Nurofen

Ibuprofen:

• Pharmacological action
• Pharmacokinetics
• Why is Nurofen prescribed?
• Dosage and administration
• Nurofen side effects
• Contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Nurofen drug interactions
• Nurofen in case of emergency / overdose
• Storage conditions
• Nurofen (Ibuprofen) reviews

Pharmacological action

NSAIDs, a derivative of phenylpropionic acid, Nurofen has anti-inflammatory, analgesic and antipyretic effect.

The mechanism of action is associated with inhibition of COX activity - the main enzyme metabolism of arachidonic acid, which is a precursor of prostaglandins, which play a major role in the pathogenesis of inflammation, pain and fever. Analgesic effect is due to both peripheral (indirectly, through suppression of prostaglandin synthesis), and a central mechanism (due to inhibition of prostaglandin synthesis in the central and peripheral nervous system). Inhibits platelet aggregation.

For topical use anti-inflammatory and analgesic action. Reduces morning stiffness, increased the amount of motion in joints.

Pharmacokinetics

When oral administered Nurofen (Ibuprofen) almost completely absorbed from the gastrointestinal tract. Simultaneous food intake slows the rate of absorption. Metabolised in the liver (90%). T1 / 2 is 2-3 hours.

80% of the dose excreted in urine mainly as metabolites (70%), 10% - unchanged, 20% eliminated through the intestine in the form of metabolites.

Why is Nurofen prescribed?

Inflammatory, degenerative diseases of joints and spine (including rheumatic and rheumatoid arthritis, ankylosing spondylitis, osteoarthritis), articular syndrome in patients with acute gout, psoriatic arthritis, ankylosing spondylitis, tendonitis, bursitis, sciatica, traumatic inflammation of soft tissue and musculoskeletal apparatus. Neuralgia, myalgia, pain in infectious and inflammatory diseases of ENT organs, bursitis, algomenorrhea, headache and toothache. Fever in infectious and inflammatory diseases.

Dosage and administration

Setting individually, depending on etiology of disease, severity of clinical manifestations. When administered rectally or adult single dose of 200-800 mg, the frequency of reception - 3-4; for children - 20-40 mg / kg in divided doses.

Topical applied within 2-3 weeks.

The maximum daily dose for adults when administered oral or rectally or is 2.4 g.

Oral, after a meal. Rheumatoid arthritis - by 0.8 g 3 times a day in osteoarthrosis and ankylosing spondylitis - by 0.4-0.6 g 3-4 times a day, in juvenile rheumatoid arthritis - at 30-40 mg / kg / day in several stages.

When soft tissue injuries, sprains - 1.6-2.4 g / day in divided doses.

At moderate pain syndrome - 1.2 g per day.

Nurofen side effects

Digestive system: frequently - nausea, anorexia, vomiting, epigastric discomfort, diarrhea, possibly the development of erosive and ulcerative lesions of the gastrointestinal tract; rare - bleeding from the gastrointestinal tract, long-term use possible liver problems.

Central nervous system and peripheral nervous systems: frequently - headache, dizziness, sleep disturbances, agitation, visual impairment.

Hemopoietic system: long-term use may be anemia, thrombocytopenia, agranulocytosis.

Urinary tract: long-term use possible renal dysfunction.

Allergic reactions: often - skin rash, Quincke's edema, rarely - aseptic meningitis (usually in patients with autoimmune diseases), bronchospasm syndrome.

Local reactions: when topical used may be hyperemia of the skin, burning or tingling.

Contraindications

Erosive-ulcerative lesions in the gastrointestinal tract exacerbation, diseases of the optic nerve, "aspirin triad", hemodyscrasia, pronounced renal dysfunction and / or liver, children age, hypersensitivity to Nurofen (Ibuprofen).

Using during pregnancy and breastfeeding

Do not use Nurofen (Ibuprofen) in the III trimester of pregnancy. Application I and II trimesters of pregnancy is justified only in cases where the expected benefit to the mother than the possible harm to the fetus.

This medication Nurofen (Ibuprofen) in small amounts excreted in breast milk. Possible using in lactation for pain and fever. If necessary, prolonged use or use in high doses (800 mg / 24 h), should decide on the termination of breastfeeding.

Special instructions

Precautions are used with the attendant liver and kidney diseases, chronic heart failure, with dyspeptic symptoms before treatment, immediately after surgery, with indications of a history of gastrointestinal bleeding in diseases of the digestive tract, allergic reactions associated with NSAID intake.

In the course of treatment requires systematic monitoring of the liver and kidneys, peripheral blood picture.

It should not be applied externally to the damaged skin.

Nurofen drug interactions

With simultaneous use of Nurofen (Ibuprofen) reduces the effect of antihypertensive agents (ACE inhibitors, beta-blockers), diuretics (furosemide, hypothiazide).

With the simultaneous use of anticoagulants may enhance their action.

With simultaneous application of SCS increases the risk of side effects from the gastrointestinal tract.

With the simultaneous application of Nurofen (Ibuprofen) may displace from compounds with plasma proteins indirect anticoagulants (acenocoumarol), derivatives of hydantoin (phenytoin), oral hypoglycemic drugs sulfonylurea derivatives.

With the simultaneous use of amlodipine may be a slight reduction of antihypertensive action of amlodipine, with acetylsalicylic acid - decreased concentration of Nurofen (Ibuprofen) in blood plasma, with baclofen - described a case of toxic gain of baclofen.

