U.S. BRAND NAMES — Tekturna HCT®
PHARMACOLOGIC CATEGORY
Diuretic, Thiazide
Renin Inhibitor
DOSING: ADULTS — Hypertension: Oral: One tablet daily; dosage must be individualized (see below). May be substituted for previously titrated dosages of the individual components. Titrate at 2- to 4-week intervals as necessary.
Patients not controlled with single-agent therapy: Initiate by adding the lowest available dose of the alternative component (aliskiren 150 mg or hydrochlorothiazide 12.5 mg); titrate to effect (maximum daily aliskiren dose: 300 mg; maximum daily hydrochlorothiazide dose: 25 mg)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Not recommended in patients with Clcr <30 mL/minute
DOSING: HEPATIC IMPAIRMENT — Dosage adjustment not required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna HCT®:
150/12.5: Aliskiren 150 mg and hydrochlorothiazide 12.5 mg
150/25: Aliskiren 150 mg and hydrochlorothiazide 25 mg
300/12.5: Aliskiren 300 mg and hydrochlorothiazide 12.5 mg
300/25: Aliskiren 300 mg and hydrochlorothiazide 25 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna HCT®: 150/12.5: Aliskiren 150 mg and hydrochlorothiazide 12.5 mg; 150/25: Aliskiren 150 mg and hydrochlorothiazide 25 mg; 300/12.5: Aliskiren 300 mg and hydrochlorothiazide 12.5 mg; 300/25: Aliskiren 300 mg and hydrochlorothiazide 25 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without meals.
USE — Treatment of hypertension (not recommended for initial treatment)
ADVERSE REACTIONS SIGNIFICANT — Frequencies reported with combination product. See individual monographs for additional adverse effects reported with each agent.
>10%: Renal: BUN increased (12%)
1% to 10%:
Central nervous system: Dizziness (2%), vertigo (1%)
Endocrine & metabolic: Hypokalemia (2%), uric acid level increased (2%)
Gastrointestinal: Diarrhea (2%)
Hepatic: ALT increased (1%)
Neuromuscular & skeletal: Arthralgia (1%), weakness (1%)
Respiratory: Cough (1%)
Miscellaneous: Flu-like syndrome (2%)
<1% (Limited to important or life-threatening): Hematocrit decreased, hemoglobin decreased, hyperkalemia
Note: Angioedema and periorbital edema have been reported with aliskiren. Severe dermatologic reactions and pancreatitis have been reported with hydrochlorothiazide.
CONTRAINDICATIONS — Hypersensitivity to hydrochlorothiazide, thiazides, or sulfonamide-derived drugs; anuria
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Electrolyte disturbances: Hyperkalemia may occur with renin inhibitors; risk factors include renal dysfunction, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely. Thiazide diuretics may cause hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia. Hypersensitivity reactions: Hypersensitivity reactions may occur with hydrochlorothiazide. Risk is increased in patients with a history of allergy or bronchial asthma. Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in volume- or salt-depleted patients. Photosensitivity: Due to the hydrochlorothiazide component photosensitization may occur. Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure); deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Diabetes: Use hydrochlorothiazide with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated by hydrochlorothiazide. Hepatic impairment: Use caution in patients with hepatic impairment. Avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: There has been no experience in treating patients with renal artery stenosis; use aliskiren with caution in patients with unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks. Renal impairment: Use with caution in patients with renal impairment; not recommended in patients with severe renal impairment (Clcr <30 mL/minute). Avoid hydrochlorothiazide in severe renal disease (ineffective); may precipitate azotemia; discontinue or consider withholding if renal impairment occurs. Systemic lupus erythematosus (SLE): Hydrochlorothiazide can cause SLE exacerbation or activation.
Concurrent drug therapy: High potential for interactions: use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine); concomitant therapy with cyclosporine is not recommended.
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — See individual agents.
DRUG INTERACTIONS
ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinolol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Analgesics (Opioid): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Barbiturates: May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification
Calcitriol: Thiazide Diuretics may enhance the hypercalcemic effect of Calcitriol. Risk C: Monitor therapy
Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Take with or without meals; a high-fat meal reduces aliskiren absorption substantially.
PRICING — (data from drugstore.com)
Tablets (Tekturna HCT)
300-25 mg (30): $102.72
MONITORING PARAMETERS — Blood pressure; serum electrolytes, BUN, serum creatinine; fluid status
MECHANISM OF ACTION — Aliskiren is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Hydrochlorothiazide inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions.
PHARMACODYNAMICS / KINETICS — See individual agents.
Thursday, May 27, 2010
Aliskiren
MEDICATION SAFETY ISSUES
International issues:
Aliskiren may be confused with Aliseum which is a brand name for diazepam in Italy
U.S. BRAND NAMES — Tekturna®
PHARMACOLOGIC CATEGORY
Renin Inhibitor
DOSING: ADULTS — Hypertension: Initial: 150 mg once daily; may increase to 300 mg once daily (maximum: 300 mg/day). Note: Prior to initiation, correct hypovolemia and/or closely monitor volume status in patients on concurrent diuretics during treatment initiation.
DOSING: PEDIATRIC — Children <18 years: Dosage not established.
DOSING: ELDERLY — Refer to adult dosing. No initial dosage adjustment required.
DOSING: RENAL IMPAIRMENT
Mild-to-moderate impairment [GFR >30 mL/minute and/or Scr <1.7 mg/dL (women); Scr <2 mg/dL (men)]: No dose adjustment required
Severe impairment [GFR<30>1.7 mg/dL (women); Scr >2 mg/dL (men)]: Use caution; not studied in severe renal impairment
DOSING: HEPATIC IMPAIRMENT — No dosage adjustment required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna®: 150 mg, 300 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna®: 150 mg, 300 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer at the same time daily; may take with or without a meal, but consistent administration with regards to meals is recommended. Avoid taking with high-fat meals.
USE — Treatment of hypertension, alone or in combination with other antihypertensive agents
USE - UNLABELED / INVESTIGATIONAL — Treatment of persistent proteinuria in patients with type 2 diabetes mellitus, hypertension, and nephropathy despite administration of optimized recommended renoprotective therapy (eg, angiotensin II receptor blocker)
ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (2%)
Dermatologic: Rash (1%)
Endocrine & metabolic: Hyperkalemia (monotherapy ≤ 1%; concurrent with ACE inhibitor in patients with diabetes 6%)
Gastrointestinal: Diarrhea (1% to 2%)
Hematologic: Creatine kinase increased (>300%: 1%)
Renal: BUN increased (≤ 7%), serum creatinine increased (≤ 7%)
Respiratory: Cough (1%)
<1% (Limited to important or life-threatening): Abdominal pain, anemia, angina, angioedema, dyspepsia, gastroesophageal reflux, gout, hypotension (severe), myositis, renal stone formation, rhabdomyolysis, seizure, uric acid increased
CONTRAINDICATIONS
U.S. labeling: There are no contraindications listed in manufacturer's labeling.
Canada labeling: Hypersensitivity to aliskiren or any component of the formulation
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Hyperkalemia: May occur (rarely) during monotherapy; risk may increase in patients with predisposing factors (eg, renal dysfunction, diabetes mellitus or concomitant use with ACE inhibitors, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts). Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in patients with an activated renin-angiotensin system (ie, volume or salt-depleted patients)
Disease-related concerns: Renal impairment: Use with caution in patients with severe renal impairment; not studied in patients with severe renal impairment [GFR <30>1.7 mg/dL (women); Scr >2 mg/dL (men)], history of dialysis, nephrotic syndrome, or renovascular hypertension. Use with caution or avoid in patients with deteriorating renal function or renal artery stenosis (bilateral or unilateral).
Concurrent drug therapy issues: High potential for interactions: Use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine).
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (minor)
DRUG INTERACTIONS
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: High-fat meals decrease absorption.
PREGNANCY RISK FACTOR — C (show table) (1st trimester); D (2nd and 3rd trimesters)
PREGNANCY IMPLICATIONS — Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken with or without food; however, a high-fat meal reduces absorption
PRICING — (data from drugstore.com)
Tablets (Tekturna)
150 mg (30): $82.38
300 mg (30): $101.80
MONITORING PARAMETERS — Blood pressure; serum potassium, BUN, serum creatinine
CANADIAN BRAND NAMES — Rasilez®
INTERNATIONAL BRAND NAMES — Enviage (EE); Rasilez (BE, CH, CZ, DE, DK, EE, GB, ID, IE, IL, NO, PE, PH, SE); Tekturna (EE)
MECHANISM OF ACTION — Aliskerin is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Ang II also functions within the Renin-Angiotensin-Aldosterone System (RAAS) as a negative inhibitory feedback mediator within the renal parenchyma to suppress the further release of renin. Thus, reductions in Ang II levels suppress this feedback loop, leading to further increased plasma renin concentrations (PRC) and subsequent activity (PRA). This disinhibition effect can be potentially problematic for ACE inhibitor and ARB therapy, as increased PRA could partially overcome the pharmacologic inhibition of the RAAS. As aliskiren is a direct inhibitor of renin activity, blunting of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous. The effect of aliskiren on bradykinin levels is unknown.
