Lemsip Cough Dry

1. Name Of The Medicinal Product

Lemsip Cough Dry

2. Qualitative And Quantitative Composition

Active ingredients	Quantity/dose	Specification
Glycerol	0.25 ml	EP
Honey	500.00 mg	HSE
Citric acid monohydrate	25.00 mg	EP
Lemon oil terpeneless	0.0005 ml	BP
Syrup	3.75 ml	BP

3. Pharmaceutical Form

Linctus.

4. Clinical Particulars

4.1 Therapeutic Indications

For the symptomatic relief of dry tickly coughs and sore throats.

4.2 Posology And Method Of Administration

Route of administration - oral.

Adults and children over 12: Two 5ml spoonfuls, three or four times daily.

Children 1-12 years: One 5ml spoonful, three or four times daily.

No special dose is required for elderly patients.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

Do not give to children under 1 year.

4.4 Special Warnings And Precautions For Use

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml.

Contains esters of parahydroxybenzoic acid which may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

As with many other medicines, this product should be avoided in the first three months of pregnancy and during lactation unless the benefits outweigh any risks; no significant problems have been reported in breast-fed infants from mothers taking this product.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

None known.

4.9 Overdose

Overdosage is unlikely but if it does occur then treatment consists of general supportive therapy and may include gastric lavage.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glycerol, honey and syrup act as demulcents and provide a soothing medium for an irritated throat.

The citric acid monohydrate and the lemon oil, terpeneless both add to the sharpness of the product and enhance the flavour.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

No preclinical findings of relevance have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Ethanol (96%), Nipasept sodium and water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Amber glass bottles with a polypropylene cap with a polyethylene tamper-evident band with expanded polyethylene wad. Pack sizes: 100 ml and 200 ml (100 ml is currently sold).

6.6 Special Precautions For Disposal And Other Handling

Oral administration.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited,

Dansom Lane,

Hull,

HU8 7DS.

8. Marketing Authorisation Number(S)

PL 0063/0038.

9. Date Of First Authorisation/Renewal Of The Authorisation

24th April, 1995.

10. Date Of Revision Of The Text

08/07/2011

Indomethacin

Class: Other Nonsteroidal Anti-inflammatory Agents
CAS Number: 53-86-1
Brands: Indocin

• Cardiovascular Risk


• 
  

  Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).⁴²⁰ Risk may increase with duration of use.⁴²⁰ Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.⁴²⁰ (See Cardiovascular Effects under Cautions.)

  
  


• 
  

  Contraindicated for the treatment of pain in the setting of CABG surgery.⁴²⁰

  
  

• GI Risk


• 
  

  Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).⁴²⁰ Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.⁴²⁰ Geriatric individuals are at greater risk for serious GI events.⁴²⁰ (See GI Effects under Cautions.)

  
  

Introduction

Prototypical NSAIA; indoleacetic acetic acid derivative.^{301 341 420}

Uses for Indomethacin

When used for inflammatory diseases, consider potential benefits and risks of indomethacin therapy as well as alternative therapies before initiating therapy with the drug.⁴²⁰ Use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.⁴²⁰

Inflammatory Diseases

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.^{341 420}

Symptomatic relief of acute gout and acute painful shoulder (i.e., bursitis and/or tendinitis).^{341 420}

Management of juvenile rheumatoid arthritis† in children ≥2 years of age.⁴²⁰

Patent Ductus Arteriosus (PDA)

Treatment of PDA in premature neonates.^{301 302 303 304 305 306 308 309 310 311 312 313 314 316 318 319 320 322 323 324 325 326} Used to promote closure of a hemodynamically significant PDA (i.e., left-to-right shunt large enough to compromise cardiorespiratory status) in premature neonates weighing 500–1750 g when 36–48 hours of usual medical management (e.g., fluid restriction, diuretics, cardiac glycosides, respiratory support) is ineffective.^{301 306 307 313}

Pericarditis

Reduction of pain, fever, and inflammation of pericarditis†;^a however, other drugs (i.e., aspirin) generally are preferred.⁴⁵²

Indomethacin Dosage and Administration

General

• 
  

  For inflammatory diseases, consider potential benefits and risks of indomethacin therapy as well as alternative therapies before initiating therapy with the drug.⁴²⁰

  
  

Administration

Administer orally or rectally (for inflammatory diseases or pericarditis)^{341 420} or by IV infusion (for PDA).³⁰¹

Oral Administration

In patients who have persistent night pain and/or morning stiffness, a large portion (maximum 100 mg) of the total daily dose may be given at bedtime.^{341 420}

Conventional Capsules and Oral Suspension

Administer conventional capsules and oral suspension in 2–4 divided doses daily.⁴²⁰

Extended-release Capsules

Administer extended-release capsules once or twice daily.³⁴¹

Extended-release capsules can be used as an alternative to conventional capsules: 75 mg once daily (extended-release) as an alternative to 25 mg 3 times daily (conventional); 75 mg twice daily (extended-release) as an alternative to 50 mg 3 times daily (conventional).³⁴¹

Swallow extended-release capsules intact.³⁴¹

Extended-release capsules are not recommended for treatment of acute gouty arthritis.³⁴¹

Rectal Administration

Administer in 2–4 divided doses daily.⁴²⁰

Retain suppositories in rectum for ≥1 hour to ensure complete absorption.⁴²⁰

IV Administration

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

Administer by IV infusion.³⁰¹

Avoid extravasation (irritating to extravascular tissues).³⁰¹

Reconstitution

Reconstitute vial containing 1 mg of indomethacin with 1 or 2 mL of preservative-free 0.9% sodium chloride injection or sterile water for injection to provide a solution containing 1 mg/mL or 0.5 mg/mL, respectively.³⁰¹ Further dilution is not recommended.³⁰¹

Use of bacteriostatic water for injection containing benzyl alcohol is not recommended because of potential risk of benzyl alcohol exposure if administered to a neonate.³⁰¹

Prepare solutions immediately before use; discard any unused solution.³⁰¹

Rate of Administration

Optimum rate not established; may administer dose over 20–30 minutes.³⁰¹

Dosage

Available as indomethacin and indomethacin sodium; dosage expressed in terms of indomethacin.^{301 341 420}

