Sdamlo

Description for Sdamlo

Sdamlo contains the besylate salt of amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C₂₀H₂₅CIN₂O₅•C₆H₆O₃S, and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol.

Sdamlo is supplied as a white to off-white powder or powder cake packaged in a unit-dose, single-use container. Each vial of Sdamlo contains 2.5, 5, and 10 mg of amlodipine, provided as 3.47, 6.94, and 13.88 mg of amlodipine besylate, respectively, and the following inactive ingredients: mannitol and neotame.

Sdamlo is for oral administration after reconstitution with water [see Dosage and Administration (2.3)].

ADVERSE REACTIONS

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows:

	Amlodipine			Placebo
	2.5 mg	5 mg	10 mg
	N=275	N=296	N=268	N=520
Edema	1.8	3.0	10.8	0.6
Dizziness	1.1	3.4	3.4	1.5
Flushing	0.7	1.4	2.6	0.0
Palpitation	0.7	1.4	4.5	0.6

Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

	Amlodipine (%) (N=1730)	Placebo (%) (N=1250)
Fatigue	4.5	2.8
Nausea	2.9	1.9
Abdominal Pain	1.6	0.3
Somnolence	1.4	0.6

For several adverse reactions, there was a greater incidence in women than men associated with amlodipine treatment as show in the following table:

	Amlodipine		Placebo
	Male=% (N=1218)	Female=% (N=512)	Male=% (N=914)	Female=% (N=336)
Edema	5.6	14.6	1.4	5.1
Flushing	1.5	4.5	0.3	0.9
Palpitations	1.4	3.3	0.9	0.9
Somnolence	1.3	1.6	0.8	0.3

The safety of amlodipine at doses of 2.5 mg and 5 mg once daily was evaluated in a randomized placebo-controlled trial in 268 pediatric patients aged 6 to 17 years with hypertension [see Clinical Studies (14.1)]. Adverse reactions were similar to those in adults.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of amlodipine. 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.

General: gynecomastia.

Hepatic: jaundice and hepatic enzyme elevations, some require hospitalization.

Neurologic: extrapyramidal disorder.

Drug Interactions for Sdamlo

Impact of Other Drugs on Amlodipine

CYP3A Inhibitors
Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].

CYP3A Inducers
No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

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)].

Warnings for Sdamlo

Included as part of the PRECAUTIONS section.

Precautions for Sdamlo

Hypotension

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

Increased Angina or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Sdamlo, particularly in patients with severe obstructive coronary artery disease.

Patients with Hepatic Failure

Because amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, titrate slowly when administering Sdamlo to patients with severe hepatic impairment.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m² basis, similar to the maximum recommended human dose of 10 mg amlodipine/day.² For the rat, the highest dose was, on a mg/m² basis, about twice the maximum recommended human dose based on a patient weight of 50 kg.

Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose² of 10 mg/day on a mg/m² basis).

OVERDOSAGE

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m² basis) caused a marked peripheral vasodilation and hypotension.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Contraindications for Sdamlo

Sdamlo is contraindicated in patients with known sensitivity to amlodipine.

Clinical Pharmacology for Sdamlo

Mechanism of Action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-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.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina: amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.

Pharmacodynamics

Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Electrophysiologic Effects: amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Drug Interactions

Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect [see Drug Interactions (7.1)].

Pharmacokinetics

Absorption

After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%.

Effect of Food
Compared to fasted state administration, standard high-fat, high-calorie breakfast did not have an effect on the absorption of Sdamlo.

Distribution

Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients.

Elimination

Metabolism
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Excretion
Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Specific Populations

Pediatric Patients
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Renal Impairment
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

Hepatic Impairment
Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40–60%, and a lower initial dose may be required.

Drug Interactions

In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Impact of other drugs on amlodipine

Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to amlodipine.

CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure.

However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7.1)].

Impact of amlodipine on other drugs

Amlodipine is a weak inhibitor of CYP3A and may increase exposure to CYP3A substrates.

Co-administered amlodipine does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.

Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone [see Drug Interactions (7.2)].

Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with amlodipine [see Drug Interactions (7.2)].

Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with amlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6).

However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 nonexpresser) upon initiation of amlodipine for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs [see Drug Interactions (7.2)].

INSTRUCTIONS FOR USE
SDAMLO (s-DAM-loh)
(amlodipine)
for oral solution

This Instructions for Use contains information on how to take or give SDAMLO.

Important Information You Need to Know Before Taking or Giving SDAMLO:

• Read this Instructions for Use before taking or giving SDAMLO.
• For oral use only (take by mouth).
• SDAMLO comes as a powder that you must mix with water to make a liquid (solution) before taking or giving it.
• The SDAMLO carton contains an aluminum pouch and a tray of 10 sealed bottles of SDAMLO.
• Do not open the pouch until you are ready to start taking or giving SDAMLO.
• Do not use SDAMLO if the bottle seal is broken or missing.
• Do not remove the bottle seal until you are ready to mix SDAMLO.
• Take or give mixed SDAMLO right away. Throw away SDAMLO if you do not take or give it within 60 minutes of mixing and get a new bottle.

Supplies needed to take or give SDAMLO:

• Clean, room temperature drinking water
• A measuring cup or spoon to measure 1 tablespoon (15 mL)

Step 1: Preparing to take or give SDAMLO:

• Wash and dry your hands.
• Remove the aluminum pouch from the carton, open the pouch, and remove a bottle from the tray. (see Figure A and Figure B)

  Figure A	Figure B

• Remove the child resistant cap from the bottle. Remove the bottle seal by gently peeling off the seal. Do not remove the seal until you are ready to mix SDAMLO and take or give a dose. (see Figure C and Figure D)
• After the seal is removed, you should mix SDAMLO as soon as possible. Throw away SDAMLO if you do not mix it within 60 minutes once the seal is removed.

  Figure C	Figure D

Step 2: Mixing SDAMLO with water and taking or giving the liquid mixture:

• Add 1 tablespoon (15 mL) of room temperature water into the bottle. (see Figure E)

  Figure E

• Wait for 60 seconds to allow the powder to fully dissolve. You do not need to shake the bottle. (see Figure F)

  Figure F

• After 60 seconds has passed, take or give all of the liquid mixture in the bottle. (see Figure G)

  Figure G

• To make sure that you take or give all of the medicine, rinse the bottle with about the same amount of water 1 to 2 times and take or give all the liquid.

Storing SDAMLO:

• Store SDAMLO at room temperature between 68° F to 77° F (20° C to 25° C).
• Keep SDAMLO in the bottle that it comes in.
• Do not store mixed SDAMLO. Throw away SDAMLO if you do not take or give it within 60 minutes of mixing.

Keep SDAMLO and all medicines away from children.

Disposing of SDAMLO:
Throw away (discard) the empty bottle and any unused or expired SDAMLO in your household trash.

Distributed by:
Brillian Pharma Inc. Edison, NJ 08817
Labeler code 84567-014
Manufactured by:Beijing Sciecure Pharmaceutical Co. Ltd. Beijing, China