Norliqva

NORLIQVA is contraindicated in patients with sensitivity to amlodipine. Sensitivity to amlodipine ( 4 )

• Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis.
• However, acute hypotension is unlikely.
• ( 5.1 ) Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of NORLIQVA, particularly in patients with severe obstructive coronary artery disease.
• ( 5.2 ) Titrate slowly in patients with severe hepatic impairment.
• ( 5.3 )
• 5.1 Hypotension Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis.
• Because of the gradual onset of action, acute hypotension is unlikely.
• 5.2 Increased Angina or Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of NORLIQVA, particularly in patients with severe obstructive coronary artery disease.
• 5.3 Patients with Hepatic Failure Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with impaired hepatic function, titrate slowly when administering NORLIQVA to patients with severe hepatic impairment.

• Risk Summary:
• The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.
• There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations] In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times the maximum recommended human dose (MRHD), respectively.
• However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold).
• Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose [see Data] .
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
• All pregnancies have a background risk of birth defect, loss or other adverse outcomes.
• 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.
• Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage).
• Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.
• Pregnant women with hypertension should be carefully monitored and managed accordingly.
• Data Animal Data No evidence of teratogenicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis.
• However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation.
• Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
• IN SPECIFIC POPULATIONS Pediatric: Effect on patients less than 6 years old is not known.
• ( 8.4 ) Geriatric: Start dosing at the low end of the dose range.
• ( 8.5 ) Hepatic Impairment: Start dosing at the low end of the dose range.
• ( 8.6 )
• 8.1 Pregnancy Risk Summary:
• The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.
• There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations] In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times the maximum recommended human dose (MRHD), respectively.
• However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold).
• Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose [see Data] .
• The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
• All pregnancies have a background risk of birth defect, loss or other adverse outcomes.
• 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.
• Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage).
• Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.
• Pregnant women with hypertension should be carefully monitored and managed accordingly.
• Data Animal Data No evidence of teratogenicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis.
• However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation.
• Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
• 8.2 Lactation Risk Summary Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%.
• No adverse effects of amlodipine on the breastfed infant have been observed.
• There is no available information on the effects of amlodipine on milk production.
• 8.4 Pediatric Use Amlodipine (2.5 to 5 mg daily) is effective in lowering blood pressure in patients 6 years of age and older [see Clinical Studies (14.1) ] .
• Effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
• 8.5 Geriatric Use Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
• Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
• In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
• Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required [see Dosage and Administration (2.1) ] .
• 8.6 Hepatic Impairment Patients with hepatic impairment have reduced clearance of amlodipine with a resulting increase of AUC.
• A lower initial dose may be required [see Dosage and Administration (2.1) ] .

• Do not exceed doses greater than 20 mg daily of simvastatin.
• ( 7.2 )
• 7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction.
• Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3) ] .
• CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine.
• Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.
• 7.2 Impact of Amlodipine on Other Drugs Simvastatin Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin.
• Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3) ] .
• Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered.
• Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3) ] .

• Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia.
• Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths.
• Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension.
• If massive overdose should occur, initiate active cardiac and respiratory monitoring.
• Frequent blood pressure measurements are essential.
• Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids.
• If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output.
• As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.