise, maintaining a healthy body weight, and making healthy food
choices [see Warnings and Precautions
(5.4)].
Pregnancy
Advise
pregnant patients and patients who may become pregnant of the
potential risk to a fetus. Advise patients to inform their healthcare
provider of a known or suspected pregnancy to discuss if PRAVACHOL should be
discontinued [see Use in Specific
Populations (8.1)].
Lactation
Advise
patients that breastfeeding is not recommended during treatment
with PRAVACHOL [see
Use in Specific
Populations (8.2)].
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