PHARMACODYNAMICS / KINETICS
Onset of action: Maximum antihypertensive effect: Within 2 weeks
Absorption: Poor; absorption decreased by high-fat meal. Aliskiren is a substrate of P-glycoprotein; concurrent use of P-glycoprotein inhibitors may increase absorption.
Metabolism: Extent of metabolism unknown; in vitro studies indicate metabolism via CYP3A4
Bioavailability: ~3%
Half-life elimination: ~24 hours (range: 16-32 hours)
Time to peak, plasma: 1-3 hours
Excretion: Urine (~25% of absorbed dose excreted unchanged in urine); feces (unchanged via biliary excretion)
International issues:
Aliskiren may be confused with Aliseum which is a brand name for diazepam in Italy
U.S. BRAND NAMES — Tekturna®
PHARMACOLOGIC CATEGORY
Renin Inhibitor
DOSING: ADULTS — Hypertension: Initial: 150 mg once daily; may increase to 300 mg once daily (maximum: 300 mg/day). Note: Prior to initiation, correct hypovolemia and/or closely monitor volume status in patients on concurrent diuretics during treatment initiation.
DOSING: PEDIATRIC — Children <18 years: Dosage not established.
DOSING: ELDERLY — Refer to adult dosing. No initial dosage adjustment required.
DOSING: RENAL IMPAIRMENT
Mild-to-moderate impairment [GFR >30 mL/minute and/or Scr <1.7 mg/dL (women); Scr <2 mg/dL (men)]: No dose adjustment required
Severe impairment [GFR<30>1.7 mg/dL (women); Scr >2 mg/dL (men)]: Use caution; not studied in severe renal impairment
DOSING: HEPATIC IMPAIRMENT — No dosage adjustment required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna®: 150 mg, 300 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna®: 150 mg, 300 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer at the same time daily; may take with or without a meal, but consistent administration with regards to meals is recommended. Avoid taking with high-fat meals.
USE — Treatment of hypertension, alone or in combination with other antihypertensive agents
USE - UNLABELED / INVESTIGATIONAL — Treatment of persistent proteinuria in patients with type 2 diabetes mellitus, hypertension, and nephropathy despite administration of optimized recommended renoprotective therapy (eg, angiotensin II receptor blocker)
ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (2%)
Dermatologic: Rash (1%)
Endocrine & metabolic: Hyperkalemia (monotherapy ≤ 1%; concurrent with ACE inhibitor in patients with diabetes 6%)
Gastrointestinal: Diarrhea (1% to 2%)
Hematologic: Creatine kinase increased (>300%: 1%)
Renal: BUN increased (≤ 7%), serum creatinine increased (≤ 7%)
Respiratory: Cough (1%)
<1% (Limited to important or life-threatening): Abdominal pain, anemia, angina, angioedema, dyspepsia, gastroesophageal reflux, gout, hypotension (severe), myositis, renal stone formation, rhabdomyolysis, seizure, uric acid increased
CONTRAINDICATIONS
U.S. labeling: There are no contraindications listed in manufacturer's labeling.
Canada labeling: Hypersensitivity to aliskiren or any component of the formulation
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Hyperkalemia: May occur (rarely) during monotherapy; risk may increase in patients with predisposing factors (eg, renal dysfunction, diabetes mellitus or concomitant use with ACE inhibitors, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts). Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in patients with an activated renin-angiotensin system (ie, volume or salt-depleted patients)
Disease-related concerns: Renal impairment: Use with caution in patients with severe renal impairment; not studied in patients with severe renal impairment [GFR <30>1.7 mg/dL (women); Scr >2 mg/dL (men)], history of dialysis, nephrotic syndrome, or renovascular hypertension. Use with caution or avoid in patients with deteriorating renal function or renal artery stenosis (bilateral or unilateral).
Concurrent drug therapy issues: High potential for interactions: Use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine).
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (minor)
DRUG INTERACTIONS
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: High-fat meals decrease absorption.
PREGNANCY RISK FACTOR — C (show table) (1st trimester); D (2nd and 3rd trimesters)
PREGNANCY IMPLICATIONS — Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken with or without food; however, a high-fat meal reduces absorption
PRICING — (data from drugstore.com)
Tablets (Tekturna)
150 mg (30): $82.38
300 mg (30): $101.80
MONITORING PARAMETERS — Blood pressure; serum potassium, BUN, serum creatinine
CANADIAN BRAND NAMES — Rasilez®
INTERNATIONAL BRAND NAMES — Enviage (EE); Rasilez (BE, CH, CZ, DE, DK, EE, GB, ID, IE, IL, NO, PE, PH, SE); Tekturna (EE)
MECHANISM OF ACTION — Aliskerin is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Ang II also functions within the Renin-Angiotensin-Aldosterone System (RAAS) as a negative inhibitory feedback mediator within the renal parenchyma to suppress the further release of renin. Thus, reductions in Ang II levels suppress this feedback loop, leading to further increased plasma renin concentrations (PRC) and subsequent activity (PRA). This disinhibition effect can be potentially problematic for ACE inhibitor and ARB therapy, as increased PRA could partially overcome the pharmacologic inhibition of the RAAS. As aliskiren is a direct inhibitor of renin activity, blunting of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous. The effect of aliskiren on bradykinin levels is unknown.
PHARMACODYNAMICS / KINETICS
Onset of action: Maximum antihypertensive effect: Within 2 weeks
Absorption: Poor; absorption decreased by high-fat meal. Aliskiren is a substrate of P-glycoprotein; concurrent use of P-glycoprotein inhibitors may increase absorption.
Metabolism: Extent of metabolism unknown; in vitro studies indicate metabolism via CYP3A4
Bioavailability: ~3%
Half-life elimination: ~24 hours (range: 16-32 hours)
Time to peak, plasma: 1-3 hours
Excretion: Urine (~25% of absorbed dose excreted unchanged in urine); feces (unchanged via biliary excretion)
Aliskiren and hydrochlorothiazide
U.S. BRAND NAMES — Tekturna HCT®
PHARMACOLOGIC CATEGORY
Diuretic, Thiazide
Renin Inhibitor
DOSING: ADULTS — Hypertension: Oral: One tablet daily; dosage must be individualized (see below). May be substituted for previously titrated dosages of the individual components. Titrate at 2- to 4-week intervals as necessary.
Patients not controlled with single-agent therapy: Initiate by adding the lowest available dose of the alternative component (aliskiren 150 mg or hydrochlorothiazide 12.5 mg); titrate to effect (maximum daily aliskiren dose: 300 mg; maximum daily hydrochlorothiazide dose: 25 mg)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Not recommended in patients with Clcr <30 mL/minute
DOSING: HEPATIC IMPAIRMENT — Dosage adjustment not required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna HCT®:
150/12.5: Aliskiren 150 mg and hydrochlorothiazide 12.5 mg
150/25: Aliskiren 150 mg and hydrochlorothiazide 25 mg
300/12.5: Aliskiren 300 mg and hydrochlorothiazide 12.5 mg
300/25: Aliskiren 300 mg and hydrochlorothiazide 25 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna HCT®: 150/12.5: Aliskiren 150 mg and hydrochlorothiazide 12.5 mg; 150/25: Aliskiren 150 mg and hydrochlorothiazide 25 mg; 300/12.5: Aliskiren 300 mg and hydrochlorothiazide 12.5 mg; 300/25: Aliskiren 300 mg and hydrochlorothiazide 25 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without meals.
USE — Treatment of hypertension (not recommended for initial treatment)
ADVERSE REACTIONS SIGNIFICANT — Frequencies reported with combination product. See individual monographs for additional adverse effects reported with each agent.
>10%: Renal: BUN increased (12%)
1% to 10%:
Central nervous system: Dizziness (2%), vertigo (1%)
Endocrine & metabolic: Hypokalemia (2%), uric acid level increased (2%)
Gastrointestinal: Diarrhea (2%)
Hepatic: ALT increased (1%)
Neuromuscular & skeletal: Arthralgia (1%), weakness (1%)
Respiratory: Cough (1%)
Miscellaneous: Flu-like syndrome (2%)
<1% (Limited to important or life-threatening): Hematocrit decreased, hemoglobin decreased, hyperkalemia
Note: Angioedema and periorbital edema have been reported with aliskiren. Severe dermatologic reactions and pancreatitis have been reported with hydrochlorothiazide.
CONTRAINDICATIONS — Hypersensitivity to hydrochlorothiazide, thiazides, or sulfonamide-derived drugs; anuria
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Electrolyte disturbances: Hyperkalemia may occur with renin inhibitors; risk factors include renal dysfunction, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely. Thiazide diuretics may cause hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia. Hypersensitivity reactions: Hypersensitivity reactions may occur with hydrochlorothiazide. Risk is increased in patients with a history of allergy or bronchial asthma. Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in volume- or salt-depleted patients. Photosensitivity: Due to the hydrochlorothiazide component photosensitization may occur. Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure); deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Diabetes: Use hydrochlorothiazide with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated by hydrochlorothiazide. Hepatic impairment: Use caution in patients with hepatic impairment. Avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: There has been no experience in treating patients with renal artery stenosis; use aliskiren with caution in patients with unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks. Renal impairment: Use with caution in patients with renal impairment; not recommended in patients with severe renal impairment (Clcr <30 mL/minute). Avoid hydrochlorothiazide in severe renal disease (ineffective); may precipitate azotemia; discontinue or consider withholding if renal impairment occurs. Systemic lupus erythematosus (SLE): Hydrochlorothiazide can cause SLE exacerbation or activation.