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.⁴²⁰ Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.⁴²⁰

Pediatric Patients

Inflammatory Diseases

Juvenile Rheumatoid Arthritis†

Oral

Children ≥2 years of age: Initially, 1–2 mg/kg daily in divided doses.^{341 420} Increase dosage until a satisfactory response is achieved, up to maximum dosage of 3 mg/kg daily or 150–200 mg daily (whichever is less) in divided doses; limited data support the use of a maximum dosage of 4 mg/kg daily or 150–200 mg daily (whichever is less) in divided doses.^{341 420} As symptoms subside, reduce dosage to the lowest effective level or discontinue the drug.^{341 420}

PDA

IV

Each course of therapy consists of up to 3 doses administered at 12- to 24-hour intervals.³⁰¹

Base dosage on neonate’s age at the time therapy is initiated.³⁰¹

Dosage for the Management of PDA in Neonates

Age at First Dose	First Dose	Second Dose	Third Dose
<48 hours	0.2 mg/kg	0.1 mg/kg	0.1 mg/kg
2–7 days	0.2 mg/kg	0.2 mg/kg	0.2 mg/kg
>7 days	0.2 mg/kg	0.25 mg/kg	0.25 mg/kg

If anuria or oliguria (urine output <0.6 mL/kg per hour) is present at the time of a second or third dose, withhold the dose until laboratory determinations indicate that renal function has returned to normal.³⁰¹

If ductus arteriosus closes or is substantially constricted 48 hours or longer after completion of the first course, no further doses are necessary.³⁰¹

If ductus reopens, a second course of 1–3 doses may be administered.³⁰¹ Surgical ligation may be necessary if ductus is unresponsive to 2 courses of therapy.³⁰¹

Pericarditis†

Oral

50–100 mg daily in 2–4 divided doses.^a

Adults

Inflammatory Diseases

Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis

Oral

Conventional capsules or oral suspension: Initially, 25 mg 2 or 3 times daily.⁴²⁰ If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.⁴²⁰

Extended-release capsules: Initially, 75 mg once daily.³⁴¹ May increase dosage to 75 mg twice daily.³⁴¹

Rectal

25 mg 2 or 3 times daily. If needed, increase dosage by 25 or 50 mg daily at weekly intervals until a satisfactory response is obtained up to a maximum dosage of 150–200 mg daily.⁴²⁰

Gout

Oral

Conventional capsules: 50 mg 3 times daily until pain is tolerable; then reduce dosage rapidly and discontinue.⁴²⁰

Painful Shoulder

Oral

Conventional capsules or oral suspension: 75–150 mg daily in 3 or 4 divided doses.⁴²⁰ Discontinue once symptoms have been controlled for several days; usual course of therapy is 7–14 days.⁴²⁰

Extended-release capsules: 75 mg once or twice daily.³⁴¹ Discontinue once symptoms have been controlled for several days; usual course of therapy is 7–14 days.³⁴¹

Rectal

75–150 mg daily in 3 or 4 divided doses.⁴²⁰ Discontinue once symptoms have been controlled for several days; usual course of therapy is 7–14 days.⁴²⁰

Pericarditis†

Oral

75–200 mg daily in 3 or 4 divided doses.^a

Prescribing Limits

Pediatric Patients

Juvenile Rheumatoid Arthritis

Oral

Maximum 4 mg/kg or 150–200 mg daily, whichever is less.⁴²⁰

Adults

Inflammatory Diseases

Rheumatoid Arthritis, Osteoarthritis, or Ankylosing Spondylitis

Oral

Maximum 200 mg daily.⁴²⁰

Rectal

Maximum 200 mg daily.⁴²⁰

Special Populations

Geriatric Patients

Careful dosage selection recommended due to possible age-related decreases in renal function.^{341 420}

Cautions for Indomethacin

Contraindications

• 
  

  Known hypersensitivity to indomethacin or any ingredient in the formulation.^{341 420}

  
  


• 
  

  History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{341 420}

  
  


• 
  

  Treatment of perioperative pain in the setting of CABG surgery.⁴²⁰

  
  


• 
  

  When administered rectally, history of proctitis or recent rectal bleeding.⁴²⁰

  
  


• 
  

  When used for PDA, known or suspected untreated infection; bleeding, especially active intracranial hemorrhage or GI bleeding; thrombocytopenia; coagulation defects; known or suspected necrotizing enterocolitis; substantial renal impairment; congenital heart disease if patency of the ductus arteriosus is necessary for pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta).³⁰¹

  
  

Warnings/Precautions

Warnings

Cardiovascular Effects

Selective COX-2 inhibitors have been associated with an increased risk of cardiovascular events in certain situations.⁴⁸⁴ Several prototypical NSAIAs also have been associated with an increased risk of cardiovascular events.^{487 488 489} Current evidence suggests that use of indomethacin is associated with increased cardiovascular risk.^{487 488 489 490}

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events), and at the lowest effective dosage for the shortest duration necessary.⁴²⁰

Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).⁴⁸⁴

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.⁴²⁰ (See Specific Drugs under Interactions.)

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.⁴²⁰ Use with caution in patients with hypertension; monitor BP.⁴²⁰ Impaired response to certain diuretics may occur.⁴²⁰ (See Specific Drugs under Interactions.)

Fluid retention and edema reported.^{341 420} Caution in patients with fluid retention or heart failure.^{341 420}

Deterioration of circulatory hemodynamics reported in patients with severe heart failure and hyponatremia.^{341 420}

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.⁴²⁰

Incidence of major GI bleeding reported in neonates receiving IV indomethacin in clinical studies similar to that in neonates receiving placebo; minor GI bleeding occurred more frequently in indomethacin-treated neonates.³⁰¹

When used for inflammatory diseases in patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{457 464} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)^{457 464} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).⁴⁶⁴

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.^{341 420}

Potential for overt renal decompensation.^{341 420} Increased risk of renal toxicity in adults with renal or hepatic impairment or heart failure, in patients with volume depletion, in geriatric patients, and in those receiving a diuretic, ACE inhibitor, or angiotension II receptor antagonist.^{420 486} (See Renal Impairment under Cautions.)

