Sodium Nitroprusside

Class: Direct Vasodilators
VA Class: CV490
CAS Number: 13755-38-9
Brands: Nitropress

• 
  

  Thoroughly review the package insert before administration.^b

  
  

• Dilution


• 
  

  After reconstitution, sodium nitroprusside is not suitable for direct injection; must be diluted further with 5% dextrose injection before infusion.^b

  
  


• 
  

  Acid-base balance and venous oxygen concentrations should be monitored and may indicate cyanide toxicity; these tests alone should not be relied upon to guide therapy.^b

  
  

• Hypotension


• 
  

  Can produce precipitous decreases in blood pressure; profound hypotension can lead to irreversible ischemic injury or death.^b

  
  


• 
  

  Administer in a setting with equipment and personnel available to continuously monitor blood pressure.^b

  
  

• Cyanide Intoxication


• 
  

  Administration (except when used for short periods of time or at low infusion rates [e.g., ≤2 mcg/kg per minute or slower]) can result in the production of clinically important levels of cyanide ion, which can reach toxic or potentially lethal concentrations.^b

  
  


• 
  

  Infusions at the maximum recommended rate of 10 mcg/kg per minute should never last longer than 10 minutes; if after 10 minutes the blood pressure has not been adequately controlled, the infusion should be immediately discontinued.^b

  
  

Introduction

Vasodilating and hypotensive agent.^{a b 207}

Uses for Sodium Nitroprusside

Hypertensive Crises

For immediate reduction of blood pressure in hypertensive crises (hypertensive emergencies).^{b 204 207} Administer with other longer-acting hypotensive agents to minimize the duration of nitroprusside therapy.^b

Can be used for most hypertensive emergencies (e.g., hypertensive encephalopathy, MI, unstable angina pectoris, pulmonary edema, preeclampsia, stroke, head trauma, life-threatening arterial bleeding, aortic dissection).^{204 207}

May be considered in the treatment of hypertensive emergencies associated with stimulant (e.g., amphetamines, methamphetamines, cocaine, phencyclidine, ephedrine) toxicity.²⁰⁷

Caution if high intracranial pressure or azotemia is present.²⁰⁴

Acute severe hypertension in preeclampsia (e.g., persistent diastolic blood pressures of ≥105–110 mm Hg): Other antihypertensives (e.g., hydralazine) preferred; sodium nitroprusside reserved for treatment failures.²⁰⁴

Ischemic stroke: Clinical trials do not support immediate antihypertensive therapy in these patients.²⁰⁴

Contraindicated in compensatory hypertension (e.g., arteriovenous shunt or coarctation of the aorta).^b (See Contraindications under Cautions.)

Heart Failure and Low-Output Syndromes

Management of acute CHF.^{b 207}

Particularly useful in severe heart failure caused by regurgitant valvular lesions of aortic insufficiency and mitral regurgitation.²⁰⁶

Also particularly useful for afterload reduction to unload the left and subsequently right ventricle when left ventricular dysfunction is accompanied by right ventricular ischemia.^{b 202} Monitoring intra-arterial pressure is useful.²⁰²

Management of low-output syndromes associated with acute MI†; in many cases, other drugs (e.g., nitroglycerin, norepinephrine, dopamine, dobutamine) are preferred.²⁰²

In acute MI complicated by CHF, nitroglycerin is the preferred vasodilator.²⁰²

Not indicated for the treatment of CHF associated with reduced peripheral vascular resistance.^b (See Contraindications under Cautions.)

Controlled Hypotension

Used to produce controlled hypotension to reduce bleeding during surgery.^b

Sodium Nitroprusside Dosage and Administration

Administration

Administer by IV infusion only.^b

Administer in a setting with equipment and personnel available to continuously monitor blood pressure.^b

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion using a controlled-infusion device to allow precise measurement of flow rate.^b

When used for the management of acute severe hypertension in preeclampsia, administer before induction of labor.²⁰⁴

Reconstitution

Dissolve 50 mg of sodium nitroprusside in 2–3 mL of 5% dextrose injection or sterile water for injection (without preservative).^{a HID} Bacteriostatic water for injection should not be used because preservatives increase the rate of nitroprusside decomposition.^a

Alternatively, reconstitute ADD-Vantage vials containing 50 mg according to the manufacturer’s directions.^a

Dilution

Add the initially reconstituted solution or the commercially available solution containing 50 mg to 250, 500, or 1000 mL of 5% dextrose injection to provide solutions containing 200, 100, or 50 mcg/mL, respectively.^{b HID 207}

Protect from light by promptly wrapping the container in aluminum foil or other opaque material;²⁰⁷ it is not necessary to cover the infusion drip chamber or tubing.^b

Rate of Administration

Adjust rate to maintain the desired hypotensive effect, determined by continuous monitoring of blood pressure, using a continually reinflated sphygmomanometer or, preferably, an intra-arterial pressure sensor.^b

When sodium nitroprusside is used in CHF, titrate rate based on results of invasive hemodynamic monitoring and urine output.^b

Dosage

Pediatric Patients

Hypertensive Crises, Heart Failure and Low-output Syndromes, Controlled Hypotension

IV

Initially, 0.3 mcg/kg per minute; gradually titrated upward every few minutes until adequate blood pressure control is achieved or the maximum infusion rate of 10 mcg/kg per minute is reached.^b Usual dosage is 3 mcg/kg (range of 0.1–10 mcg/kg) per minute.^{a 205 207}

Discontinue immediately if adequate reduction in blood pressure is not achieved within 10 minutes in patients receiving the maximum infusion rate of 10 mcg/kg per minute.^b

Adults

Hypertensive Crises, Heart Failure and Low-output Syndromes, Controlled Hypotension

IV

Initially, 0.3 mcg/kg per minute; gradually titrated upward every few minutes until adequate blood pressure control is achieved or the maximum rate of infusion of 10 mcg/kg per minute is reached.^b Usual dosage is 3 mcg/kg (range of 0.1–10 mcg/kg) per minute.^{a 207}

Management of a hypertensive emergency: Goal is to reduce mean arterial blood pressure by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2–6 hours; avoid excessive declines in pressure.²⁰¹ If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24–48 hours.²⁰⁴