Concurrent drug therapy: High potential for interactions: use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine); concomitant therapy with cyclosporine is not recommended.
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — See individual agents.
DRUG INTERACTIONS
ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinolol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Analgesics (Opioid): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Barbiturates: May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification
Calcitriol: Thiazide Diuretics may enhance the hypercalcemic effect of Calcitriol. Risk C: Monitor therapy
Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Take with or without meals; a high-fat meal reduces aliskiren absorption substantially.
PRICING — (data from drugstore.com)
Tablets (Tekturna HCT)
300-25 mg (30): $102.72
MONITORING PARAMETERS — Blood pressure; serum electrolytes, BUN, serum creatinine; fluid status
MECHANISM OF ACTION — Aliskiren is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Hydrochlorothiazide inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions.
PHARMACODYNAMICS / KINETICS — See individual agents.
PHARMACOLOGIC CATEGORY
Diuretic, Thiazide
Renin Inhibitor
DOSING: ADULTS — Hypertension: Oral: One tablet daily; dosage must be individualized (see below). May be substituted for previously titrated dosages of the individual components. Titrate at 2- to 4-week intervals as necessary.
Patients not controlled with single-agent therapy: Initiate by adding the lowest available dose of the alternative component (aliskiren 150 mg or hydrochlorothiazide 12.5 mg); titrate to effect (maximum daily aliskiren dose: 300 mg; maximum daily hydrochlorothiazide dose: 25 mg)
DOSING: ELDERLY — Refer to adult dosing.
DOSING: RENAL IMPAIRMENT — Not recommended in patients with Clcr <30 mL/minute
DOSING: HEPATIC IMPAIRMENT — Dosage adjustment not required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna HCT®:
150/12.5: Aliskiren 150 mg and hydrochlorothiazide 12.5 mg
150/25: Aliskiren 150 mg and hydrochlorothiazide 25 mg
300/12.5: Aliskiren 300 mg and hydrochlorothiazide 12.5 mg
300/25: Aliskiren 300 mg and hydrochlorothiazide 25 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna HCT®: 150/12.5: Aliskiren 150 mg and hydrochlorothiazide 12.5 mg; 150/25: Aliskiren 150 mg and hydrochlorothiazide 25 mg; 300/12.5: Aliskiren 300 mg and hydrochlorothiazide 12.5 mg; 300/25: Aliskiren 300 mg and hydrochlorothiazide 25 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer with or without meals.
USE — Treatment of hypertension (not recommended for initial treatment)
ADVERSE REACTIONS SIGNIFICANT — Frequencies reported with combination product. See individual monographs for additional adverse effects reported with each agent.
>10%: Renal: BUN increased (12%)
1% to 10%:
Central nervous system: Dizziness (2%), vertigo (1%)
Endocrine & metabolic: Hypokalemia (2%), uric acid level increased (2%)
Gastrointestinal: Diarrhea (2%)
Hepatic: ALT increased (1%)
Neuromuscular & skeletal: Arthralgia (1%), weakness (1%)
Respiratory: Cough (1%)
Miscellaneous: Flu-like syndrome (2%)
<1% (Limited to important or life-threatening): Hematocrit decreased, hemoglobin decreased, hyperkalemia
Note: Angioedema and periorbital edema have been reported with aliskiren. Severe dermatologic reactions and pancreatitis have been reported with hydrochlorothiazide.
CONTRAINDICATIONS — Hypersensitivity to hydrochlorothiazide, thiazides, or sulfonamide-derived drugs; anuria
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Electrolyte disturbances: Hyperkalemia may occur with renin inhibitors; risk factors include renal dysfunction, diabetes mellitus, and concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts. Use cautiously, if at all, with these agents and monitor potassium closely. Thiazide diuretics may cause hypokalemia, hypochloremic alkalosis, hypomagnesemia, and hyponatremia. Hypersensitivity reactions: Hypersensitivity reactions may occur with hydrochlorothiazide. Risk is increased in patients with a history of allergy or bronchial asthma. Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in volume- or salt-depleted patients. Photosensitivity: Due to the hydrochlorothiazide component photosensitization may occur. Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure); deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function. Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns: Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis. Diabetes: Use hydrochlorothiazide with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control. Gout: In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated by hydrochlorothiazide. Hepatic impairment: Use caution in patients with hepatic impairment. Avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy. Hypercholesterolemia: Use with caution in patients with moderate or high cholesterol concentrations; increased cholesterol and triglyceride levels have been reported with thiazides. Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first. Renal artery stenosis: There has been no experience in treating patients with renal artery stenosis; use aliskiren with caution in patients with unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks. Renal impairment: Use with caution in patients with renal impairment; not recommended in patients with severe renal impairment (Clcr <30 mL/minute). Avoid hydrochlorothiazide in severe renal disease (ineffective); may precipitate azotemia; discontinue or consider withholding if renal impairment occurs. Systemic lupus erythematosus (SLE): Hydrochlorothiazide can cause SLE exacerbation or activation.
Concurrent drug therapy: High potential for interactions: use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine); concomitant therapy with cyclosporine is not recommended.
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — See individual agents.
DRUG INTERACTIONS
ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinolol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Analgesics (Opioid): May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Barbiturates: May enhance the orthostatic effect of Thiazide Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification
Calcitriol: Thiazide Diuretics may enhance the hypercalcemic effect of Calcitriol. Risk C: Monitor therapy
Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — See individual agents.
LACTATION — Excretion in breast milk unknown/not recommended
BREAST-FEEDING CONSIDERATIONS — See individual agents.
DIETARY CONSIDERATIONS — Take with or without meals; a high-fat meal reduces aliskiren absorption substantially.
PRICING — (data from drugstore.com)
Tablets (Tekturna HCT)
300-25 mg (30): $102.72
MONITORING PARAMETERS — Blood pressure; serum electrolytes, BUN, serum creatinine; fluid status
MECHANISM OF ACTION — Aliskiren is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Hydrochlorothiazide inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water as well as potassium and hydrogen ions.
PHARMACODYNAMICS / KINETICS — See individual agents.
Aliskiren
MEDICATION SAFETY ISSUES
International issues:
Aliskiren may be confused with Aliseum which is a brand name for diazepam in Italy
U.S. BRAND NAMES — Tekturna®
PHARMACOLOGIC CATEGORY
Renin Inhibitor
DOSING: ADULTS — Hypertension: Initial: 150 mg once daily; may increase to 300 mg once daily (maximum: 300 mg/day). Note: Prior to initiation, correct hypovolemia and/or closely monitor volume status in patients on concurrent diuretics during treatment initiation.
DOSING: PEDIATRIC — Children <18 years: Dosage not established.
DOSING: ELDERLY — Refer to adult dosing. No initial dosage adjustment required.
DOSING: RENAL IMPAIRMENT
Mild-to-moderate impairment [GFR >30 mL/minute and/or Scr <1.7 mg/dL (women); Scr <2 mg/dL (men)]: No dose adjustment required
Severe impairment [GFR<30>1.7 mg/dL (women); Scr >2 mg/dL (men)]: Use caution; not studied in severe renal impairment
DOSING: HEPATIC IMPAIRMENT — No dosage adjustment required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna®: 150 mg, 300 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna®: 150 mg, 300 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer at the same time daily; may take with or without a meal, but consistent administration with regards to meals is recommended. Avoid taking with high-fat meals.
USE — Treatment of hypertension, alone or in combination with other antihypertensive agents
USE - UNLABELED / INVESTIGATIONAL — Treatment of persistent proteinuria in patients with type 2 diabetes mellitus, hypertension, and nephropathy despite administration of optimized recommended renoprotective therapy (eg, angiotensin II receptor blocker)
ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (2%)
Dermatologic: Rash (1%)
Endocrine & metabolic: Hyperkalemia (monotherapy ≤ 1%; concurrent with ACE inhibitor in patients with diabetes 6%)
Gastrointestinal: Diarrhea (1% to 2%)
Hematologic: Creatine kinase increased (>300%: 1%)
Renal: BUN increased (≤ 7%), serum creatinine increased (≤ 7%)
Respiratory: Cough (1%)
<1% (Limited to important or life-threatening): Abdominal pain, anemia, angina, angioedema, dyspepsia, gastroesophageal reflux, gout, hypotension (severe), myositis, renal stone formation, rhabdomyolysis, seizure, uric acid increased
CONTRAINDICATIONS
U.S. labeling: There are no contraindications listed in manufacturer's labeling.
Canada labeling: Hypersensitivity to aliskiren or any component of the formulation
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Hyperkalemia: May occur (rarely) during monotherapy; risk may increase in patients with predisposing factors (eg, renal dysfunction, diabetes mellitus or concomitant use with ACE inhibitors, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts). Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in patients with an activated renin-angiotensin system (ie, volume or salt-depleted patients)
Disease-related concerns: Renal impairment: Use with caution in patients with severe renal impairment; not studied in patients with severe renal impairment [GFR <30>1.7 mg/dL (women); Scr >2 mg/dL (men)], history of dialysis, nephrotic syndrome, or renovascular hypertension. Use with caution or avoid in patients with deteriorating renal function or renal artery stenosis (bilateral or unilateral).