May precipitate renal insufficiency in neonates; increased risk in those with extracellular volume depletion, CHF, sepsis, or hepatic dysfunction or those receiving concomitant therapy with a nephrotoxic drug.³⁰¹ If a substantial reduction in urine output occurs, withhold additional doses until output returns to normal.³⁰¹ (See PDA under Dosage and Administration.)

Hyponatremia reported in neonates.^{301 302 303 306 314 324 325 326 329 348 371} Monitor renal function and serum electrolytes.³⁰¹

Hyperkalemia reported in adults.^{341 420}

Hematologic Effects

Potential for spontaneous intraventricular hemorrhage in neonates.³⁰¹ Observe premature infants for signs of bleeding.³⁰¹

Contraindicated in neonates who are bleeding and in those with thrombocytopenia or coagulation defects.³⁰¹

Ocular Effects

Corneal deposits and retinal disturbances reported in patients receiving long-term therapy.^{341 420} Ophthalmic examination recommended in patients with blurred vision; periodic ophthalmic examinations recommended in patients receiving long-term therapy.^{341 420}

CNS Effects

May aggravate depression or other psychiatric disturbances, epilepsy, or parkinsonism; use with caution in patients with these conditions.^{341 420}

May cause drowsiness; may impair ability to perform activities requiring mental alertness.^{341 420}

May cause headache.^{341 420} Discontinue the drug in patients in whom indomethacin-induced headache persists despite a reduction in dosage.^{341 420}

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions (e.g., anaphylaxis, angioedema) reported.^{341 420}

Immediate medical intervention and discontinuance for anaphylaxis.^{341 420}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.^{341 420}

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.⁴²⁰ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).⁴²⁰

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.^{341 420}

Elevations of serum ALT or AST reported.^{341 420}

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^{341 420} Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.^{301 341 420}

Hematologic Precautions

Anemia reported rarely.⁴²⁰ Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.⁴²⁰

May inhibit platelet aggregation and prolong bleeding time.^{341 420} When used for inflammatory diseases, use with caution in patients with coagulation defects.^{341 420}

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.⁴²⁰

May mask certain signs of infection.^{340 341 420}

Obtain CBC and chemistry profile periodically during long-term use.⁴²⁰

Specific Populations

Pregnancy

Category C.⁴²⁰ Avoid use in third trimester because of possible premature closure of the ductus arteriosus.^{341 420}

Lactation

Distributed into milk; use not recommended.^{341 420}

Pediatric Use

Safety and efficacy established in neonates receiving the drug for PDA.³⁰¹

Safety and efficacy of oral or rectal indomethacin not established in children ≤14 years of age.^{341 420}

Indomethacin should not be used in children 2–14 years of age unless toxicity or lack of efficacy with other drugs justifies the risk.⁴²⁰

Adverse effects reported in children receiving indomethacin capsules generally comparable to those reported in adults.⁴²⁰ Hepatotoxicity, sometimes fatal, has been reported in pediatric patients with juvenile rheumatoid arthritis.⁴²⁰ Periodic assessment of liver function recommended.⁴²⁰

Geriatric Use

Caution advised.⁴²⁰ Geriatric patients appear to tolerate NSAIA-induced adverse effects less well than younger individuals.^{341 420} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{341 420}

Possible confusion or, rarely, psychosis in geriatric patients.⁴²⁰

Substantially eliminated by the kidney; select dosage carefully and assess renal function periodically since geriatric patients more likely to have decreased renal function.^{341 420}

Renal Impairment

Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.⁴²⁰

Common Adverse Effects

With oral therapy, nausea, dyspepsia, headache, dizziness.^{341 420}

With rectal administration, rectal irritation, tenesmus; adverse effects associated with oral administration possible.⁴²⁰

With IV therapy, bleeding,^{301 302 303 305 306 310 315 316 322 323 346 347 348 349 350 351 352 353 354} transient oliguria,^{301 302 303 306 309 314 315 324 325 326 329 346 347 348 350 353 354 355 357 358 359 371} increases in serum creatinine concentrations,^{301 302 303 306 314 324 325 326 329 348 371} hyponatremia,³⁰¹ elevated serum potassium concentrations.³⁰¹

Interactions for Indomethacin

Protein-bound Drugs

Possible pharmacokinetic interaction; observe for adverse effects if used with other protein-bound drugs.^a

Drugs Excreted by the Kidney

Possible pharmacokinetic interaction with drugs that rely on adequate renal function for excretion.³⁰¹ In neonates receiving IV indomethacin, consider dosage adjustment for drugs that rely on adequate renal function for excretion.³⁰¹