Patients with aortic dissection: Goal is to reduce systolic pressure to <100 mm Hg if tolerated.²⁰⁴

Management of acute severe hypertension in preeclampsia: Goal is to reduce diastolic blood pressure to 95–105 mm Hg.²⁰⁴

Discontinue immediately if adequate reduction in blood pressure is not achieved within 10 minutes in patients receiving the maximum infusion rate of 10 mcg/kg per minute.^b

Prescribing Limits

Pediatric Patients

Hypertensive Crises, Heart Failure and Low-output Syndromes, Controlled Hypotension

IV

Maximum 10 mcg/kg per minute.^{b 205 207}

Prolonged infusions should not exceed 3 mcg/kg per minute; monitor thiocyanate concentrations if this rate is exceeded for prolonged periods.^b

Adults

Hypertensive Crises, Heart Failure and Low-output Syndromes, Controlled Hypotension

IV

Maximum 10 mcg/kg per minute.^{b 207}

Prolonged infusions should not exceed 3 mcg/kg per minute; monitor thiocyanate concentrations if this rate is exceeded for prolonged periods.^b

Special Populations

Renal Impairment

Anuric patients: Prolonged infusions should not exceed 1 mcg/kg per minute (to maintain thiocyanate concentrations <60 mcg/mL).^b

Cautions for Sodium Nitroprusside

Contraindications

• 
  

  Treatment of compensatory hypertension (e.g., arteriovenous shunt or coarctation of the aorta).^b

  
  


• 
  

  Controlled hypotension during surgery in patients with inadequate cerebral circulation.^b

  
  


• 
  

  Use during emergency surgery in patients near death.^b

  
  


• 
  

  Congenital (Leber’s) optic atrophy or tobacco amblyopia (associated with absent or deficient thiosulfate sulfurtransferase; patients have unusually high cyanide to thiocyanate ratios).^b (See Cyanide Toxicity under Cautions.)

  
  


• 
  

  Treatment of acute CHF associated with reduced peripheral vascular resistance (e.g., high-output heart failure as seem in endotoxic sepsis).^b

  
  

Warnings/Precautions

Warnings

Excessive Hypotension

Slightly excessive infusion rates can result in profound hypotension; subsequent hemodynamic changes can result in various associated symptoms or blood pressure may decrease to the point where perfusion of vital organs may be compromised.^b

This reaction is self-limiting within 1–10 minutes following discontinuance of the infusion; place patient in Trendelenburg’s position during this time to maximize venous return.^b

If BP does not normalize within a few minutes, sodium nitroprusside may not be the cause of the hypotension and another cause should be sought.^b

May cause hypotension with reflex tachycardia in the presence of hypovolemia. ²⁰⁷

Invasive hemodynamic monitoring may be useful during therapy.²⁰⁷

Cyanide Toxicity

Infusion at rates >2 mcg/kg per minute generate cyanide ion (CN^-) in amounts greater than can be effectively buffered by the methemoglobin normally present in the body.^b

The capacity of the buffering system is exhausted by the CN^- produced by 500 mcg/kg of sodium nitroprusside; this amount is administered in <1 hour when the drug is administered at 10 mcg/kg per minute.^b

The actual frequency of clinically important cyanide toxicity has not been established.^b

The only patients whose deaths have been unequivocally attributed to cyanide toxicity received the drug at rates (e.g., 30–120 mcg/kg per minute) exceeding the recommended maximum rate.^b Elevated cyanide levels, metabolic acidosis, and marked clinical deterioration have been reported in patients receiving sodium nitroprusside at the recommended rates of infusion for only a few hours, and in 1 case, for only 35 minutes.^b

Toxic effects of cyanide may be rapid, serious, and fatal; toxicity may manifest as venous hyperoxemia (secondary to the inability of tissues to extract oxygen from erythrocytes, with resultant bright red venous blood), lactic acidosis, air hunger, confusion, and death.^b

Cyanide may accumulate in patients with hepatic or renal disease or those receiving infusions at rates >3 mcg/kg per minute for >72 hours; monitor for cyanide toxicity (e.g., metabolic acidosis).²⁰⁷

Monitor acid-base balance and venous oxygen concentrations; these tests may indicate cyanide toxicity.^b (See Boxed Warning.)

Hypertensive patients and those receiving other antihypertensive agents may be more sensitive to the effects of sodium nitroprusside than healthy individuals.^b

Sodium thiosulfate has been administered with sodium nitroprusside at infusion rates 5–10 times that of the sodium nitroprusside to accelerate the metabolism of cyanide; coadministration of these agents has not been extensively researched and further study is needed.^b

Caution advised; avoid prolonged or excessive dosages of sodium nitroprusside with sodium thiosulfate, since thiocyanate toxicity and/or hypovolemia may result.^b The same precautions and contraindications apply to this method of administration as to the administration of sodium nitroprusside alone.^b

Major Toxicities

Methemoglobinemia

Administration of sodium nitroprusside can result in the sequestration of hemoglobulin as methemoglobin.^b The conversion of methemoglobin back to hemoglobin is normally rapid; clinically important methemoglobinemia (>10%) occurs rarely.^b

Suspect methemoglobinemia in patients who have received >10 mg/kg and who exhibit signs of impaired oxygen delivery despite adequate cardiac output and arterial PaO₂.^b

Methylene blue 1–2 mg/kg administered IV over several minutes may be used to treat methemoglobinemia; use with extreme caution in patients who are likely to have substantial amounts of cyanide bound to methemoglobin.^b

Thiocyanate Accumulation

Thiocyanate may accumulate in the blood, especially in patients with impaired hepatic or renal function or hyponatremia^{b 207} or in patients receiving sodium nitroprusside infusions at rates >3 mcg/kg per minute for >72 hours or receiving sodium thiosulfate.^{a 207} These patients should be monitored for thiocyanate intoxication (e.g., metabolic acidosis).²⁰⁷

Thiocyanate is mildly neurotoxic at serum concentrations of 60 mcg/mL and may be life-threatening at concentrations of 200 mcg/mL.^b Toxicity is manifested as confusion, hyperreflexia, and seizures.²⁰⁷