Concurrent drug therapy issues: High potential for interactions: Use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine).
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (minor)
DRUG INTERACTIONS
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: High-fat meals decrease absorption.
PREGNANCY RISK FACTOR — C (show table) (1st trimester); D (2nd and 3rd trimesters)
PREGNANCY IMPLICATIONS — Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken with or without food; however, a high-fat meal reduces absorption
PRICING — (data from drugstore.com)
Tablets (Tekturna)
150 mg (30): $82.38
300 mg (30): $101.80
MONITORING PARAMETERS — Blood pressure; serum potassium, BUN, serum creatinine
CANADIAN BRAND NAMES — Rasilez®
INTERNATIONAL BRAND NAMES — Enviage (EE); Rasilez (BE, CH, CZ, DE, DK, EE, GB, ID, IE, IL, NO, PE, PH, SE); Tekturna (EE)
MECHANISM OF ACTION — Aliskerin is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Ang II also functions within the Renin-Angiotensin-Aldosterone System (RAAS) as a negative inhibitory feedback mediator within the renal parenchyma to suppress the further release of renin. Thus, reductions in Ang II levels suppress this feedback loop, leading to further increased plasma renin concentrations (PRC) and subsequent activity (PRA). This disinhibition effect can be potentially problematic for ACE inhibitor and ARB therapy, as increased PRA could partially overcome the pharmacologic inhibition of the RAAS. As aliskiren is a direct inhibitor of renin activity, blunting of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous. The effect of aliskiren on bradykinin levels is unknown.
PHARMACODYNAMICS / KINETICS
Onset of action: Maximum antihypertensive effect: Within 2 weeks
Absorption: Poor; absorption decreased by high-fat meal. Aliskiren is a substrate of P-glycoprotein; concurrent use of P-glycoprotein inhibitors may increase absorption.
Metabolism: Extent of metabolism unknown; in vitro studies indicate metabolism via CYP3A4
Bioavailability: ~3%
Half-life elimination: ~24 hours (range: 16-32 hours)
Time to peak, plasma: 1-3 hours
Excretion: Urine (~25% of absorbed dose excreted unchanged in urine); feces (unchanged via biliary excretion)
International issues:
Aliskiren may be confused with Aliseum which is a brand name for diazepam in Italy
U.S. BRAND NAMES — Tekturna®
PHARMACOLOGIC CATEGORY
Renin Inhibitor
DOSING: ADULTS — Hypertension: Initial: 150 mg once daily; may increase to 300 mg once daily (maximum: 300 mg/day). Note: Prior to initiation, correct hypovolemia and/or closely monitor volume status in patients on concurrent diuretics during treatment initiation.
DOSING: PEDIATRIC — Children <18 years: Dosage not established.
DOSING: ELDERLY — Refer to adult dosing. No initial dosage adjustment required.
DOSING: RENAL IMPAIRMENT
Mild-to-moderate impairment [GFR >30 mL/minute and/or Scr <1.7 mg/dL (women); Scr <2 mg/dL (men)]: No dose adjustment required
Severe impairment [GFR<30>1.7 mg/dL (women); Scr >2 mg/dL (men)]: Use caution; not studied in severe renal impairment
DOSING: HEPATIC IMPAIRMENT — No dosage adjustment required.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Tekturna®: 150 mg, 300 mg
DOSAGE FORMS: CONCISE
Tablet:
Tekturna®: 150 mg, 300 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Administer at the same time daily; may take with or without a meal, but consistent administration with regards to meals is recommended. Avoid taking with high-fat meals.
USE — Treatment of hypertension, alone or in combination with other antihypertensive agents
USE - UNLABELED / INVESTIGATIONAL — Treatment of persistent proteinuria in patients with type 2 diabetes mellitus, hypertension, and nephropathy despite administration of optimized recommended renoprotective therapy (eg, angiotensin II receptor blocker)
ADVERSE REACTIONS SIGNIFICANT
1% to 10%:
Central nervous system: Dizziness (2%)
Dermatologic: Rash (1%)
Endocrine & metabolic: Hyperkalemia (monotherapy ≤ 1%; concurrent with ACE inhibitor in patients with diabetes 6%)
Gastrointestinal: Diarrhea (1% to 2%)
Hematologic: Creatine kinase increased (>300%: 1%)
Renal: BUN increased (≤ 7%), serum creatinine increased (≤ 7%)
Respiratory: Cough (1%)
<1% (Limited to important or life-threatening): Abdominal pain, anemia, angina, angioedema, dyspepsia, gastroesophageal reflux, gout, hypotension (severe), myositis, renal stone formation, rhabdomyolysis, seizure, uric acid increased
CONTRAINDICATIONS
U.S. labeling: There are no contraindications listed in manufacturer's labeling.
Canada labeling: Hypersensitivity to aliskiren or any component of the formulation
WARNINGS / PRECAUTIONS
Boxed warnings: Pregnancy: See "Special populations" below.
Concerns related to adverse effects: Angioedema: Since the effect of aliskiren on bradykinin levels is unknown, the risk of kinin-mediated etiologies of angioedema occurring is also unknown. Use caution in any patient with a history of angioedema (of any etiology) as angioedema has been observed (rarely) with aliskiren use. Discontinue immediately following any signs and symptoms of angioedema. Prolonged frequent monitoring may be required especially if tongue, glottis, or larynx are involved as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Aggressive early and appropriate management is critical. Hyperkalemia: May occur (rarely) during monotherapy; risk may increase in patients with predisposing factors (eg, renal dysfunction, diabetes mellitus or concomitant use with ACE inhibitors, potassium-sparing diuretics, potassium supplements, and/or potassium-containing salts). Hypotension: During the initiation of therapy, symptomatic hypotension may occur (rarely), particularly in patients with an activated renin-angiotensin system (ie, volume or salt-depleted patients)
Disease-related concerns: Renal impairment: Use with caution in patients with severe renal impairment; not studied in patients with severe renal impairment [GFR <30>1.7 mg/dL (women); Scr >2 mg/dL (men)], history of dialysis, nephrotic syndrome, or renovascular hypertension. Use with caution or avoid in patients with deteriorating renal function or renal artery stenosis (bilateral or unilateral).
Concurrent drug therapy issues: High potential for interactions: Use caution in patients taking strong inhibitors of P-glycoprotein (eg, cyclosporine).
Special populations: Pediatrics: Safety and efficacy have not been established in children. Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
METABOLISM / TRANSPORT EFFECTS — Substrate of CYP3A4 (minor)
DRUG INTERACTIONS
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Atorvastatin: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Aliskiren. Risk X: Avoid combination
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Furosemide: Aliskiren may decrease the serum concentration of Furosemide. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Ketoconazole: May increase the serum concentration of Aliskiren. Risk C: Monitor therapy
MAO Inhibitors: May enhance the hypotensive effect of Antihypertensives. MAO Inhibitors may enhance the orthostatic effect of Antihypertensives. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
ETHANOL / NUTRITION / HERB INTERACTIONS — Food: High-fat meals decrease absorption.
PREGNANCY RISK FACTOR — C (show table) (1st trimester); D (2nd and 3rd trimesters)
PREGNANCY IMPLICATIONS — Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Aliskiren should be discontinued as soon as possible once pregnancy is detected.
LACTATION — Excretion in breast milk unknown/not recommended
DIETARY CONSIDERATIONS — May be taken with or without food; however, a high-fat meal reduces absorption
PRICING — (data from drugstore.com)
Tablets (Tekturna)
150 mg (30): $82.38
300 mg (30): $101.80
MONITORING PARAMETERS — Blood pressure; serum potassium, BUN, serum creatinine
CANADIAN BRAND NAMES — Rasilez®
INTERNATIONAL BRAND NAMES — Enviage (EE); Rasilez (BE, CH, CZ, DE, DK, EE, GB, ID, IE, IL, NO, PE, PH, SE); Tekturna (EE)
MECHANISM OF ACTION — Aliskerin is a direct renin inhibitor, resulting in blockade of the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II (Ang II), a potent blood pressure-elevating peptide (via direct vasoconstriction, aldosterone release, and sodium retention). Ang II also functions within the Renin-Angiotensin-Aldosterone System (RAAS) as a negative inhibitory feedback mediator within the renal parenchyma to suppress the further release of renin. Thus, reductions in Ang II levels suppress this feedback loop, leading to further increased plasma renin concentrations (PRC) and subsequent activity (PRA). This disinhibition effect can be potentially problematic for ACE inhibitor and ARB therapy, as increased PRA could partially overcome the pharmacologic inhibition of the RAAS. As aliskiren is a direct inhibitor of renin activity, blunting of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous. The effect of aliskiren on bradykinin levels is unknown.
PHARMACODYNAMICS / KINETICS
Onset of action: Maximum antihypertensive effect: Within 2 weeks
Absorption: Poor; absorption decreased by high-fat meal. Aliskiren is a substrate of P-glycoprotein; concurrent use of P-glycoprotein inhibitors may increase absorption.
