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Label Changes for:

Amturnide (amlodipine/aliskiren/hydrochlorothiazide) tablets

February 2012

Changes have been made to the BOXED WARNING, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)- October and November 2011, February 2012

 

February 2012 

 

BOXED WARNING

WARNING: FETAL TOXICITY
  • When pregnancy is detected, discontinue Amturnide as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

WARNINGS AND PRECAUTIONS

Fetal toxicity

Pregnancy Category D

  • Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal...
Impaired Renal Function
  • Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics... Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Amturnide
Serum Electrolyte Abnormalities
  • Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
Hydrochlorothiazide:
  • If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Amturnide should be discontinued. Correction of hypokalemia and any coexisting hypomagnesaemia is recommended prior to the initiation of thiazides.
Metabolic Disturbances
  • Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides…may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients…decreases urinary calcium excretion and may cause elevation of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Amturnide.

 

ADVERSE REACTIONS

Postmarketing Experience

Hydrochlorothiazide:

  • Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hyperchloremic alkalosis, impotence, visual impairment. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.

 

DRUG INTERACTIONS

Hydrochlorothiazide
  • Lithium: Monitoring of serum lithium concentrations is recommended during concurrent use.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) and cox2 selective agents
  • Ion exchange resins: Staggering the dosage of hydrochlorothiazide and resin (e.g., cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimize the interaction.

 

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D

  • Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Amturnide as soon…
Pediatric Use
  • Neonates with a history of in utero exposure to Amturnide: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
HCTZ
  • Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion…Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications (e.g. heart disease) in pregnancy should be avoided.
Geriatric Use
  • Patients ≥ 75 years of age should start amlodipine at 2.5 mg, which is not available with Amturnide
Renal Impairment
  • Safety and effectiveness of Amturnide in patients with severe renal impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60-90 mL/min) or moderate (CrCl 30-60) renal impairment.
Hepatic Impairment
  • Aliskiren: No dose adjustment is necessary for patients with mild-to-severe liver disease.
  • Hydrochlorothiazide: Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

 

PATIENT COUNSELING INFORMATION

Pregnancy
  • Female patients of childbearing age should be told about the consequences of exposure to Amturnide during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
  • Amturnide can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking Amturnide, tell your doctor right away.

  

November 2011

WARNINGS AND PRECAUTIONS

Drug Interactions with Amlodipine
  • Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

 

October 2011 

 

WARNINGS AND PRECAUTIONS

Cyclosporine or Itraconazole
  • When aliskiren was given with cyclosporine or itraconoazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or intraconazole [see Drug Interactions (7)]

 

ADVERSE REACTIONS

Post-marketing Experience
  • Hypersensitivity: angioedema requiring airway management and hospitalization
  • Aliskiren: Peripheral edema, Blood creatinine increased

 

DRUG INTERACTIONS

Aliskiren
  • Cyclosporine: Avoid co-administration of cyclosporine with aliskiren.
  • Itraconazole: Avoid co-administration of itraconazole with aliskiren. [See Clinical Pharmacology (12.3).]

 

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