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Reduced BP response to ACE inhibitor341 420 440 441 442 443 444 445 446 447 Possible deterioration of renal function in individuals with renal impairment420	Monitor BP341 420
Aminoglycosides (amikacin, gentamicin)	Increased plasma aminoglycoside concentrations reported in neonates receiving IV indomethacin301 372	Monitor serum aminoglycoside concentrations and renal function372
Angiotensin II receptor antagonists	Reduced BP response to angiotensin II receptor antagonist420 Possible deterioration of renal function in individuals with renal impairment420	Monitor BP420
Antacids (aluminum- or magnesium-containing)	Slight reduction or delay in peak plasma indomethacin concentrationa	Clinical importance not establisheda
Anticoagulants	Possible bleeding complications; pharmacodynamic interaction not observed in clinical studies 420	Monitor anticoagulant activity;341 420 caution advised420
Alcohol	Bleeding time prolongeda
β-adrenergic blocking agents	Reduced BP response to β-adrenergic blocking agent341 420	Monitor BP 420
Cyclosporine	Possible increase in cyclosporine toxicity341 420	Use with caution; monitor renal function341 420
Digoxin	Increased serum concentration and half-life of digoxin301 341 369 370 420	Monitor serum digoxin concentrations301 341 420 Consider digoxin dosage reduction in neonates; 369 370 monitor ECG301 369 370
Diuretics (furosemide, thiazides)	Reduced natriuretic effects301 341 420 Pharmacokinetic interaction with hydrochlorothiazide unlikely367 368	Monitor for diuretic efficacy and renal failure420 Concomitant administration of furosemide used to therapeutic advantage in neonates301 324
Diuretics (potassium-sparing)	Increased serum potassium concentrations341 420 Acute renal failure reported in adults receiving triamterene341 366 420	Should not be administered concomitantly with triamterene341 420
Hydantoins	Potential pharmacokinetic (protein binding) interactiona	Monitor for toxicitya
Hydralazine	Reduced BP response to hydralazine393	Monitor BP393
Lithium	Increased plasma lithium concentrations341 420	Monitor for lithium toxicity341 420
Methotrexate	Possible increased plasma methotrexate concentrations420	Caution advised341 420
NSAIAs	NSAIAs including aspirin: Potential for increased risk of GI toxicity with little or no increase in efficacy341 420 Aspirin: No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs420 Aspirin: Decreased plasma indomethacin concentrations reported with concomitant aspirin (3.6 g daily) therapy341 420 Diflunisal: Increased plasma indomethacin concentrations and serious GI adverse effects reported341 420	Concomitant use not recommended341 420
Potassium supplements	Increased serum potassium concentrations362	Caution advised362
Prednisolone	Increased plasma concentrations of free prednisolone; total plasma prednisolone concentrations unchangeda
Probenecid	Increased plasma concentrations of indomethacin341 420	Select and adjust indomethacin dosage with care; lower dosage may be adequate341 420
Sulfonamides	Potential pharmacokinetic (protein binding) interactiona	Monitor for toxicitya
Sulfonylureas	Potential pharmacokinetic (protein binding) interactiona	Monitor for toxicitya
Thrombolytic agents	Possible bleeding complicationsa	Caution adviseda

Indomethacin Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract.^{341 420} Almost completely absorbed following oral administration as conventional or extended-release capsules;^{341 420} bioavailability following rectal administration is 80–90% of that of the conventional capsule.⁴²⁰

Indomethacin extended-release capsules release 25 mg of drug initially and the remaining 50 mg over 12 hours.³⁴¹

When administered with food, the commercially available conventional capsules and oral suspension are bioequivalent.⁴²⁰

Distribution

Extent

Crosses the placenta and blood-brain barrier.³⁰¹

Concentrations in synovial fluid 20% of those in serum.^a

Distributed into milk.^{341 420}

Plasma Protein Binding

99% (in adults).^{341 420}

Elimination

Metabolism

Metabolized in the liver.^{341 420}

Elimination Route

Undergoes appreciable enterohepatic circulation.^{301 341 420} Following oral administration, excreted in the urine (60%) and feces (33%) as unchanged drug and metabolites.^{341 420}

Half-life

Adults: 4.5 hours.^{341 420}

Neonates <7 days of age: 20 hours.³⁰¹

Neonates >7 days of age: 12 hours.³⁰¹

Neonates weighing <1 kg: 21 hours.³⁰¹

Neonates weighing >1 kg: 15 hours.³⁰¹

Stability

Storage

Oral

Conventional or Extended-release Capsules

15–30°C.^{a 341}

Suspension

<30°C; avoid temperatures >50°C.⁴²⁰ Protect from freezing.⁴²⁰

Rectal

Suppositories

<30°C; avoid temperatures >40°C (even transiently).⁴²⁰

Parenteral

Powder for Injection

<30°C; protect from light.³⁰¹

Compatibility

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

Parenteral

Solution Compatibility

Reconstitute with preservative-free sterile water for injection or preservative-free 0.9% sodium chloride injection.³⁰¹ Further dilution with IV solutions is not recommended.³⁰¹

Drug Compatibility

Syringe CompatibilityHID

Incompatible
Pantoprazole sodium

Y-Site CompatibilityHID

Compatible
Furosemide
Potassium chloride
Sodium bicarbonate
Sodium nitroprusside
Incompatible
Amino acid injection (TrophAmine)
Calcium gluconate
Cimetidine HCl
Dobutamine HCl
Dopamine HCl
Gentamicin sulfate
Levofloxacin
Tobramycin sulfate
Variable
Dextrose injection

ActionsActions

• 
  

  Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{301 341 420 455 456 457 458 461 462 463}

  
  


• 
  

  Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{301 341 420}

  
  


• 
  

  Permits closure of the ductus arteriosus in premature neonates by inhibiting prostaglandin synthesis.³⁰¹

  
  

Advice to Patients

• 
  

  Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.⁴²⁰

  
  


• 
  

  Risk of serious cardiovascular events with long-term use.⁴²⁰

  
  


• 
  

  Risk of GI bleeding and ulceration.^{341 420}

  
  


• 
  

  Risk of serious skin reactions.⁴²⁰ Risk of anaphylactoid and other sensitivity reactions.⁴²⁰

  
  


• 
  

  Risk of hepatotoxicity.^{341 420}

  
  


• 
  

  Risk of ocular toxicity.^{341 420}

  
  


• 
  

  Potential for drug to impair mental alertness; use caution when driving or operating machinery until effects on individual are known.^{341 420}

  
  


• 
  

  Importance of notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.⁴²⁰

  
  


• 
  

  Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.^{341 420}

  
  


• 
  

  Importance of discontinuing indomethacin and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.⁴²⁰ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{341 420}

  
  


• 
  

  Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.^{341 420}

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{341 420} Importance of avoiding indomethacin in late pregnancy (third trimester).^{341 420}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{341 420}

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{341 420} (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

Indomethacin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	25 mg*	Indocin	Merck
			Indomethacin Capsules	Clonmel, Mutual, Mylan, Par, Pliva, Sandoz, Teva
		50 mg*	Indocin	Merck
			Indomethacin Capsules	Clonmel, Mutual, Mylan, Par, Pliva, Sandoz, Teva
	Capsules, extended-release	75 mg*	Indomethacin Extended-release Capsules	Inwood
	Suspension	25 mg/5 mL	Indocin (with alcohol 1% and sorbic acid)	Merck
Rectal	Suppositories	50 mg*	Indomethacin Suppositories	G&W, PD-RX

Indomethacin Sodium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, for IV use only	1 mg (of anhydrous indomethacin)	Indocin I.V.	Ovation

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.