Metabolism: Extent of metabolism unknown; in vitro studies indicate metabolism via CYP3A4
Bioavailability: ~3%
Half-life elimination: ~24 hours (range: 16-32 hours)
Time to peak, plasma: 1-3 hours
Excretion: Urine (~25% of absorbed dose excreted unchanged in urine); feces (unchanged via biliary excretion)
Alglucosidase alfa
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alglucosidase alfa may be confused with agalsidase alfa, agalsidase beta, alglucerase
SPECIAL ALERTS
Myozyme® Shortage - January 2009
Inventory levels of Myozyme® (alglucosidase alfa) are low because of increased global demand. Increased production is planned once regulatory agencies throughout the world approve a larger scale manufacturing process. In the U.S., the Food and Drug Administration (FDA) is expected to respond by the end of February. In the meantime, recommended guidelines have been developed to help with clinical decisions during this temporary period of supply constraint. Pediatric dosing regimens will be maintained. However, to continue providing therapy to adult patients, adult regimens will be adjusted by increasing the dosing interval. Children with newly-diagnosed disease may begin therapy, but no new adults will be enrolled in the Myozyme® Temporary Access Program (MTAP). Any physician who feels their patient is in urgent need of therapy may contact Genzyme Medical Information at (800) 745-4447, option 2.
Additional information may be found at:
http://www.myozyme.com/pdf/MTAP_Supply_Update_January%202009.pdf
http://www.myozyme.com/MTAP/mtap_pt.asp
U.S. BRAND NAMES — Myozyme®
PHARMACOLOGIC CATEGORY
Enzyme
DOSING: PEDIATRIC — Replacement therapy for Pompe disease (infantile onset): Children 1 month to 3.5 years (at first infusion): I.V.: 20 mg/kg over ~4 hours every 2 weeks
(For additional information see "Alglucosidase alfa: Pediatric drug information")
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg [contains mannitol 210 mg; polysorbate 80; derived from Chinese hamster ovary cells]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Infuse over ~4 hours; initiate at 1 mg/kg/hour. If tolerated, increase by 2 mg/kg/hour every 30 minutes to a maximum rate of 7 mg/kg/hour. Decrease rate or temporarily hold for infusion reactions. Infuse through a low protein-binding, 0.2 micron in-line filter.
COMPATIBILITY — Stable in NS; do not infuse with other products.
USE — Replacement therapy for Pompe disease (infantile onset)
ADVERSE REACTIONS SIGNIFICANT
>20%:
Cardiovascular: Tachycardia (23%), bradycardia (21%), flushing (21%)
Central nervous system: Fever (92%), pain (postprocedural: 26%)
Dermatologic: Rash (54%), diaper dermatitis (36%), urticaria (21%)
Gastrointestinal: Diarrhea (62%), vomiting (49%), gastroenteritis (41%), oral candidiasis (31%), gastroesophageal reflux (26%), constipation (23%)
Hematologic: Anemia (31%)
Local: Catheter-related infections (28%)
Otic: Otitis media (33% to 44%)
Respiratory: Cough (46%), pneumonia (46%), upper respiratory tract infection (44%), oxygen saturation decreased (41%), pharyngitis (36%), respiratory distress (33%), respiratory failure (31%), rhinorrhea (28%), bronchiolitis (23%), nasopharyngitis (23%), tachypnea (23%)
Miscellaneous: Antibodies to alglucosidase alfa (89%; may affect efficacy), infusion reaction (51%)
Frequency not reported and/or case reports: Abdominal pain, agitation, anaphylactic reactions, bronchospasm, cardiac arrest, cardiorespiratory failure, chest discomfort/pain, conjunctivitis, cyanosis, erythema, face edema, facial erythema, fatigue, fluid overload, headache, hyperhidrosis, hypersensitivity, hyper-/hypotension, irritability, lacrimation increased, livedo reticularis, malaise, muscle spasm, nausea, pallor, periorbital edema, peripheral edema, pruritus, respiratory syncytial virus infection, restlessness, retching, rhinitis, rigors, skin lesions (ulcerative/necrotizing), tremor, wheezing
CONTRAINDICATIONS — There are no contraindications listed in the manufacturer's labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Anaphylaxis/hypersensitivity reactions: See "Concerns related to adverse effects" below. Cardiovascular disease: See "Disease-related concerns" below. Respiratory disease: See "Disease-related concerns" below.
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: [U.S. Boxed Warning]: Severe hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported during and within 3 hours after infusion. Immediate medical support should be readily available. Immune-mediated reactions: Severe immune-mediated reactions (eg, ulcerative and necrotizing skin lesions, type-III immune complex-mediated reactions, inflammatory arthropathy) have occurred up to 3 years after initiation of therapy; monitor for development. Infusion reactions: Infusion-related reactions are common; discontinue immediately for severe hypersensitivity or anaphylactic reaction; mild-to-moderate reactions may be managed by reducing the infusion rate and/or administering antihistamines and/or antipyretics. Appropriate medical support for the management of infusion reactions should be readily available. Use caution with subsequent infusions; infusion reactions have occurred despite premedication with antihistamines, antipyretics, and/or steroids. Patients with acute underlying illness are at greater risk for infusion reactions, including cardiorespiratory failure.
Disease-related concerns: Cardiovascular disease: [U.S. Boxed Warning]: Use with caution in patients with compromised cardiac function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted. Cardiorespiratory failure has been observed in patients with cardiac hypertrophy up to 72 hours after infusion; arrhythmias have also been observed in patients with cardiac hypertrophy. Pompe disease: Safety and efficacy have not been established in juvenile-onset and adult-onset Pompe disease. Patients with Pompe disease are at increased risk for infusion-related cardiorespiratory failure (possibly due to fluid overload); monitor closely during infusion. Respiratory disease: [U.S. Boxed Warning]: Use with caution in patients with compromised respiratory function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted.
Other warnings/precautions: Registry: A registry has been created to monitor therapeutic responses and adverse effects during long-term treatment; patients should be encouraged to register (www.pomperegistry.com or 1-800-745-4447).
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Animal studies have not demonstrated teratogenicity or fertility impairment. There are no adequate and well-controlled studies in pregnant women. A registry has been established for Pompe patients; women of childbearing potential are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447).
LACTATION — Excretion in breast milk unknown/use caution
BREAST-FEEDING CONSIDERATIONS — A registry has been established for Pompe patients; women who are nursing are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447)
MONITORING PARAMETERS — Liver enzymes (baseline and periodically; elevation may be due to disease process); vital signs during and following infusion; volume overload
The manufacturer recommends monitoring for IgG antibody formation every 3 months. No commercial tests are available; however, sampling kits can be obtained by contacting Genzyme Corporation at 1-800-745-4447.
INTERNATIONAL BRAND NAMES — Myozyme (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, IE, IL, IT, NL, NO, PT, RU, SE, TR, TW)
MECHANISM OF ACTION — Alglucosidase alfa is a recombinant form of the enzyme acid alpha-glucosidase (GAA), which is required for glycogen cleavage. Due to an inherited GAA deficiency, glycogen accumulates in the tissues of patients with Pompe disease, leading to progressive muscle weakness. In infantile-onset Pompe disease, glycogen accumulates in cardiac and skeletal muscles and hepatic tissue, leading to cardiomyopathy and respiratory failure. Juvenile- and adult-onset Pompe disease are limited to glycogen accumulation in skeletal muscle, leading to respiratory failure. Alglucosidase alfa binds to mannose-6-phosphate receptors on the cell surface, becomes internalized and transported to lysosomes resulting in increased enzymatic activity and glycogen cleavage.
PHARMACODYNAMICS / KINETICS
Distribution: Vss: 80-147 mL/kg
Half-life elimination: 2-3 hours
Sound-alike/look-alike issues:
Alglucosidase alfa may be confused with agalsidase alfa, agalsidase beta, alglucerase
SPECIAL ALERTS
Myozyme® Shortage - January 2009
Inventory levels of Myozyme® (alglucosidase alfa) are low because of increased global demand. Increased production is planned once regulatory agencies throughout the world approve a larger scale manufacturing process. In the U.S., the Food and Drug Administration (FDA) is expected to respond by the end of February. In the meantime, recommended guidelines have been developed to help with clinical decisions during this temporary period of supply constraint. Pediatric dosing regimens will be maintained. However, to continue providing therapy to adult patients, adult regimens will be adjusted by increasing the dosing interval. Children with newly-diagnosed disease may begin therapy, but no new adults will be enrolled in the Myozyme® Temporary Access Program (MTAP). Any physician who feels their patient is in urgent need of therapy may contact Genzyme Medical Information at (800) 745-4447, option 2.
Additional information may be found at:
http://www.myozyme.com/pdf/MTAP_Supply_Update_January%202009.pdf
http://www.myozyme.com/MTAP/mtap_pt.asp
U.S. BRAND NAMES — Myozyme®
PHARMACOLOGIC CATEGORY
Enzyme
DOSING: PEDIATRIC — Replacement therapy for Pompe disease (infantile onset): Children 1 month to 3.5 years (at first infusion): I.V.: 20 mg/kg over ~4 hours every 2 weeks
(For additional information see "Alglucosidase alfa: Pediatric drug information")
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg [contains mannitol 210 mg; polysorbate 80; derived from Chinese hamster ovary cells]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Infuse over ~4 hours; initiate at 1 mg/kg/hour. If tolerated, increase by 2 mg/kg/hour every 30 minutes to a maximum rate of 7 mg/kg/hour. Decrease rate or temporarily hold for infusion reactions. Infuse through a low protein-binding, 0.2 micron in-line filter.