General Precautions

Effects on Intracranial Pressure

Sodium nitroprusside can increase intracranial pressure.^b

Use with caution in patients with increased intracranial pressure.^b

Use in Pulmonary Disease

May reverse hypoxic pulmonary vasoconstriction in patients with pulmonary disease (e.g., pneumonia, adult respiratory distress syndrome), which may exacerbate intrapulmonary shunting resulting in worsened hypoxemia.²⁰⁷

Use in Anesthesia

Tolerance to loss of blood, anemia, and hypovolemia may be decreased when used for controlled hypotension during anesthesia.^b

If possible, correct preexisting anemia and hypovolemia prior to use.^b

Use with extreme caution in patients who are especially poor surgical risks.^b

Specific Populations

Pregnancy

Category C.^{b d}

Lactation

Not known whether sodium nitroprusside or its metabolites are distributed into milk; discontinue nursing or the drug.^b

Hepatic Impairment

Caution in patients with hepatic impairment.^b

Cyanide and thiocyanate may accumulate in patients with hepatic disease; monitor for cyanide and thiocyanate toxicity.^{b 207} (See Cyanide Toxicity and also Thiocyanate Accumulation under Cautions.)

Renal Impairment

Caution in patients with severe renal impairment.^a (See Renal Impairment under Dosage and Administration and Thiocyanate Accumulation under Cautions.)

Cyanide and thiocyanate may accumulate in patients with renal disease; monitor for cyanide and thiocyanate toxicity.^{b 207} (See Cyanide Toxicity and also Thiocyanate Accumulation under Cautions.)

Common Adverse Effects

Excessive hypotension, cyanide toxicity.^b

Interactions for Sodium Nitroprusside

The hypotensive effects are additive when used with ganglionic blocking agents, negative inotropic agents, general anesthetics (e.g., halothane, enflurane), and most other circulatory depressants.^a

Sodium Nitroprusside Pharmacokinetics

Absorption

Onset

Immediate reduction in blood pressure.^b

Duration

Blood pressure begins to rise immediately when infusion is slowed or stopped; blood pressure returns to pretreatment levels within 1–10 minutes.^b

Distribution

Extent

Rapidly distributed.^b

Elimination

Metabolism

Sodium nitroprusside is metabolized by combination with hemoglobin to form cyanmethemoglobin and cyanide.^b

Essentially all cyanide in the blood is bound to methemoglobin until intraerythrocytic methemoglobin is saturated.^b

Cyanide is enzymatically converted to thiocyanate by thiosulfate sulfurtransferase (a mitochondrial enzyme).^{b 207} This enzyme normally is present in excess quantities; the rate-limiting step in the conversion to thiocyanate is the availability of sulfur donors (e.g., thiosulfate, cystine, cysteine).^b

Cyanide not otherwise removed binds to cytochromes.^b

Elimination Route

Eliminated principally in urine as thiocyanate.^b Some cyanide is expired as hydrogen cyanide.^b

Half-life

Sodium nitroprusside: Circulation half-life: 2 minutes.^b

Thiocyanate: 3 days.^b

Special Populations

Half-life of thiocyanate is increased in patients with renal failure.^b

Stability

Storage

Parenteral

Injection

15–30°C; protect from light by storing in the carton.^b

If properly protected from light, reconstituted solutions and solutions for infusion are stable for 24 hours.^b

Sodium nitroprusside solution can be inactivated by reactions with trace contaminants; products of these reactions are often blue, green, or red and are much brighter than the very faint brownish tint of freshly prepared unreacted sodium nitroprusside solutions.^b Discard discolored solutions or solutions with visible particulate matter.^b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

The manufacturer states that no other drug should be admixed in the sodium nitroprusside solution.^b

Parenteral

Solution Compatibility^HID

Compatible
Ringer’s injection, lactated (when protected from light)
Variable
Dextrose 4% in sodium chloride 0.18% (compatible when protected from light)
Dextrose 5% in water (compatible when protected from light)
Sodium chloride 0.9% (compatible when protected from light)

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Alcohol 10% in dextrose 5%
Alprostadil
Atracurium besylate
Bivalirudin
Calcium chloride
Dexmedetomidine HCl
Diltiazem HCl
Dopamine HCl
Dopamine HCl with dobutamine HCl
Dopamine HCl with lidocaine HCl
Dopamine HCl with nitroglycerin
Enalaprilat
Epinephrine HCl
Esmolol HCl
Famotidine
Furosemide
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Inamrinone lactate
Indomethacin sodium trihydrate
Isoproterenol HCl
Labetalol HCl
Lidocaine HCl
Lidocaine HCl with dobutamine HCl
Lidocaine HCl with dopamine HCl
Lidocaine HCl with nitroglycerin
Magnesium sulfate
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nicardipine HCl
Nitroglycerin
Nitroglycerin with dobutamine HCl
Nitroglycerin with dopamine HCl
Nitroglycerin with lidocaine HCl
Norepinephrine bitrate
Pancuronium bromide
Potassium chloride
Potassium phosphates
Procainamide HCl
Propofol
Tacrolimus
Theophylline
Vecuronium bromide
Incompatible
Drotrecogin alfa (activated)
Levofloxacin
Variable
Amiodarone HCl
Dobutamine HCl
Haloperidol lactate
Propafenone

ActionsActions

• 
  

  The hypotensive action results from peripheral vasodilation caused by a direct action on vascular smooth muscle.^b

  
  


• 
  

  Direct vasodilation causes decreases in right and left ventricular filling (preload) resulting in relief of pulmonary congestion and reduced left ventricular volume and pressure.^{b 207} Arteriolar relaxation causes decreases in peripheral arterial resistance (afterload) resulting in enhanced systolic emptying with reduced left ventricular volume and wall stress and reduced myocardial oxygen consumption.^{b 207}

  
  


• 
  

  No direct effect on the myocardium,^a but may exert a direct coronary vasodilator effect.^b

  
  


• 
  

  Induces renal vasodilation generally proportional to decreases in systemic blood pressure with no appreciable changes in renal blood flow or glomerular filtration rate.^b

  
  

Advice to Patients

• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^b

  
  


• 
  

  Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.^b

  
  


• 
  

  Importance of informing patients of other important precautionary information.^b (See Cautions).