Indomethacin 25MG Capsules (MYLAN): 30/$15.99 or 60/$20.99

Indomethacin 50MG Capsules (TEVA PHARMACEUTICALS USA): 30/$15.99 or 60/$21.98

Indomethacin CR 75MG Controlled-release Capsules (SANDOZ): 30/$82.15 or 90/$208.97

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 thoroug

Nurofen Maximum Strength Migraine Pain 684mg Caplets

1. Name Of The Medicinal Product

Nurofen Maximum Strength Migraine Pain 684mg Caplets

Nurofen Express 684mg Caplets

2. Qualitative And Quantitative Composition

Ibuprofen Lysine 684mg/tablet (equivalent to 400mg ibuprofen)

For excipients, see 6.1

3. Pharmaceutical Form

Coated tablet

A white, film-coated, capsule-shaped tablet, printed with an identifying logo in black on one face.

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of headache and migraine

4.2 Posology And Method Of Administration

For oral administration and short-term use only.

Adults, the elderly and children over 12 years:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 10 days.

Take 1 caplet with water, up to three times a day as required.

Leave at least 4 hours between doses.

Do not take more than 3 caplets in any 24 hour period.

4.3 Contraindications

Hypersensitivity to ibuprofen or any of the excipients in the product.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema, or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Severe heart failure, renal failure or hepatic failure (see section 4.4)

Last trimester of pregnancy (see section 4.6).

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory:

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Other NSAIDs:

The use of Ibuprofen with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8)

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8).

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8)

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is some evidence that drugs which inhibit cyclooxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Ibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The label will include:

Read the enclosed leaflet before taking this product

Do not take if you:

• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding

• are allergic to ibuprofen, to any of the ingredients, or to aspirin or other painkillers

• are taking other NSAID pain killers or aspirin with a daily dose above 75mg

• or the patient is under 12 years of age.

Speak to your doctor or pharmacist before use if you

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, heart, liver, kidney or bowel problems

• are a smoker

• are pregnant

If symptoms persist or worsen, or if new symptoms occur, consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ibuprofen (like other NSAIDs) should not be used in combination with:

Aspirin unless low-dose aspirin (not above 75mg daily) has been advised by a doctor as this may increase the risk of adverse reactions (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).

Other NSAIDs including cyclooxygenase-2 selective inhibitors: Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4)

Ibuprofen should be used with caution in combination with:

Corticosteroids: as these may increase the risk of gastrointestinal ulceration or bleeding (see section 4.4)

Antihypertensives and diuretics: since NSAIDs may diminish the effects of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Anticoagulants: NSAIDs may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding (see section 4.4).

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium: There is evidence for potential increase in plasma levels of lithium.

Methotrexate: There is evidence for the potential increase in plasma levels of methotrexate.

Ciclosporin: Increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine: Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Quinolone antibiotics: Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

4.6 Pregnancy And Lactation

No specific studies have been conducted with ibuprofen lysine.

Whilst no teratogenic effects have been demonstrated with ibuprofen acid in animal experiments, the use of ibuprofen during pregnancy should, if possible, be avoided during the first 6 months of pregnancy. It should not be used for the last trimester of pregnancy as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and duration increased with an increased bleeding tendency in both mother and child. (See section 4.3).

In limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.

See section 4.4 regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

None expected at recommended dose and duration of therapy.

4.8 Undesirable Effects

Hypersensitivity reactions have been reported and these may consist of

a. non-specific allergic reactions and anaphylaxis;

b. respiratory tract reactivity e.g. asthma, aggravated asthma, bronchospasm, dyspnoea;

c. various skin reactions e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

The list of the following adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritis.

Very rare: severe hypersensitivity reactions. Symptoms could be facial, tongue and laryngeal swelling, dysponoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

The most commonly observed adverse events are gastrointestinal in nature.

Uncommon: abdominal pain, nausea, dyspepsia.

Rare: Diarrhoea, flatulence, constipation and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.

Exacerbation of colitis and Crohn's disease (section 4.4).

Nervous System:

Uncommon: Headache

Very rare: Aseptic meningitis – single cases have been reported very rarely.

Renal:

Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Dermatological :

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as bullous reactions including Stevens-Johnson syndrome, erythema multiforme and toxic epidermal necrolysis can occur.

Immune System:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4).

Cardiovascular and Cerebrovascular:

Oedema, hypertension and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that the use of NSAIDS (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

In children ingestion of more than 400mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms – Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/ INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management – Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen lysine is the lysine salt of ibuprofen. Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans, ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. In one study, when a single dose of ibuprofen 400mg was taken within 8 h before or within 30 min after immediate release aspirin dosing (81mg), a decreased effect of ASA on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no relevant effect is considered to be likely for occasional ibuprofen use.

Each tablet contains 684mg of ibuprofen lysine. Following oral administration, ibuprofen lysine dissociates to ibuprofen acid and lysine. Lysine has no recognised pharmacological activity. The pharmacological properties of ibuprofen lysine, therefore, are the same as those of ibuprofen acid.

5.2 Pharmacokinetic Properties

Most pharmacokinetic data obtained following the administration of ibuprofen acid also apply to ibuprofen lysine.

Ibuprofen is well absorbed from the gastrointestinal tract. Ibuprofen is extensively bound to plasma proteins. Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food peak serum concentration occurs 1 - 2 hours after administration. However, ibuprofen is more rapidly absorbed from the gastrointestinal tract following the administration of Ibuprofen Lysine 400mg Tablets, with peak serum concentration occurring approximately 38 minutes after administration when taken on an empty stomach.

Ibuprofen is metabolised in the liver to two major metabolites with primary excretion via the kidneys, either as such or as major conjugates, together with a negligible amount of unchanged ibuprofen. Excretion by the kidney is both rapid and complete.

Elimination half-life is approximately 2 hours.

No significant differences in pharmacokinetic profile are observed in the elderly.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the SmPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Povidone, sodium starch glycollate, magnesium stearate, hypromellose, talc, Opaspray White M-1-7111B (contains hypromellose and titanium dioxide (E171)) and Black Printing Ink (contains shellac, Iron oxide black (E172) and propylene glycol).