COMPATIBILITY — Stable in NS; do not infuse with other products.
USE — Replacement therapy for Pompe disease (infantile onset)
ADVERSE REACTIONS SIGNIFICANT
>20%:
Cardiovascular: Tachycardia (23%), bradycardia (21%), flushing (21%)
Central nervous system: Fever (92%), pain (postprocedural: 26%)
Dermatologic: Rash (54%), diaper dermatitis (36%), urticaria (21%)
Gastrointestinal: Diarrhea (62%), vomiting (49%), gastroenteritis (41%), oral candidiasis (31%), gastroesophageal reflux (26%), constipation (23%)
Hematologic: Anemia (31%)
Local: Catheter-related infections (28%)
Otic: Otitis media (33% to 44%)
Respiratory: Cough (46%), pneumonia (46%), upper respiratory tract infection (44%), oxygen saturation decreased (41%), pharyngitis (36%), respiratory distress (33%), respiratory failure (31%), rhinorrhea (28%), bronchiolitis (23%), nasopharyngitis (23%), tachypnea (23%)
Miscellaneous: Antibodies to alglucosidase alfa (89%; may affect efficacy), infusion reaction (51%)
Frequency not reported and/or case reports: Abdominal pain, agitation, anaphylactic reactions, bronchospasm, cardiac arrest, cardiorespiratory failure, chest discomfort/pain, conjunctivitis, cyanosis, erythema, face edema, facial erythema, fatigue, fluid overload, headache, hyperhidrosis, hypersensitivity, hyper-/hypotension, irritability, lacrimation increased, livedo reticularis, malaise, muscle spasm, nausea, pallor, periorbital edema, peripheral edema, pruritus, respiratory syncytial virus infection, restlessness, retching, rhinitis, rigors, skin lesions (ulcerative/necrotizing), tremor, wheezing
CONTRAINDICATIONS — There are no contraindications listed in the manufacturer's labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Anaphylaxis/hypersensitivity reactions: See "Concerns related to adverse effects" below. Cardiovascular disease: See "Disease-related concerns" below. Respiratory disease: See "Disease-related concerns" below.
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: [U.S. Boxed Warning]: Severe hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported during and within 3 hours after infusion. Immediate medical support should be readily available. Immune-mediated reactions: Severe immune-mediated reactions (eg, ulcerative and necrotizing skin lesions, type-III immune complex-mediated reactions, inflammatory arthropathy) have occurred up to 3 years after initiation of therapy; monitor for development. Infusion reactions: Infusion-related reactions are common; discontinue immediately for severe hypersensitivity or anaphylactic reaction; mild-to-moderate reactions may be managed by reducing the infusion rate and/or administering antihistamines and/or antipyretics. Appropriate medical support for the management of infusion reactions should be readily available. Use caution with subsequent infusions; infusion reactions have occurred despite premedication with antihistamines, antipyretics, and/or steroids. Patients with acute underlying illness are at greater risk for infusion reactions, including cardiorespiratory failure.
Disease-related concerns: Cardiovascular disease: [U.S. Boxed Warning]: Use with caution in patients with compromised cardiac function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted. Cardiorespiratory failure has been observed in patients with cardiac hypertrophy up to 72 hours after infusion; arrhythmias have also been observed in patients with cardiac hypertrophy. Pompe disease: Safety and efficacy have not been established in juvenile-onset and adult-onset Pompe disease. Patients with Pompe disease are at increased risk for infusion-related cardiorespiratory failure (possibly due to fluid overload); monitor closely during infusion. Respiratory disease: [U.S. Boxed Warning]: Use with caution in patients with compromised respiratory function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted.
Other warnings/precautions: Registry: A registry has been created to monitor therapeutic responses and adverse effects during long-term treatment; patients should be encouraged to register (www.pomperegistry.com or 1-800-745-4447).
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Animal studies have not demonstrated teratogenicity or fertility impairment. There are no adequate and well-controlled studies in pregnant women. A registry has been established for Pompe patients; women of childbearing potential are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447).
LACTATION — Excretion in breast milk unknown/use caution
BREAST-FEEDING CONSIDERATIONS — A registry has been established for Pompe patients; women who are nursing are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447)
MONITORING PARAMETERS — Liver enzymes (baseline and periodically; elevation may be due to disease process); vital signs during and following infusion; volume overload
The manufacturer recommends monitoring for IgG antibody formation every 3 months. No commercial tests are available; however, sampling kits can be obtained by contacting Genzyme Corporation at 1-800-745-4447.
INTERNATIONAL BRAND NAMES — Myozyme (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, IE, IL, IT, NL, NO, PT, RU, SE, TR, TW)
MECHANISM OF ACTION — Alglucosidase alfa is a recombinant form of the enzyme acid alpha-glucosidase (GAA), which is required for glycogen cleavage. Due to an inherited GAA deficiency, glycogen accumulates in the tissues of patients with Pompe disease, leading to progressive muscle weakness. In infantile-onset Pompe disease, glycogen accumulates in cardiac and skeletal muscles and hepatic tissue, leading to cardiomyopathy and respiratory failure. Juvenile- and adult-onset Pompe disease are limited to glycogen accumulation in skeletal muscle, leading to respiratory failure. Alglucosidase alfa binds to mannose-6-phosphate receptors on the cell surface, becomes internalized and transported to lysosomes resulting in increased enzymatic activity and glycogen cleavage.
PHARMACODYNAMICS / KINETICS
Distribution: Vss: 80-147 mL/kg
Half-life elimination: 2-3 hours
Alglucosidase alfa
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alglucosidase alfa may be confused with agalsidase alfa, agalsidase beta, alglucerase
SPECIAL ALERTS
Myozyme® Shortage - January 2009
Inventory levels of Myozyme® (alglucosidase alfa) are low because of increased global demand. Increased production is planned once regulatory agencies throughout the world approve a larger scale manufacturing process. In the U.S., the Food and Drug Administration (FDA) is expected to respond by the end of February. In the meantime, recommended guidelines have been developed to help with clinical decisions during this temporary period of supply constraint. Pediatric dosing regimens will be maintained. However, to continue providing therapy to adult patients, adult regimens will be adjusted by increasing the dosing interval. Children with newly-diagnosed disease may begin therapy, but no new adults will be enrolled in the Myozyme® Temporary Access Program (MTAP). Any physician who feels their patient is in urgent need of therapy may contact Genzyme Medical Information at (800) 745-4447, option 2.
Additional information may be found at:
http://www.myozyme.com/pdf/MTAP_Supply_Update_January%202009.pdf
http://www.myozyme.com/MTAP/mtap_pt.asp
U.S. BRAND NAMES — Myozyme®
PHARMACOLOGIC CATEGORY
Enzyme
DOSING: PEDIATRIC — Replacement therapy for Pompe disease (infantile onset): Children 1 month to 3.5 years (at first infusion): I.V.: 20 mg/kg over ~4 hours every 2 weeks
(For additional information see "Alglucosidase alfa: Pediatric drug information")
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg [contains mannitol 210 mg; polysorbate 80; derived from Chinese hamster ovary cells]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Infuse over ~4 hours; initiate at 1 mg/kg/hour. If tolerated, increase by 2 mg/kg/hour every 30 minutes to a maximum rate of 7 mg/kg/hour. Decrease rate or temporarily hold for infusion reactions. Infuse through a low protein-binding, 0.2 micron in-line filter.
COMPATIBILITY — Stable in NS; do not infuse with other products.
USE — Replacement therapy for Pompe disease (infantile onset)
ADVERSE REACTIONS SIGNIFICANT
>20%:
Cardiovascular: Tachycardia (23%), bradycardia (21%), flushing (21%)
Central nervous system: Fever (92%), pain (postprocedural: 26%)
Dermatologic: Rash (54%), diaper dermatitis (36%), urticaria (21%)
Gastrointestinal: Diarrhea (62%), vomiting (49%), gastroenteritis (41%), oral candidiasis (31%), gastroesophageal reflux (26%), constipation (23%)
Hematologic: Anemia (31%)
Local: Catheter-related infections (28%)
Otic: Otitis media (33% to 44%)
Respiratory: Cough (46%), pneumonia (46%), upper respiratory tract infection (44%), oxygen saturation decreased (41%), pharyngitis (36%), respiratory distress (33%), respiratory failure (31%), rhinorrhea (28%), bronchiolitis (23%), nasopharyngitis (23%), tachypnea (23%)
Miscellaneous: Antibodies to alglucosidase alfa (89%; may affect efficacy), infusion reaction (51%)
Frequency not reported and/or case reports: Abdominal pain, agitation, anaphylactic reactions, bronchospasm, cardiac arrest, cardiorespiratory failure, chest discomfort/pain, conjunctivitis, cyanosis, erythema, face edema, facial erythema, fatigue, fluid overload, headache, hyperhidrosis, hypersensitivity, hyper-/hypotension, irritability, lacrimation increased, livedo reticularis, malaise, muscle spasm, nausea, pallor, periorbital edema, peripheral edema, pruritus, respiratory syncytial virus infection, restlessness, retching, rhinitis, rigors, skin lesions (ulcerative/necrotizing), tremor, wheezing
CONTRAINDICATIONS — There are no contraindications listed in the manufacturer's labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Anaphylaxis/hypersensitivity reactions: See "Concerns related to adverse effects" below. Cardiovascular disease: See "Disease-related concerns" below. Respiratory disease: See "Disease-related concerns" below.