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Sodium Nitroprusside

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, concentrate, for IV infusion only	25 mg/mL*	Nitropress	Hospira
			Sodium Nitroprusside Injection
	For injection, for IV infusion only	50 mg	Nitropress ADD-Vantage	Hospira

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

200. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83. [IDIS 309043] [PubMed 8422206]

201. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

202. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). From and .

203. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (). (Also published in JAMA. 2003; 289.

204. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Complete Version. Bethesda, MD: 2003 Nov 5. Hypertension. 2003; 42:1206-52. [PubMed 14656957]

205. National high blood pressure education program working group on hypertension control in children and adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004; 114(Suppl 2):555-76.

206. The American Heart Association in Collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2000; 102(Suppl I): I-133.

207. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1493-1501.

a. AHFS drug information 2007. McEvoy GK, ed. Sodium Nitroprusside. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1743-6.

b. Abbott Laboratories. Nitropress (Sodium Nitroprusside) injection prescribing information. North Chicago, Il; 2000 Jan.

d. Nitroprusside. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002:1008.

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Beechams Decongestant Plus With Paracetamol

1. Name Of The Medicinal Product

Beechams Decongestant Plus with Paracetamol

2. Qualitative And Quantitative Composition

Active Constituents	mg / Capsule
Paracetamol	300.00
Caffeine	25.00
Phenylephrine Hydrochloride	5.00

3. Pharmaceutical Form

Capsule

4. Clinical Particulars

4.1 Therapeutic Indications

Symptomatic relief of symptoms of influenza, feverishness, chills and colds including feverish colds.

The symptomatic relief of nasal congestion and difficult breathing arising from this, sinusitis and its associated pain, acute nasal catarrh.

4.2 Posology And Method Of Administration

Recommended Dose and Dosage Schedule

Adults (including elderly) and children aged 12 years and over:

2 capsules every 4 to 6 hours as required, but no more than 12 capsules in any 24 hours.

Do not take continuously for more than 7 days without medical advice

Children under 12 years of age

Not to be given under the age of 12

4.3 Contraindications

Concomitant use of other sympathomimetic decongestants

Phaeochromocytoma

Closed angle glaucoma

Known hypersensitivity to paracetamol or any of the other ingredients. Hepatic or severe renal impairment, hypertension, hyperthyroidism, diabetes, and heart disease.

Patients taking tricyclic antidepressants, or beta blocking drugs and those who are taking or who have taken within the last two weeks monoamine oxidase inhibitors (see section 4.5).

4.4 Special Warnings And Precautions For Use

Medical advice should be sought before using this product in patients with these conditions:

An enlargement of the prostate gland

Occlusive vascular disease (e.g. Raynaud's phenomenon)

Cardiovascular disease

This product should not be used by patients taking other sympathomimetics (such as decongestants, appetite suppressants and amphetamine-like psychostimulants) (see interactions).

Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product.

Keep out of the reach and sight of children

Contains Paracetamol

Do not exceed the stated dose

If symptoms persist consult your doctor

If you are under the care of your doctor or receiving prescribed medicines consult your doctor before taking this product.

Do not take other flu, cold or decongestant medicines or other paracetamol-containing medicines, with this product.

Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Special Label Warnings

Do not take with any other paracetamol-containing products. Do not take with other flu, cold or decongestant products.

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Special Leaflet Warnings

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Enzyme-inducing drugs may increase hepatic damage, as does excessive intake of alcohol. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. These interactions are considered to be of unlikely clinical significance in acute usage at the dosage regimen proposed.

Medical advice should be sought before taking paracetamol-caffeine phenylephrine in combination with the following drugs:

Monoamine oxidase inhibitors (including moclobemide)	Hypertensive interactions occur between sympathomimetic amines such as phenylephrine and monoamine Oxidase inhibitors (see contraindications).
Sympathomimetic amines	Concomitant use of phenylephrine with other sympathomimetics amines can increase the risk of cardiovascular side effects (see warnings and precautions).
Beta-blockers and other antihypertensives (including debrisoquine, guanethidine, reserpine, methyldopa)	Phenylephrine may reduce the efficacy of beta-blocking drugs and antihypertensive drugs. The risk of hypertension and other cardiovascular side effects may be increased (see contraindications).
Tricyclic antidepressants (eg amitriptyline)	May increase the risk of cardiovascular side effects with phenylephrine (see contraindications).
Digoxin and cardiac glycosides	Concimitant use of phenylephrine with digoxin or cardiac glycosides may increase the ris of irregular heartbeat or heart attack.
Ergot alkaloids	(ergotamine and methylsergide) increased risk of ergotism
Warfarin and other coumarins	The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with an increased risk of bleeding; occasional doses have no significant effect.

4.6 Pregnancy And Lactation

This product is not recommended for use in pregnancy due to the phenylephrine and caffeine content. There is a potential increased risk of lower birth weight and spontaneous abortion associated with caffeine consumption during pregnancy.

This product should not be used while breast-feeding without medical advice.

Caffeine in breast milk may have a stimulating effect on breast-fed infants.

Phenylephrine may be excreted in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness.

4.8 Undesirable Effects

Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class. The frequency of these adverse events is not known (cannot be estimated from available data).

Paracetamol

Body System	Undesirable effect
Blood and lymphatic system disorders	Thrombocytopenia Agranulocytosis These are not necessarily causally related to paracetamol.
Immune system disorders	Anaphylaxis Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens Johnson syndrome, toxic epidermal necrolysis
Respiratory, thoracic and mediastinal disorders	Bromchospasm*
Hepatobiliary disorders	Hepatic dysfunction

* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Caffeine

Adverse reactions identified through post-marketing use with caffeine are listed below. The frequency of these reactions is unknown.

Central Nervous system

Nervousness and anxiety Irritability, Restlessness and Excitability Dizziness

When the recommended paracetamol-caffeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.

Phenylephrine

The following adverse events have been observed in clinical trials with phenylephrine and may therefore represent the most commonly occurring adverse events.