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 30ºC

Store tablets in the original packaging

6.5 Nature And Contents Of Container

Either:

A blister pack consisting of opaque, white 250µm polyvinyl chloride (PVC)/ 23µm polychlorotrifluoroethylene (Aclar) laminate heat sealed to 20µm aluminium foil. The blisters are packed in cardboard cartons.

Or:

A blister pack consisting of an opaque, white 250µm polyvinyl chloride (PVC)/ 40gsm polyvinylidene chloride (PVdC) laminate heat sealed to 20µm aluminium foil. The blisters are packed in cardboard cartons.

Pack sizes: 4, 6, 8, 12, 16 and 24 tablets

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Ltd

Slough

SL1 4AQ

8. Marketing Authorisation Number(S)

PL 00063/0384

9. Date Of First Authorisation/Renewal Of The Authorisation

17/01/2006 / 24/11/2010

10. Date Of Revision Of The Text

19/04/2011

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)

NeutrapHorus Rex

Generic Name: topical emollients (TOP i kal ee MOL i ents)

Brand Names: Aloe Vesta Cream, AlphaSoft, AmeriPhor, Aqua Glycolic, Aqua Lube, Aquaphor, Aveeno, Baby Lotion, Baby Oil, Bag Balm, Baza-Pro, Beta Care, Blistex Lip Balm, Carmex, CarraKlenz, CeraVe, CeraVe AM, Cetaphil Lotion, Chap Stick, Citraderm, CoolBottoms, Corn Huskers Lotion, Curel Moisture Lotion, Derma Soothe, Dr Scholl's Essentials Cracked Skin Repair, Eucerin, Herpecin-L, K-Y Jelly, Keri Lotion, Lamisilk Heel Balm, Lubri-Soft, Lubriderm, Mederma, Moisturel, Natural Ice, NeutrapHor, NeutrapHorus Rex, Neutrogena Cleansing, Neutrogena Lotion, Nivea, Nutraderm, Pacquin, Phisoderm, Pretty Feet & Hands, Proshield Skincare Kit, Remedy 4-in-1 Cleansing Lotion, Replens, Secura, Sensi-Care, Soft Sense, St. Ives, Theraplex Lotion, Vaseline Intensive Care

What are NeutrapHorus Rex (topical emollients)?

Emollients are substances that moisten and soften your skin.

Topical (for the skin) emollients are used to treat or prevent dry skin. Topical emollients are sometimes contained in products that also treat acne, chapped lips, diaper rash, cold sores, or other minor skin irritation.

There are many brands and forms of topical emollients available and not all are listed on this leaflet.

Topical emollients may also be used for purposes not listed in this medication guide.

What is the most important information I should know about NeutrapHorus Rex (topical emollients)?

You should not use a topical emollient if you are allergic to it. Topical emollients will not treat or prevent a skin infection.

Ask a doctor or pharmacist before using this medication if you have deep wounds or open sores, swelling, warmth, redness, oozing, bleeding, large areas of skin irritation, or any type of allergy.

What should I discuss with my healthcare provider before using NeutrapHorus Rex (topical emollients)?

You should not use a topical emollient if you are allergic to it. Topical emollients will not treat or prevent a skin infection.

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

• 
  

  deep wounds or open sores;

  
  


• 
  

  swelling, warmth, redness, oozing, or bleeding;

  
  


• 
  

  large areas of skin irritation;

  
  


• 
  

  any type of allergy; or

  
  


• if you are pregnant or breast-feeding.

How should I use NeutrapHorus Rex (topical emollients)?

Use exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.

Clean the skin where you will apply the topical emollient. It may help to apply this product when your skin is wet or damp. Follow directions on the product label.

Shake the product container if recommended on the label.

Apply a small amount of topical emollient to the affected area and rub in gently.

If you are using a stick, pad, or soap form of topical emollient, follow directions for use on the product label.

Do not use this product over large area of skin. Do not apply a topical emollient to a deep puncture wound or severe burn without medical advice.

If your skin appears white or gray and feels soggy, you may be applying too much topical emollient or using it too often.

Some forms of topical emollient may be flammable and should not be used near high heat or open flame, or applied while you are smoking.

Store as directed away from moisture, heat, and light. Keep the bottle, tube, or other container tightly closed when not in use.

What happens if I miss a dose?

Since this product is used as needed, it does not have a daily dosing schedule. Seek medical advice if your condition does not improve after using a topical emollient.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking NeutrapHorus Rex (topical emollients)?

Avoid getting topical emollients in your eyes, nose, or mouth. If this does happen, rinse with water. Avoid exposure to sunlight or tanning beds. Some topical emollients can make your skin more sensitive to sunlight or UV rays.

NeutrapHorus Rex (topical emollients) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using the topical emollient and call your doctor if you have severe burning, stinging, redness, or irritation where the product was applied.

Less serious side effects are more likely, and you may have none at all.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect NeutrapHorus Rex (topical emollients)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied products. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

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Compare NeutrapHorus Rex with other medications

• Dry Skin

Where can I get more information?

• Your pharmacist can provide more information about topical emollients.

Kyowa Pharmaceutical, Inc.

Address Kyowa Pharmaceutical, Inc. , 212 Carnegie Center Suite 101 Princeton, NJ 08540 Contact Details Phone: (609) 919-1100 Website: http://www.kyowa-kpi.com/ Careers: http://www.kyowa-kpi.com/

Kineret 100 mg solution for injection in a vial

1. Name Of The Medicinal Product

Kineret 100 mg solution for injection in a vial.

2. Qualitative And Quantitative Composition

Each vial contains 100 mg of anakinra* per 0.67 ml (150 mg/ml).

* Human interleukinEscherichia coli cells by recombinant DNA technology.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection) in a vial.

Clear, colourless

4. Clinical Particulars

4.1 Therapeutic Indications

Kineret is indicated for the treatment of the signs and symptoms of rheumatoid arthritis in combination with methotrexate, in patients with an inadequate response to methotrexate alone.