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: [U.S. Boxed Warning]: Severe hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported during and within 3 hours after infusion. Immediate medical support should be readily available. Immune-mediated reactions: Severe immune-mediated reactions (eg, ulcerative and necrotizing skin lesions, type-III immune complex-mediated reactions, inflammatory arthropathy) have occurred up to 3 years after initiation of therapy; monitor for development. Infusion reactions: Infusion-related reactions are common; discontinue immediately for severe hypersensitivity or anaphylactic reaction; mild-to-moderate reactions may be managed by reducing the infusion rate and/or administering antihistamines and/or antipyretics. Appropriate medical support for the management of infusion reactions should be readily available. Use caution with subsequent infusions; infusion reactions have occurred despite premedication with antihistamines, antipyretics, and/or steroids. Patients with acute underlying illness are at greater risk for infusion reactions, including cardiorespiratory failure.
Disease-related concerns: Cardiovascular disease: [U.S. Boxed Warning]: Use with caution in patients with compromised cardiac function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted. Cardiorespiratory failure has been observed in patients with cardiac hypertrophy up to 72 hours after infusion; arrhythmias have also been observed in patients with cardiac hypertrophy. Pompe disease: Safety and efficacy have not been established in juvenile-onset and adult-onset Pompe disease. Patients with Pompe disease are at increased risk for infusion-related cardiorespiratory failure (possibly due to fluid overload); monitor closely during infusion. Respiratory disease: [U.S. Boxed Warning]: Use with caution in patients with compromised respiratory function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted.
Other warnings/precautions: Registry: A registry has been created to monitor therapeutic responses and adverse effects during long-term treatment; patients should be encouraged to register (www.pomperegistry.com or 1-800-745-4447).
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Animal studies have not demonstrated teratogenicity or fertility impairment. There are no adequate and well-controlled studies in pregnant women. A registry has been established for Pompe patients; women of childbearing potential are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447).
LACTATION — Excretion in breast milk unknown/use caution
BREAST-FEEDING CONSIDERATIONS — A registry has been established for Pompe patients; women who are nursing are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447)
MONITORING PARAMETERS — Liver enzymes (baseline and periodically; elevation may be due to disease process); vital signs during and following infusion; volume overload
The manufacturer recommends monitoring for IgG antibody formation every 3 months. No commercial tests are available; however, sampling kits can be obtained by contacting Genzyme Corporation at 1-800-745-4447.
INTERNATIONAL BRAND NAMES — Myozyme (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, IE, IL, IT, NL, NO, PT, RU, SE, TR, TW)
MECHANISM OF ACTION — Alglucosidase alfa is a recombinant form of the enzyme acid alpha-glucosidase (GAA), which is required for glycogen cleavage. Due to an inherited GAA deficiency, glycogen accumulates in the tissues of patients with Pompe disease, leading to progressive muscle weakness. In infantile-onset Pompe disease, glycogen accumulates in cardiac and skeletal muscles and hepatic tissue, leading to cardiomyopathy and respiratory failure. Juvenile- and adult-onset Pompe disease are limited to glycogen accumulation in skeletal muscle, leading to respiratory failure. Alglucosidase alfa binds to mannose-6-phosphate receptors on the cell surface, becomes internalized and transported to lysosomes resulting in increased enzymatic activity and glycogen cleavage.
PHARMACODYNAMICS / KINETICS
Distribution: Vss: 80-147 mL/kg
Half-life elimination: 2-3 hours
Sound-alike/look-alike issues:
Alglucosidase alfa may be confused with agalsidase alfa, agalsidase beta, alglucerase
SPECIAL ALERTS
Myozyme® Shortage - January 2009
Inventory levels of Myozyme® (alglucosidase alfa) are low because of increased global demand. Increased production is planned once regulatory agencies throughout the world approve a larger scale manufacturing process. In the U.S., the Food and Drug Administration (FDA) is expected to respond by the end of February. In the meantime, recommended guidelines have been developed to help with clinical decisions during this temporary period of supply constraint. Pediatric dosing regimens will be maintained. However, to continue providing therapy to adult patients, adult regimens will be adjusted by increasing the dosing interval. Children with newly-diagnosed disease may begin therapy, but no new adults will be enrolled in the Myozyme® Temporary Access Program (MTAP). Any physician who feels their patient is in urgent need of therapy may contact Genzyme Medical Information at (800) 745-4447, option 2.
Additional information may be found at:
http://www.myozyme.com/pdf/MTAP_Supply_Update_January%202009.pdf
http://www.myozyme.com/MTAP/mtap_pt.asp
U.S. BRAND NAMES — Myozyme®
PHARMACOLOGIC CATEGORY
Enzyme
DOSING: PEDIATRIC — Replacement therapy for Pompe disease (infantile onset): Children 1 month to 3.5 years (at first infusion): I.V.: 20 mg/kg over ~4 hours every 2 weeks
(For additional information see "Alglucosidase alfa: Pediatric drug information")
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg [contains mannitol 210 mg; polysorbate 80; derived from Chinese hamster ovary cells]
DOSAGE FORMS: CONCISE
Injection, powder for reconstitution [preservative free]:
Myozyme®: 50 mg
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — Infuse over ~4 hours; initiate at 1 mg/kg/hour. If tolerated, increase by 2 mg/kg/hour every 30 minutes to a maximum rate of 7 mg/kg/hour. Decrease rate or temporarily hold for infusion reactions. Infuse through a low protein-binding, 0.2 micron in-line filter.
COMPATIBILITY — Stable in NS; do not infuse with other products.
USE — Replacement therapy for Pompe disease (infantile onset)
ADVERSE REACTIONS SIGNIFICANT
>20%:
Cardiovascular: Tachycardia (23%), bradycardia (21%), flushing (21%)
Central nervous system: Fever (92%), pain (postprocedural: 26%)
Dermatologic: Rash (54%), diaper dermatitis (36%), urticaria (21%)
Gastrointestinal: Diarrhea (62%), vomiting (49%), gastroenteritis (41%), oral candidiasis (31%), gastroesophageal reflux (26%), constipation (23%)
Hematologic: Anemia (31%)
Local: Catheter-related infections (28%)
Otic: Otitis media (33% to 44%)
Respiratory: Cough (46%), pneumonia (46%), upper respiratory tract infection (44%), oxygen saturation decreased (41%), pharyngitis (36%), respiratory distress (33%), respiratory failure (31%), rhinorrhea (28%), bronchiolitis (23%), nasopharyngitis (23%), tachypnea (23%)
Miscellaneous: Antibodies to alglucosidase alfa (89%; may affect efficacy), infusion reaction (51%)
Frequency not reported and/or case reports: Abdominal pain, agitation, anaphylactic reactions, bronchospasm, cardiac arrest, cardiorespiratory failure, chest discomfort/pain, conjunctivitis, cyanosis, erythema, face edema, facial erythema, fatigue, fluid overload, headache, hyperhidrosis, hypersensitivity, hyper-/hypotension, irritability, lacrimation increased, livedo reticularis, malaise, muscle spasm, nausea, pallor, periorbital edema, peripheral edema, pruritus, respiratory syncytial virus infection, restlessness, retching, rhinitis, rigors, skin lesions (ulcerative/necrotizing), tremor, wheezing
CONTRAINDICATIONS — There are no contraindications listed in the manufacturer's labeling.
WARNINGS / PRECAUTIONS
Boxed warnings: Anaphylaxis/hypersensitivity reactions: See "Concerns related to adverse effects" below. Cardiovascular disease: See "Disease-related concerns" below. Respiratory disease: See "Disease-related concerns" below.
Concerns related to adverse effects: Anaphylaxis/hypersensitivity reactions: [U.S. Boxed Warning]: Severe hypersensitivity reactions, including anaphylactic reactions and anaphylactic shock have been reported during and within 3 hours after infusion. Immediate medical support should be readily available. Immune-mediated reactions: Severe immune-mediated reactions (eg, ulcerative and necrotizing skin lesions, type-III immune complex-mediated reactions, inflammatory arthropathy) have occurred up to 3 years after initiation of therapy; monitor for development. Infusion reactions: Infusion-related reactions are common; discontinue immediately for severe hypersensitivity or anaphylactic reaction; mild-to-moderate reactions may be managed by reducing the infusion rate and/or administering antihistamines and/or antipyretics. Appropriate medical support for the management of infusion reactions should be readily available. Use caution with subsequent infusions; infusion reactions have occurred despite premedication with antihistamines, antipyretics, and/or steroids. Patients with acute underlying illness are at greater risk for infusion reactions, including cardiorespiratory failure.