Body System	Undesirable effect
Psychiatric disorders	Nervousness
Nervous system disorders	Headache, dizziness, insomnia
Cardiac disorders	Increased blood pressure
Gastrointestinal disorders	Nausea, vomiting, diarrhoea

Adverse reactions identified during post-marketing use are listed below. The frequency of these reactions is unknown.

Eye disorders	Mydriasis, acute angle closure glaucoma, most likely to occur in those with closed angle glaucoma
Cardiac disorders	Tachycardia, palpitations
Skin and subcutaneous disorders	Allergic reactions (e.g. rash, urticaria, allergic dermatitis). Hypersensitivity reactions – including that cross-sensitivity may occur with other sympathomimetics
Renal and urinary disorders	Dysuria, urinary retention. This is most likely to occur in those with bladder outlet obstruction, such as prostatic hypertrophy.

4.9 Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors:

If the patient

a, Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

b, Regularly consumes ethanol in excess of recommended amounts.

Or

c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms:

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management:

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Caffeine

Symptoms and signs

Overdose of caffeine may result in epigastric pain, vomiting, diurese, tachycardia or cardiac arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors and convulsions).

It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.

Treatment

No specific antidote is available, but supportive measures may be used.

Phenylephrine

Symptoms and signs

Phenylephrine overdosage is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include hypertension, and possibly reflex bradycardia. In severe cases confusion, hallucinations, seizures and arrhythmias may occur. However the amount required to produce serious phenylephrine toxicity would be greater than that required to cause paracetamol-related liver toxicity.

Treatment

Treatment should be as clinically appropriate. Severe hypertension may need to be treated with alpha blocking drugs such as phentolamine.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol: An analgesic and antipyretic.

Caffeine: A mild stimulant

Phenylephrine hydrochloride:A sympathomimetic decongestant.

The active ingredients are not known to cause sedation.

5.2 Pharmacokinetic Properties

Paracetamol: is readily absorbed from the gastrointestinal tract. It is metabolised in the liver and excreted in the urine, mainly as glucoronide and sulphate conjugates.

Caffeine: is absorbed readily after oral administration, maximal plasma concentrations are achieved within one hour and the plasma half-life is about 3.5 hours. 65-80% of administered caffeine is excreted in the urine as 1-methyluric acid and 1-methylxanthine.

Phenylephrine Hydrochloride: is irregularly absorbed from the gastrointestinal tract and undergoes first-pass metabolism by monoamine oxidase in the gut and liver; orally administered phenylephrine thus has reduced bioavailability. It is excreted in the urine almost entirely as the sulphate conjugate.

5.3 Preclinical Safety Data

Pre-clinical safety data on these active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use of the product and which have not already been mentioned elsewhere in this Summary.

The toxicity of paracetamol has been extensively studied in numerous animal species. Pre-clinical studies in rats and mice have indicated single dose oral LD₅₀ values of 3.7 g/kg and 338 mg/kg, respectively. Chronic toxicity in these species at large multiples of the human therapeutic dose, occurs as degeneration and necrosis of hepatic, renal and lymphoid tissue, and blood count changes. The metabolites believed responsible for these effects have also been demonstrated in man. Paracetamol should not, therefore, be taken for long periods of time, and in excessive doses. At normal therapeutic doses, paracetamol is not associated with genotoxic or carcinogenic risk. There is no evidence of embryo-or foetus-toxicity from paracetamol in animal studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Colloidal silica

Dimeticone

Shell capsule (G dye/100g capsule part)

Amaranth (E123)

Erthyrosine (E127)

Sunset yellow (E110)

Titanium dioxide (E171)

Gelatin

Shell body (G dye/100G capsule part)

Gelatin

Titanium dioxide (E171)

6.2 Incompatibilities

None known

6.3 Shelf Life

Five years

6.4 Special Precautions For Storage

None stated

6.5 Nature And Contents Of Container

Opaque blisters of polyvinyl chloride (PVC)/polyvinylidene chloride (PVdC) backed with aluminium foil. Ten or 16 capsules are blistered and packed into boxboard cartons.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Beecham Group Plc

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

Trading as: GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8. Marketing Authorisation Number(S)

PL 00079/0205

9. Date Of First Authorisation/Renewal Of The Authorisation

1.7.82 / 1.7.97

10. Date Of Revision Of The Text

May 2010.

Amantadine Hydrochloride

Class: Adamantanes
VA Class: AM800
CAS Number: 665-66-7
Brands: Symmetrel

Introduction

Antiviral;¹ antiparkinsonian agent;¹ adamantane derivative.¹

Uses for Amantadine Hydrochloride

Treatment of Seasonal Influenza A Virus Infections

Symptomatic treatment of uncomplicated respiratory tract illness caused by susceptible influenza A virus in adults, adolescents, and children ≥1 year of age.¹

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.^{116 137 149} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,^{116 144} and emergence of amantadine-resistant influenza virus may decrease effectiveness of the drug.¹

Beginning in the 2005–2006 influenza season, most strains of influenza A (H3N2) circulating in the US were resistant to adamantanes (amantadine, rimantadine),^{10 77 116 121} and resistance to these drugs among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.^{10 117 129 162} In addition, the 2009 pandemic influenza A (H1N1) virus was resistant to amantadine and rimantadine,^{52 117 151 162} and this strain is expected to continue to circulate during the 2010–2011 influenza season.^{144 162}

Amantadine and rimantadine have little or no activity against influenza B.^{1 24 26 27 45}

CDC recommends that adamantanes (amantadine, rimantadine) not be used for treatment of seasonal influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.⁷⁷

CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season.¹⁴⁴ Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .

Prevention of Seasonal Influenza A Virus Infections

Prophylaxis of signs and symptoms of influenza infection caused by susceptible influenza A in adults, adolescents, and children ≥1 year of age.¹

Annual vaccination with seasonal influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.^{1 10 116 144 149 161} Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza in certain individuals.^{1 10 116 144 149 161}

Conisder viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for the prophylaxis of influenza.^{116 137 149} The most appropriate antiviral for prevention of influenza is selected based on information regarding the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.^{137 144} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;^{137 144} consider the possibility that emergence of amantadine-resistant influenza virus may decrease effectiveness of the drug.¹

CDC recommends that adamantanes (amantadine, rimantadine) not be used for prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.⁷⁷

CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.¹⁴⁴ Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .

Avian Influenza A Virus Infections

May be used for treatment of avian influenza A virus infections† in certain situations.^{94 104}

The WHO recommends use of a neuraminidase inhibitor (i.e., oseltamivir) for the treatment of avian influenza A infections.^{94 104}

Concomitant use of a neuraminidase inhibitor (i.e., oseltamivir) and an adamantane (amantadine, rimantadine) can be considered in a patient with pneumonic disease or clinical progression if local surveillance data indicate the H5N1 virus is known or likely to be susceptible to an adamantane.¹⁰⁴

Should not be used alone for treatment of avian influenza A if a neuraminidase inhibitor is available.^{94 104 126}

Parkinsonian Syndrome and Drug-induced Extrapyramidal Effects

Symptomatic treatment of parkinsonian syndrome including postencephalitic, idiopathic, arteriosclerotic types and for the relief of parkinsonian signs and symptoms of carbon monoxide poisoning.¹ Less effective than levodopa.¹

Symptomatic treatment of antipsychotic-induced extrapyramidal effects.¹

Amantadine Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally.¹

Treatment or prophylaxis of influenza: Given as a single daily dose or in 2 equally divided doses (may minimize adverse CNS effects).¹

Parkinsonian syndrome and drug-induced extrapyramidal effects: Usually administered twice daily.¹

If insomnia occurs, the last dose should be taken several hours before bedtime.¹

Dosage

Available as amantadine hydrochloride; dosage expressed in terms of amantadine hydrochloride.¹

Usual dosage may need to be reduced in patients with congestive heart failure, peripheral edema, orthostatic hypotension, or impaired renal function.¹

Pediatric Patients

Treatment of Seasonal Influenza A Virus Infections

Oral

Children 1–9 years of age: 4.4–8.8 mg/kg (maximum 150 mg) daily recommended by manufacturer.¹ AAP recommends 5 mg/kg (up to 150 mg) daily in 2 divided doses.¹⁰

Children 9–12 years of age: 100 mg twice daily recommended by manufacturer.¹

Children ≥10 years of age: AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 200 mg daily in 2 divided doses in those weighing ≥40 kg.¹⁰

Children and adolescents ≥12 years of age: 200 mg once daily or 100 mg twice daily recommended by manufacturer.¹

Initiate amantadine treatment as soon as possible, preferably within 24–48 hours after onset of symptoms, and continue for up to 5 days or 24–48 hours after symptoms disappear.¹

Prevention of Seasonal Influenza A Virus Infections

Oral

Children 1–9 years of age: 4.4–8.8 mg/kg (maximum 150 mg) daily recommended by manufacturer.¹ AAP recommends 5 mg/kg (up to 150 mg) daily in 2 divided doses.¹⁰

Children 9–12 years of age: 100 mg twice daily recommended by manufacturer.¹

Children ≥10 years of age: AAP recommends 5 mg/kg daily in 2 divided doses in those weighing <40 kg or 200 mg daily in 2 divided doses in those weighing ≥40 kg.¹⁰

Children and adolescents ≥12 years of age: 200 mg once daily or 100 mg twice daily recommended by manufacturer.¹

Alternatively, AAP states children weighing >20 kg can receive 100 mg daily.¹⁰

Adults

Treatment of Seasonal Influenza A Virus Infections

Oral

200 mg once daily or 100 mg twice daily.¹

Dosage may be decreased to 100 mg daily in those who experience CNS or other toxicities with 200 mg daily;¹ relative efficacy of lower dosage not elucidated.¹

Initiate amantadine treatment as soon as possible, preferably within 24–48 hours after onset of symptoms, and continue for up to 5 days or 24–48 hours after symptoms disappear.¹

Prevention of Seasonal Influenza A Virus Infections

Oral

200 mg once daily or 100 mg twice daily.¹

Dosage may be decreased to 100 mg daily in those who experience CNS or other toxicities with 200 mg daily;¹ relative efficacy of lower dosage not elucidated.¹

Parkinsonian Syndrome and Drug-induced Extrapyramidal Effects

Oral

100 mg twice daily.¹

Patients with serious illness or receiving other antiparkinsonian drugs: 100 mg once daily for ≥1 week, then increase to 100 mg twice daily if necessary.¹

Dosage can be increased to 400 mg daily in divided doses in patients with parkinsonian syndrome.¹

Dosage can be increased to 300 mg daily in divided doses in patients with drug-induced extrapyramidal reactions.¹

Prescribing Limits

Pediatric Patients

Treatment or Prevention of Seasonal Influenza A Virus Infections

Oral

Children 1–9 years of age: Maximum 150 mg daily.¹

Special Populations

Renal Impairment

Dosage in Adults with Renal Impairment1

Clcr (mL/minute)	Dosage
30–50	200 mg on first day, then 100 mg daily
15–29	200 mg on first day, then 100 mg every other day
<15	200 mg every 7 days
Hemodialysis patients	200 mg every 7 days

Geriatric Patients

100 mg daily for treatment or prophylaxis of influenza A virus infection in those ≥65 years of age.^{1 11 20 23 101} Dosage may need to be further reduced in some patients.³⁵

Cautions for Amantadine Hydrochloride

Contraindications

• 
  

  Known hypersensitivity to amantadine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Acute Toxicity and Suicide Risk

Fatalities reported following overdosage.¹ Overdosage has resulted in cardiac (arrhythmia, tachycardia, hypertension), respiratory, renal, or CNS toxicity; may be related to anticholinergic effects of the drug.¹

Suicide attempts (including some fatalities) reported rarely; many patients received short courses of the drug for influenza prophylaxis or treatment.¹

Suicide ideation or attempts reported in patients with or without a prior history of psychiatric disorders.¹ Amantadine can exacerbate mental status in patients with a history of psychiatric disorders or substance abuse.¹ Patients with suicidal tendencies may exhibit abnormal mental states including disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, somnolence, or insomnia.¹

Use with caution in patients with uncontrolled psychosis or severe psychoneurosis.¹

Lowest reported lethal dose is 1 g.¹ Prescriptions should be written for smallest quantity consistent with good patient management.¹

CNS Effects

Patients with a history of seizure disorders should be observed closely for possible increased seizure activity.¹ (See Pediatric Use under Cautions.)