4.2 Posology And Method Of Administration

The recommended dose of Kineret is 100 mg administered once a day by subcutaneous injection. The dose should be administered at approximately the same time each day.

Kineret is supplied ready for use in a vial. The instructions for use and handling are given in section 6.6.

Alternating the injection site is recommended to avoid discomfort at the site of injection.

Kineret treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis.

Elderly patients (

No dose adjustment is required. Posology and administration are the same as for adults 18 to 64 years of age.

Children and adolescents (< 18 years)

There are insufficient data to recommend the use of Kineret in children and adolescents under 18 years of age.

Hepatic impairment

No dose adjustment is required.

Renal impairment

No dosage adjustment is needed for patients with mild renal impairment (CL_cr 50 to 80 ml/minute). In the absence of adequate data, Kineret should be used with caution in patients with moderate renal impairment (CL_cr 30 to 50 ml/minute). Kineret should not be used in patients with severe renal impairment (CL_cr < 30 ml/minute) (see section 4.3).

4.3 Contraindications

Hypersensitivity to the active substance, any of the excipients or to E. coli derived proteins.

Kineret should not be used in patients with severe renal impairment (CL_cr < 30 ml/minute) (see section 4.2).

4.4 Special Warnings And Precautions For Use

Allergic reactions

Allergic reactions associated with administration of Kineret during clinical trials were rare. The majority of these reactions were maculopapular or urticarial rashes. If a severe allergic reaction occurs, administration of Kineret should be discontinued and appropriate treatment initiated.

The vial stopper contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Serious infections

Kineret has been associated with an increased incidence of serious infections (1.8%) vs. placebo (0.7%). For a small number of patients with asthma, the incidence of serious infection was higher in Kineret-treated patients (4.5%) vs. placebo-treated patients (0%). The safety and efficacy of Kineret in patients with chronic infections have not been evaluated.

Physicians should exercise caution when administering Kineret to patients with a history of recurring infections or with underlying conditions which may predispose them to infections.

Neutropenia

Administration of Kineret was associated with neutropenia (ANC < 1.5 x 10⁹/l) in 2.4% of patients compared with 0.4% of placebo patients. None of these patients had serious infections associated with the neutropenia.

Kineret treatment should not be initiated in patients with neutropenia (ANC < 1.5 x 10⁹/l). It is recommended that neutrophil counts be assessed prior to initiating Kineret treatment, and while receiving Kineret, monthly during the first 6 months of treatment and quarterly hereafter. In patients who become neutropenic (ANC < 1.5 x 10⁹/l) the ANC should be monitored closely and Kineret treatment should be discontinued.

Immunosuppression

The impact of treatment with Kineret on pre-existing malignancy has not been studied. Therefore the use of Kineret in patients with pre-existing malignancy is not recommended.

Vaccinations

In a placebo-controlled clinical trial (n = 126), no difference was detected in anti-tetanus antibody response between the Kineret and placebo treatment groups when a tetanus/diphtheria toxoid vaccine was administered concurrently with Kineret. No data are available on the effects of vaccination with other inactivated antigens in patients receiving Kineret.

No data are available on either the effects of live vaccination or on the secondary transmission of infection by live vaccines in patients receiving Kineret. Therefore, live vaccines should not be given concurrently with Kineret.

Elderly patients (

A total of 635 patients

Concurrent Kineret and TNF antagonist treatment

Concurrent administration of Kineret and etanercept has been associated with an increased risk of serious infections and neutropenia compared to etanercept alone. This treatment combination has not demonstrated increased clinical benefit.

The concurrent administration of Kineret and etanercept or other TNF antagonists is not recommended (see section 4.5).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interactions between Kineret and other medicinal products have not been investigated in formal studies.In clinical trials, interactions between Kineret and other medicinal products (including nonsteroidal anti-inflammatory drugs, corticosteroids, and DMARDs) have not been observed.

Concurrent Kineret and TNF antagonist treatment

In a clinical trial with patients receiving background methotrexate, patients treated with Kineret and etanercept were observed to have a higher rate of serious infections (7%) and neutropenia than patients treated with etanercept alone and higher than observed in previous trials where Kineret was used alone. Concurrent Kineret and etanercept treatment has not demonstrated increased clinical benefit.

The concurrent use of Kineret with etanercept or any other TNF antagonist is not recommended (see section 4.4).

For information on vaccinations see section 4.4.

4.6 Pregnancy And Lactation

There are no adequate data from the use of Kineret in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).

The use of Kineret in pregnant women is not recommended.

Women of child-bearing potential must use effective contraception during treatment.

It is not known whether anakinra is excreted in human milk. The use of Kineret in women who are breast

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of Kineret on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

In all placebo-controlled studies, the most frequently reported adverse event with Kineret was injection site reaction (ISRs), which was mild to moderate in the majority of patients. The most common reason for withdrawal from study in Kineret-treated patients is injection site reaction. The subject incidence of serious adverse events at the recommended dose of Kineret (100 mg/day) is comparable with placebo (7.1% compared with 6.5% in the placebo group). The incidence of serious infection was higher in Kineret-treated patients compared with patients receiving placebo (1.8% vs. 0.7%). Neutrophil decreases occurred more frequently in patients receiving Kineret compared with placebo.

MedDRA Organ System	Frequency	Undesirable Effect
Blood and lymphatic system disorders	Common (	Neutropenia
Nervous system disorders	Very common (	Headache
Skin and subcutaneous tissue disorders	Very common (	Injection site reaction
Infections and infestations	Common (	Serious infections requiring hospitalisation

Injection site reactions

The most common and consistently reported treatment-related adverse events associated with Kineret were ISRs. The majority (95%) of ISRs were reported as mild to moderate. These were typically characterised by 1 or more of the following: erythaema, ecchymosis, inflammation, and pain. At a dose of 100 mg/day, 71% of patients developed an ISR compared to 28% of the placebo treated patients, which was typically reported within the first 4 weeks of therapy. The median duration of the above mentioned typical symptoms was 14 to 28 days. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.

Serious infections

The incidence of serious infections in the studies conducted at the recommended dose (100 mg/day) was 1.8% in Kineret treated patients and 0.7% in placebo-treated patients. In observations up to 3 years, the serious infection rate remained stable over time. The infections observed consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Most patients continued on study drug after the infection resolved. There were no on-study deaths due to serious infectious episodes.

