Amlodipine and Valsartan: Package Insert and Label Information (Page 2 of 4)
6.2 Postmarketing Experience
The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Amlodipine
Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Valsartan
The following additional adverse reactions have been reported in postmarketing experience with valsartan:
Hypersensitivity:
Angiodema has been reported. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Diovan should not be re-administered to patients who have had angioedema.
Digestive:
Elevated liver enzymes and reports of hepatitis
Musculoskeletal :
Rhabdomyolysis
Renal:
Impaired renal function, renal failure
Dermatologic:
Alopecia, bullous dermatitis
Blood and Lymphatic:
Thrombocytopenia
Vascular:
Vasculitis
7 DRUG INTERACTIONS
No drug interaction studies have been conducted with amlodipine and valsartan tablets and other drugs, although studies have been conducted with the individual amlodipine and valsartan components.
Amlodipine
Impact of Other Drugs on Amlodipine
CYP3A Inhibitors :
Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].
CYP3A Inducers :
No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. (e.g. rifampicin, St. John’s Wort).
Sildenafil :
Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)].
Impact of Amlodipine on Other Drugs
Simvastatin:
Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3)].
Immunosuppressants:
Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3)].
Valsartan
Agents Increasing Serum Potassium:
Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.
Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS):
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on valsartan and other agents that affect the RAS.
Do not coadminister aliskiren with amlodipine and valsartan in patients with diabetes. Avoid use of aliskiren with amlodipine and valsartan in patients with renal impairment (GFR <60 mL/min).
Lithium:
Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Amlodipine and valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan (see Clinical Considerations).
When pregnancy is detected, discontinue amlodipine and valsartan as soon as possible.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease- Associated Maternal and/or Embryo/Fetal risk:
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal Adverse Reactions:
Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death.
Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to amlodipine and valsartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to amlodipine and valsartan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function.
Data
Animal Data:
In rats, administered 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. This corresponds to dose multiples of 9 and 19.5 times, respectively, the maximum recommended human dose (MRHD) of 10 mg/day for amlodipine and 320 mg/day for valsartan (based on body surface area and considering a 60 kg patient).
8.2 Lactation
There is limited information regarding the presence of amlodipine and valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. Valsartan is present in rat milk. Limited published studies report that amlodipine is present in human milk. Because of the potential for serious adverse reactions in breastfed infants, advise a nursing woman that breastfeeding is not recommended during treatment with amlodipine and valsartan tablets.
Data
Valsartan was detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose.
8.4 Pediatric Use
Safety and effectiveness of amlodipine and valsartan tablets in pediatric patients have not been established.
8.5 Geriatric Use
In controlled clinical trials, 323 (22.5%) hypertensive patients treated with amlodipine and valsartan tablets were ≥65 years and 79 (5.5%) were ≥75 years. No overall differences in the efficacy or safety of amlodipine and valsartan tablets were observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
Amlodipine
The recommended starting dose of amlodipine 2.5 mg is not an available strength with amlodipine and valsartan tablets.
Clinical studies of amlodipine besylate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of area under the curve (AUC) of approximately 40% to 60%.
Valsartan
In the controlled clinical trials of valsartan, 1214 (36.2%) of hypertensive patients treated with valsartan were ≥65 years and 265 (7.9%) were ≥75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Renal Impairment
Safety and effectiveness of amlodipine and valsartan tablets in patients with severe renal impairment (CrCl< 30 mL/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment.
8.7 Hepatic Impairment
Exposure to amlodipine is increased in patients with hepatic insufficiency [see Clinical Pharmacology (12.3)]. The recommended initial dose of amlodipine in patients with hepatic impairment is 2.5 mg, which is not an available strength with amlodipine and valsartan tablets.
Valsartan
No dose adjustment is necessary for patients with mild-to-moderate disease. No dosing recommendations can be provided for patients with severe liver disease.
10 OVERDOSAGE
Single oral doses of amlodipine maleate equivalent to 40 mg/kg and 100 mg/kg amlodipine in mice and rats, respectively, caused deaths. Single oral doses equivalent to 4 or more mg/kg amlodipine in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension. In humans, experience with intentional overdosage of amlodipine is limited. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
Valsartan
Limited data are available related to overdosage in humans. The most likely effect of overdose with valsartan would be peripheral vasodilation, hypotension, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse, and shock have been reported. If symptomatic hypotension should occur institute supportive treatment.
Valsartan is not removed from the plasma by hemodialysis.
Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets, except for the salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose (60 and 37 times, respectively, the (MRHD) on a mg/m2 basis). (Calculations assume an oral dose of 320 mg/day and a 60 kg patient.)
11 DESCRIPTION
Amlodipine and valsartan tablet USP is a fixed combination of amlodipine and valsartan.
Amlodipine and valsartan tablets USP contain the besylate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate’s chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate; its structural formula is
Its empirical formula is C20 H25 ClN2 O5 •C6 H6 O3 S and its molecular weight is 567.1.
Valsartan is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is a white to practically white fine powder, soluble in ethanol and methanol and slightly soluble in water. Valsartan’s chemical name is N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine; its structural formula is
Its empirical formula is C24 H29 N5 O3 and its molecular weight is 435.5.
Amlodipine and valsartan tablets USP are formulated in 4 strengths for oral administration with a combination of amlodipine besylate (6.9 mg or 13.9 mg, equivalent to 5 mg or 10 mg of amlodipine respectively), with 160 mg, or 320 mg of valsartan providing for the following available combinations: 5/160 mg, 10/160 mg, 5/320 mg, and 10/320 mg.
The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, croscarmellose sodium, crospovidone, magnesium stearate and microcrystalline cellulose. The film coating contains hypromellose, polyethylene glycol, iron oxide yellow and titanium dioxide. Additionally, the 5/160 mg and 5/320 mg strengths contain iron oxide red.
Amlodipine and valsartan tablets USP meets USP Dissolution Test 2.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Valsartan
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
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