Cardiovascular Effects

CHF reported; monitor patients with a history of CHF or peripheral edema.¹ Dosage adjustment may be needed.¹

Ocular Effects

Amantadine may cause mydriasis; the drug should not be used in patients with untreated angle-closure glaucoma.¹

Sensitivity Reactions

Allergic reactions, including anaphylactic reaction,¹ rash,¹ eczematoid dermatitis,¹ photosensitization,⁸⁶ pruritus,¹ and diaphoresis,¹ reported rarely.

Use with caution in patients with recurrent eczematoid dermatitis.¹

General Precautions

Abrupt Withdrawal of Amantadine

Do not abruptly discontinue amantadine in patients with parkinsonian syndrome; some patients have developed parkinsonian crises after abrupt discontinuance of the drug.¹ Abrupt discontinuance also may precipitate delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, and slurred speech.¹

Neuroleptic Malignant Syndrome

Possible neuroleptic malignant syndrome (NMS) reported; associated with dosage reduction or withdrawal of amantadine.¹ Patients should be observed closely when dosage is reduced or the drug discontinued; this precaution is especially important in patients receiving concomitant therapy with an antipsychotic agent.¹

Melanoma

Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to sixfold higher risk of developing melanoma than the general population.¹ Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat Parkinson’s disease).¹

Monitor for melanomas frequently and on a regular basis when using amantadine for any indication.¹ Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).¹

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving drugs that increase central dopaminergic tone and generally are used for treatment of parkinsonian syndrome, including amantadine.¹ Although causal relationship not established, these urges stopped in some cases when dosage was reduced or the drug discontinued.¹

Ask patients whether they have developed new or increased gambling urges, sexual urges, or other urges while receiving amantadine; advise them of the importance of reporting such urges.¹ Consider reducing dosage or discontinuing amantadine if a patient develops such urges while receiving the drug.¹

Other Viral or Bacterial Infections

Not effective for treatment or prophylaxis of viral respiratory tract illnesses other than those due to influenza A virus.¹ (See Uses.)

Serious bacterial infections may present with influenza-like symptoms, coexist with influenza, or occur during influenza.¹ Amantadine does not prevent such complications.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Distributed into milk.¹ Use not recommended.¹

Pediatric Use

Safety and efficacy not established in neonates or infants <1 year of age.¹

Increased incidence of seizures reported in children with epilepsy.¹⁰

Geriatric Use

Substantially eliminated by the kidneys.¹ Consider age-related decreases in renal function and the potential for concomitant disease when selecting dosage.¹ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Caution in patients with liver disease.¹ Increased concentrations of liver enzymes reported.¹

Renal Impairment

Dosage adjustment needed based on degree of renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, ^{1 35} dizziness (lightheadedness),^{1 23 32 35 49} insomnia.^{1 23 32 35 49}

Interactions for Amantadine Hydrochloride

Specific Drugs

Drug	Interaction	Comments
Alcohol	Potential for increased CNS effects (dizziness, confusion, lightheadedness, orthostatic hypotension)1	Avoid excessive usage of alcohol1
Anticholinergic agents	Potential for increased adverse anticholinergic and CNS effects1 90 91 92 93	Dosage adjustment of both drugs may be needed1 90 91 92 93
Antihistamines	Potential for increased CNS effects51 127
Antipsychotic agents	Possible increased risk of NMS1 (see Neuroleptic Malignant Syndrome under Cautions)	Observe closely if amantadine dosage is reduced or amantadine discontinued1
CNS agents	Potential for increased adverse effects1	Use with caution1
CNS stimulants	Possibility of additive CNS stimulant effects127	Caution1 127
Co-triamterzide (triamterene and hydrochlorothiazide)	Possible increased amantadine plasma concentrations 1 90 126
Co-trimoxazole	Toxic delirium reported in an individual who received co-trimoxazole and amantadine concomitantly98
Influenza virus vaccines	Influenza virus vaccine inactivated: Amantadine does not interfere with the antibody response to the vaccine1 24 Influenza virus vaccine live intranasal: Potential interference with antibody response to the live vaccine; no specific studies1 144	Influenza virus vaccine inactivated: May be administered concomitantly with or at any interval before or after amantadine1 24 144 Influenza virus vaccine live intranasal: Do not administer the live intranasal vaccine until at least 48 hours after amantadine is discontinued; do not administer amantadine until at least 2 weeks after administration of the live intranasal vaccine;1 144 repeat vaccination if influenza antiviral is given 2 days before to 14 days after the vaccine144
Quinidine or quinine	Potential for a reduction in renal clearance of amantadine1 97
Thioridazine	Worsened tremor in geriatric patients with parkinsonian syndrome reported1	Not known whether a similar effect could occur with other phenothiazines1
Urine acidifying drugs	Possible increased elimination of amantadine1

Amantadine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak plasma concentrations achieved in 2–4 hours.^{1 12 27 45 56 63 67}

Onset

When used for parkinsonian syndrome, onset of action usually within 48 hours.¹

Plasma Concentrations

Peak plasma concentrations are directly related to amantadine hydrochloride dose up to 200 mg daily; dosages >200 mg daily may result in a greater than proportional increase in peak plasma concentration.^{1 67}

There appears to be a relationship between plasma concentrations of amantadine and toxicity.¹ As concentrations increase, toxicity becomes more prevalent.¹

Special Populations

Plasma concentrations increased in patients with renal impairment.⁶⁴

Plasma concentrations in geriatric patients receiving a dosage of 100 mg daily approximate those attained in younger adults receiving a dosage of 200 mg daily.¹

Distribution

Extent

Not fully characterized.^{1 67 99}

Distributed into nasal secretions, erythrocytes, CSF, and milk.^{1 12 65 67}

Plasma Protein Binding

67%.^{1 67}

Elimination

Metabolism

Undergoes N-acetylation.^{1 67}

Elimination Route

Principally excreted unchanged in urine by glomerular filtration and tubular secretion; about 5–15% excreted in urine as acetylamantadine.^{1 67}