In clinical studies and post-marketing experience, rare cases of opportunistic infections have been observed and included fungal, mycobacterial, bacterial, and viral pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Kineret alone or in combination with immunosuppressive agents.

Neutropenia

In placebo-controlled studies with Kineret, treatment was associated with small reductions in the mean values for total white blood count and absolute neutrophil count (ANC). Neutropenia (ANC < 1.5 x 10⁹/l) was reported in 2.4% patients receiving Kineret compared with 0.4% of placebo patients.

Malignancies

Rheumatoid arthritis (RA) patients may be at a higher risk (on average 2-3 fold) for the development of lymphoma. In clinical trials, whilst patients treated with Kineret had a higher incidence of lymphoma than the expected rate in the general population, this rate is consistent with rates reported in general for RA patients.

In clinical trials, the crude incidence rate of malignancy was the same in the Kineret-treated patients and the placebo-treated patients and did not differ from that in the general population. Furthermore, the overall incidence of malignancies was not increased during 3 years of patient exposure to Kineret.

Immunogenicity

In clinical trials, up to 3% of adult patients tested seropositive at least once during the study for antibodies capable of neutralising the biologic effects of anakinra. The occurrence of antibodies was typically transient and not associated with clinical adverse reactions or diminished efficacy. In addition, in a clinical trial 6% of paediatric patients tested seropositive at least once during the study for antibodies capable of neutralising the biologic effects of anakinra.

4.9 Overdose

No dose-limiting toxicities were observed during clinical trials in rheumatoid arthritis patients.

In studies of sepsis, 1,015 patients received Kineret at doses up to 2 mg/kg/hour over a 72 hour treatment period. The adverse event profile from these studies show no overall difference from that seen in the rheumatoid arthritis studies.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Immunosuppressants, ATC code: L04AC03

Anakinra neutralises the biologic activity of interleukin-1α (IL-1α) and interleukin-1β(IL-1β) by competitively inhibiting their binding to interleukin-1 type I receptor (IL-1RI). Interleukin-1 (IL-1) is a pivotal pro-inflammatory cytokine mediating many cellular responses including those important in synovial inflammation.

IL-1 is found in the plasma and synovial fluid of patients with rheumatoid arthritis, and a correlation has been reported between IL-1 concentrations in the plasma and the activity of the disease.

Anakinra inhibits responses elicited by ILin vitro, including the induction of nitric oxide and prostaglandin E₂ and/or collagenase production by synovial cells, fibroblasts, and chondrocytes.

Clinical data

The safety and efficacy of anakinra in combination with methotrexate have been demonstrated in patients with varying degrees of disease severity.

A clinical response to anakinra generally appeared within 2 weeks of initiation of treatment and was sustained with continued administration of anakinra. Maximal clinical response was generally seen within 12 weeks after starting treatment.

Combined anakinra and methotrexate treatment demonstrates a statistically and clinically significant reduction in the severity of the signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate alone (38% vs. 22% responders as measured by ACR₂₀ criteria. Significant improvements are seen in the pain, tender joint count, physical function (HAQ score), acute phase reactants and in the patient's and physician's global assessment.

X-ray examinations have been undertaken in one clinical study with anakinra. These have shown no deleterious effect on joint cartilage.

Immunogenicity

See section 4.8.

5.2 Pharmacokinetic Properties

The absolute bioavailability of anakinra after a 70 mg SC bolus injection in healthy subjects (n = 11) is 95%. The absorption process is the rate

The influence of demographic covariates on the pharmacokinetics of anakinra was studied using population pharmacokinetic analysis encompassing 341 patients receiving daily SC injection of anakinra at doses of 30, 75, and 150 mg for up to 24 weeks. The estimated anakinra clearance increased with increasing creatinine clearance and body weight. Population pharmacokinetic analysis demonstrated that the mean plasma clearance value after SC bolus administration was approximately 14% higher in men than in women and approximately 10% higher in subjects < 65 years than in subjects

5.3 Preclinical Safety Data

Anakinra had no observed effect on the fertility, early development, embryo-foetal development, or peri- and postnatal development in the rat at doses up to 100 times the human dose. No effects on embryo-foetal development in the rabbit were observed at doses 100 times the human dose.

In a standard battery of tests designed to identify hazards with respect to DNA, anakinra did not induce bacterial or mammalian cell gene mutations. Neither did anakinra increase the incidence of chromosomal abnormalities or micronuclei in bone marrow cells in mice. Long-term studies have not been performed to evaluate the carcinogenic potential of anakinra. Data from mice over expressing IL-1ra and IL-1ra mutant knock-out mice, did not indicate an increased risk of tumour development.

A formal toxicologic and toxicokinetic interaction study in rats revealed no evidence that Kineret alters the toxicologic or pharmacokinetic profile of methotrexate.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium citrate

Sodium chloride

Disodium edetate

Polysorbate 80

Sodium hydroxide

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

18 months.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Store in the original container in order to protect from light.

For the purpose of ambulatory use, Kineret may be removed from the refrigerator for 12 hours at temperature not above 25°C, without exceeding the expiry date. At the end of this period, the product must not be put back in the refrigerator and must be disposed of.

6.5 Nature And Contents Of Container

0.67 ml of solution for injection in a vial (Type I glass) with rubber stoppers, aluminium seals and plastic flip

The vial stopper contains dry natural rubber (a derivative of latex). See section 4.4.

6.6 Special Precautions For Disposal And Other Handling

Kineret is a sterile unpreserved solution. For single use only.

Do not shake. Allow the vial to reach room temperature before injecting.

Before administration, visually inspect the solution for particulate matter and discolouration. Only clear, colourless

The presence of these particles does not affect the quality of the product.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Biovitrum AB (publ)

SE-112 76 Stockholm

Sweden

8. Marketing Authorisation Number(S)

EU/1/02/203/004

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 8 March 2002

Date of latest renewal: 20 March 2007

10. Date Of Revision Of The Text

26 January 2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.