Disease-related concerns: Cardiovascular disease: [U.S. Boxed Warning]: Use with caution in patients with compromised cardiac function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted. Cardiorespiratory failure has been observed in patients with cardiac hypertrophy up to 72 hours after infusion; arrhythmias have also been observed in patients with cardiac hypertrophy. Pompe disease: Safety and efficacy have not been established in juvenile-onset and adult-onset Pompe disease. Patients with Pompe disease are at increased risk for infusion-related cardiorespiratory failure (possibly due to fluid overload); monitor closely during infusion. Respiratory disease: [U.S. Boxed Warning]: Use with caution in patients with compromised respiratory function; risk of acute cardiorespiratory failure secondary to infusion-related reactions may be increased. Additional monitoring is warranted.
Other warnings/precautions: Registry: A registry has been created to monitor therapeutic responses and adverse effects during long-term treatment; patients should be encouraged to register (www.pomperegistry.com or 1-800-745-4447).
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — B (show table)
PREGNANCY IMPLICATIONS — Animal studies have not demonstrated teratogenicity or fertility impairment. There are no adequate and well-controlled studies in pregnant women. A registry has been established for Pompe patients; women of childbearing potential are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447).
LACTATION — Excretion in breast milk unknown/use caution
BREAST-FEEDING CONSIDERATIONS — A registry has been established for Pompe patients; women who are nursing are encouraged to enroll in the registry (www.pomperegistry.com or 1-800-745-4447)
MONITORING PARAMETERS — Liver enzymes (baseline and periodically; elevation may be due to disease process); vital signs during and following infusion; volume overload
The manufacturer recommends monitoring for IgG antibody formation every 3 months. No commercial tests are available; however, sampling kits can be obtained by contacting Genzyme Corporation at 1-800-745-4447.
INTERNATIONAL BRAND NAMES — Myozyme (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, IE, IL, IT, NL, NO, PT, RU, SE, TR, TW)
MECHANISM OF ACTION — Alglucosidase alfa is a recombinant form of the enzyme acid alpha-glucosidase (GAA), which is required for glycogen cleavage. Due to an inherited GAA deficiency, glycogen accumulates in the tissues of patients with Pompe disease, leading to progressive muscle weakness. In infantile-onset Pompe disease, glycogen accumulates in cardiac and skeletal muscles and hepatic tissue, leading to cardiomyopathy and respiratory failure. Juvenile- and adult-onset Pompe disease are limited to glycogen accumulation in skeletal muscle, leading to respiratory failure. Alglucosidase alfa binds to mannose-6-phosphate receptors on the cell surface, becomes internalized and transported to lysosomes resulting in increased enzymatic activity and glycogen cleavage.
PHARMACODYNAMICS / KINETICS
Distribution: Vss: 80-147 mL/kg
Half-life elimination: 2-3 hours
Alglucerase (glucocerebrosidase)
MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alglucerase may be confused with agalsidase alfa, agalsidase beta, alglucosidase alfa
Ceredase® may be confused with Cerezyme®
U.S. BRAND NAMES — Ceredase®
PHARMACOLOGIC CATEGORY
Enzyme
DOSING: ADULTS — Gaucher's disease: I.V.: Initial: 30-60 units/kg every 2 weeks; dosing is individualized based on disease severity; average dose: 60 units/kg every 2 weeks. Range: 2.5 units/kg 3 times/week to 60 units/kg once weekly to every 4 weeks. Once patient response is well established, dose may be reduced every 3-6 months to determine maintenance therapy.
DOSING: PEDIATRIC — Refer to adult dosing.
(For additional information see "Alglucerase (glucocerebrosidase): Pediatric drug information")
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL) [contains human albumin 1%]
DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — I.V.: Infuse I.V. over 1-2 hours. Use of an in-line filter is recommended. Do not shake solution as it denatures the enzyme.
COMPATIBILITY — Stable in NS; do not mix with any other additives.
USE — Replacement therapy for Gaucher's disease (type 1)
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Peripheral edema
Central nervous system: Chills, fatigue, fever, headache, lightheadedness
Endocrine & metabolic: Hot flashes, menstrual abnormalities
Gastrointestinal: Abdominal discomfort, diarrhea, nausea, oral ulcerations, vomiting
Local: Injection site: Abscess, burning, discomfort, pruritus, swelling
Neuromuscular & skeletal: Backache, weakness
Miscellaneous: Dysosmia; hypersensitivity reactions (abdominal cramping, angioedema, chest discomfort, flushing, hypotension, nausea, pruritus, respiratory symptoms, urticaria); IgG antibody formation (~13%)
CONTRAINDICATIONS — Hypersensitivity to any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypersensitivity reactions: Patients who develop IgG antibodies may be at a higher risk for developing hypersensitivity. Use with caution in patients with prior allergies to hCG.
Disease-related concerns: Androgen-sensitive malignancies: Use with caution in patients with androgen-sensitive malignancies.
Special populations: Pediatrics: Safety and efficacy have not been established in children <2 years of age (limited experience). May cause early virilization in males <10 years of age.
Dosage form specific issues: Placental tissue: Prepared from pooled human placental tissue that may contain the causative agents of some viral diseases.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Animal studies have not been conducted.
LACTATION — Excretion in breast milk unknown/use caution
MONITORING PARAMETERS — CBC, platelets, liver function tests, IgG antibody formation, acid phosphatase (AP); MRI or CT of liver and spleen, skeletal x-rays, physical exam every 6-12 months
INTERNATIONAL BRAND NAMES — Ceredase (DE, ES, GB, NL)
MECHANISM OF ACTION — Alglucerase is a modified form of glucocerebrosidase; it is prepared from human placental tissue. Glucocerebrosidase is an enzyme deficient in Gaucher's disease. It is needed to catalyze the hydrolysis of glucocerebroside to glucose and ceramide.
PHARMACODYNAMICS / KINETICS — Half-life elimination: ~3-11 minutes
Sound-alike/look-alike issues:
Alglucerase may be confused with agalsidase alfa, agalsidase beta, alglucosidase alfa
Ceredase® may be confused with Cerezyme®
U.S. BRAND NAMES — Ceredase®
PHARMACOLOGIC CATEGORY
Enzyme
DOSING: ADULTS — Gaucher's disease: I.V.: Initial: 30-60 units/kg every 2 weeks; dosing is individualized based on disease severity; average dose: 60 units/kg every 2 weeks. Range: 2.5 units/kg 3 times/week to 60 units/kg once weekly to every 4 weeks. Once patient response is well established, dose may be reduced every 3-6 months to determine maintenance therapy.
DOSING: PEDIATRIC — Refer to adult dosing.
(For additional information see "Alglucerase (glucocerebrosidase): Pediatric drug information")
DOSING: ELDERLY — Refer to adult dosing.
DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL) [contains human albumin 1%]
DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL)
GENERIC EQUIVALENT AVAILABLE — No
ADMINISTRATION — I.V.: Infuse I.V. over 1-2 hours. Use of an in-line filter is recommended. Do not shake solution as it denatures the enzyme.
COMPATIBILITY — Stable in NS; do not mix with any other additives.
USE — Replacement therapy for Gaucher's disease (type 1)
ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.
Cardiovascular: Peripheral edema
Central nervous system: Chills, fatigue, fever, headache, lightheadedness
Endocrine & metabolic: Hot flashes, menstrual abnormalities
Gastrointestinal: Abdominal discomfort, diarrhea, nausea, oral ulcerations, vomiting
Local: Injection site: Abscess, burning, discomfort, pruritus, swelling
Neuromuscular & skeletal: Backache, weakness
Miscellaneous: Dysosmia; hypersensitivity reactions (abdominal cramping, angioedema, chest discomfort, flushing, hypotension, nausea, pruritus, respiratory symptoms, urticaria); IgG antibody formation (~13%)
CONTRAINDICATIONS — Hypersensitivity to any component of the formulation
WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypersensitivity reactions: Patients who develop IgG antibodies may be at a higher risk for developing hypersensitivity. Use with caution in patients with prior allergies to hCG.
Disease-related concerns: Androgen-sensitive malignancies: Use with caution in patients with androgen-sensitive malignancies.
Special populations: Pediatrics: Safety and efficacy have not been established in children <2 years of age (limited experience). May cause early virilization in males <10 years of age.
Dosage form specific issues: Placental tissue: Prepared from pooled human placental tissue that may contain the causative agents of some viral diseases.
DRUG INTERACTIONS — There are no known significant interactions.
PREGNANCY RISK FACTOR — C (show table)
PREGNANCY IMPLICATIONS — Animal studies have not been conducted.
LACTATION — Excretion in breast milk unknown/use caution
MONITORING PARAMETERS — CBC, platelets, liver function tests, IgG antibody formation, acid phosphatase (AP); MRI or CT of liver and spleen, skeletal x-rays, physical exam every 6-12 months
INTERNATIONAL BRAND NAMES — Ceredase (DE, ES, GB, NL)
MECHANISM OF ACTION — Alglucerase is a modified form of glucocerebrosidase; it is prepared from human placental tissue. Glucocerebrosidase is an enzyme deficient in Gaucher's disease. It is needed to catalyze the hydrolysis of glucocerebroside to glucose and ceramide.
PHARMACODYNAMICS / KINETICS — Half-life elimination: ~3-11 minutes
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