Only minimally removed by hemodialysis.^{1 8 9 67}

Half-life

16 hours (range 9–31 hours).¹

Special Populations

Half-life prolonged in patients with renal impairment (Cl_cr<40 mL/minute).^{1 8 9} Half-life of 18.5–81.3 hours reported in patients with Cl_cr 13.7–43.1 mL/minute; half-life averages 8.3 days (range: 7–10.3 days) in patients undergoing chronic hemodialysis.^{1 9}

Half-life prolonged in healthy geriatric adults.^{1 5 12} Half-life of 29 hours (range: 20–41 hours) reported in geriatric men 60–76 years of age.^{1 5}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Solution

25°C (may be exposed to 15–30°C).¹

ActionsActions and Spectrum

• 
  

  Adamantane-derivative (a symmetric tricyclic amine);^{1 26 27 44 45} structurally related to rimantadine.^{22 26 27 29 44 45 49}

  
  


• 
  

  Has antiviral activity against some strains of influenza A, including some strains of H1N1, H2N2, and H3N2.^{1 24 25 26 27 41 42 45 48 58 59}

  
  


• 
  

  Has little or no activity against influenza B.^{1 24 26 27 45}

  
  


• 
  

  Worldwide incidence of influenza A viruses resistant to adamantanes (amantadine, rimantadine) has increased over the last several years.^{119 128}

  
  


• 
  

  Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to amantadine and rimantadine.^{77 121} Resistance to amantadine and rimantadine among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.^{10 117 129 162}

  
  


• 
  

  Although amantadine and rimantadine were active against most seasonal influenza A (H1N1) viruses circulating in the US during the 2008–2009 and 2009–2010 influenza seasons,^{117 133 139 162} the 2009 pandemic influenza A (H1N1) virus is resistant to amantadine and rimantadine.^{52 117 151 162}

  
  


• 
  

  Some strains of avian influenza A (H5N1) have been susceptible to amantadine;^{41 42 126} other strains, including influenza A (H5N1) isolated from patients in Asia during 2004 and 2005, have been resistant.^{112 126}

  
  


• 
  

  Inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein.^{1 24 26 27 45 46 47 48}

  
  


• 
  

  Strains of influenza A virus with reduced susceptibility to amantadine have been produced in vitro and have emerged during therapy with the drug.^{1 21 22 24 25 26 27 28 29 39 45}

  
  


• 
  

  Amantadine-resistant influenza A viruses also are resistant to rimantadine,^{21 22 23 27 43 45 46 47 54} but may be susceptible to oseltamivir or zanamivir.²³

  
  


• 
  

  Mechanism of action in treatment of parkinsonian syndrome and drug-induced extrapyramidal reactions unknown.¹ May enhance extracellular concentrations of dopamine at dopaminergic neurons, directly stimulating the dopamine receptor, or increasing sensitivity at receptors.¹

  
  

Advice to Patients

• 
  

  Risk of CNS effects and blurred vision; use caution when alertness and motor coordination is needed.¹

  
  


• 
  

  Advise patients with parkinsonian syndrome to gradually increase physical activity as symptoms improve.¹

  
  


• 
  

  Importance of avoiding excessive alcohol usage.¹

  
  


• 
  

  Importance of not getting up suddenly from a sitting or lying position; notify clinician if dizziness or lightheadedness occurs.¹

  
  


• 
  

  Importance of notifying clinician if mood/mental changes, swelling of extremities, difficulty urinating, and/or dyspnea occur.¹

  
  


• 
  

  Importance of taking amantadine as prescribed; importance of not taking more drug than prescribed.¹ Importance of consulting clinician if there is no improvement after a few days or if drug appears less effective after a few weeks.¹

  
  


• 
  

  Importance of seeking immediate medical attention for suspected overdose.¹

  
  


• 
  

  Importance of consulting clinician before discontinuing amantadine.¹

  
  


• 
  

  Importance of informing clinician if new or increased gambling urges, sexual urges, or other urges occur while receiving amantadine.¹

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Amantadine Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	100 mg*	Amantadine Hydrochloride Capsules
	Solution	50 mg/5 mL*	Amantadine Hydrochloride Oral Solution
	Tablets	100 mg*	Amantadine Hydrochloride Tablets
			Symmetrel	Endo

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Amantadine HCl 100MG Capsules (SANDOZ): 30/$21.99 or 60/$43.17

Amantadine HCl 100MG Tablets (UPSHER-SMITH): 30/$39.99 or 90/$109.97

Amantadine HCl 50MG/5ML Syrup (HI-TECH): 120/$15.99 or 360/$43.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions December 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Endo Laboratories. Symmetrel (amantadine hydrochloride) tablets and syrup prescribing information. Chadds Ford, PA; 2009 Jan.

3. Sartori M, Pratt CM, Young JB. Torsade de pointe: malignant cardiac arrhythmia induced by amantadine poisoning. Am J Med. 1984; 77:388-91. [IDIS 189139] [PubMed 6465184]

4. Aoki FY, Stiver HG, Sitar DS et al. Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults. Clin Pharmacol Ther. 1985; 37:128-36. [IDIS 196933] [PubMed 3967455]

5. Aoki FY, Sitar DS. Amantadine kinetics in healthy elderly men: implications for influenza prevention. Clin Pharmacol Ther. 1985; 37:137-44. [IDIS 196934] [PubMed 3967456]

7. Atkinson WL, Arden NH, Patriarca PA et al. Amantadine prophylaxis during an institutional outbreak of type A (H1N1) influenza. Arch Intern Med. 1986; 146:1751-6. [IDIS 220817] [PubMed 3753115]

8. Soung LS, Ing TS, Daugirdas JT et al. Amantadine hydrochloride pharmacokinetics in hemodialysis patients. Ann Intern Med. 1980; 93(1 Part 1):46-9. [IDIS 122052] [PubMed 7396313]

9. Horadam VW, Sharp JG, Smilack JD et al. Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function. Ann Intern Med. 1981; 94(4 Part 1):454-8. [IDIS 130720] [PubMed 7212501]

10. American Academy of Pediatrics. 2009 Red Book. Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.

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