When applied simultaneously with warfarin may increase bleeding time, were also observed microhematuria, bruises with hydrochlorothiazide - perhaps a slight reduction of antihypertensive action of hydrochlorothiazide, captopril - may reduce antihypertensive effect of captopril, with cholestyramine - moderately decrease absorption of Nurofen (Ibuprofen).

With simultaneous application of lithium carbonate increased the concentration of lithium in blood plasma.

With simultaneous application of magnesium hydroxide increases the initial absorption of Nurofen (Ibuprofen), with methotrexate - increases the toxicity of methotrexate.

Nurofen in case of emergency / overdose

In case of overdose, call your local poison control center or emergency services.

Symptoms of overdose may include: dizziness; fast eye movements that you cannot control; slow breathing or short periods of time without breathing; blue color around the lips, mouth, and nose.

Storage conditions

In a dry, protected from light place, at temperatures below 25°C.Common expiration date for Nurofen (Ibuprofen) tablets: 3 years.

Ibuprofen Sodium Dihydrate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Overdosage
• Description
• Clinical pharmacology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Nurofen (Ibuprofen Sodium Dihydrate) reviews

1 INDICATIONS AND USAGE

Nurofen (Ibuprofen Sodium Dihydrate) is indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA.

Nurofen (Ibuprofen Sodium Dihydrate) is indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA. (1)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

A course of therapy is three doses of Nurofen (Ibuprofen Sodium Dihydrate) administered intravenously (administration via an umbilical arterial line has not been evaluated). An initial dose of 10 mg per kilogram is followed by two doses of 5 mg per kilogram each, after 24 and 48 hours. All doses should be based on birth weight. If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of Nurofen (Ibuprofen Sodium Dihydrate), no additional dosage should be given until laboratory studies indicate that renal function has returned to normal. If the ductus arteriosus closes or is significantly reduced in size after completion of the first course of Nurofen (Ibuprofen Sodium Dihydrate), no further doses are necessary. If during continued medical management the ductus arteriosus fails to close or reopens, then a second course of Nurofen (Ibuprofen Sodium Dihydrate), alternative pharmacological therapy, or surgery may be necessary.

2.2 Directions for Use

For intravenous administration only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use Nurofen (Ibuprofen Sodium Dihydrate) if particulate matter is observed.

After the first withdrawal from the vial, any solution remaining must be discarded because Nurofen (Ibuprofen Sodium Dihydrate) contains no preservative.

For administration, Nurofen (Ibuprofen Sodium Dihydrate) should be diluted to an appropriate volume with dextrose or saline. Nurofen (Ibuprofen Sodium Dihydrate) should be prepared for infusion and administered within 30 minutes of preparation and infused continuously over a period of 15 minutes. The drug should be administered via the IV port that is nearest the insertion site. After the first withdrawal from the vial, any solution remaining must be discarded because Nurofen (Ibuprofen Sodium Dihydrate) contains no preservative.

Since Nurofen (Ibuprofen Sodium Dihydrate) is potentially irritating to tissues, it should be administered carefully to avoid extravasation.

Nurofen (Ibuprofen Sodium Dihydrate) should not be simultaneously administered in the same intravenous line with Total Parenteral Nutrition (TPN). If necessary, TPN should be interrupted for a 15-minute period prior to and after drug administration. Line patency should be maintained by using dextrose or saline.

• A course of therapy is three doses administered I.V. (2.1)
• An initial dose of 10 mg/kg (based on birth weight) is followed by two doses of 5 mg/kg each, after 24 and 48 hours (2.1)
• Do not administer if anuria or marked oliguria (<0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose (2.1)

3 DOSAGE FORMS AND STRENGTHS

10 mg/mL as a clear sterile preservative-free solution of the L-lysine salt of Nurofen (Ibuprofen Sodium Dihydrate) in a 2 mL single-use vial.

• 10 mg/mL as a clear sterile preservative-free solution of the L-lysine salt of Nurofen (Ibuprofen Sodium Dihydrate) in a 2 mL single-use vial (3)

4 CONTRAINDICATIONS

Nurofen (Ibuprofen Sodium Dihydrate) is contraindicated in:

• Preterm infants with proven or suspected infection that is untreated;
• Preterm infants with congenital heart disease in whom patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta);
• Preterm infants who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding;
• Preterm infants with thrombocytopenia;
• Preterm infants with coagulation defects;
• Preterm infants with or who are suspected of having necrotizing enterocolitis;
• Preterm infants with significant impairment of renal function.

Nurofen (Ibuprofen Sodium Dihydrate) is contraindicated in preterm infants:

• With proven or suspected infection that is untreated (4)
• With congenital heart disease in whom patency of the PDA is necessary for satisfactory pulmonary or systemic blood flow (4)
• With impaired renal function (4)
• With thrombocytopenia, coagulation defects or who are bleeding (4)
• With or who are suspected of having necrotizing enterocolitis (4)

5 WARNINGS AND PRECAUTIONS

5.1 General

There are no long-term evaluations of the infants treated with Nurofen (Ibuprofen Sodium Dihydrate) at durations greater than the 36 weeks post-conceptual age observation period. Ibuprofen’s effects on neurodevelopmental outcome and growth as well as disease processes associated with prematurity (such as retinopathy of prematurity and chronic lung disease) have not been assessed.

5.2 Infection

Nurofen (Ibuprofen Sodium Dihydrate) may alter the usual signs of infection. The physician must be continually on the alert and should use the drug with extra care in the presence of controlled infection and in infants at risk of infection.

5.3 Platelet Aggregation

Nurofen (Ibuprofen Sodium Dihydrate), like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation. Preterm infants should be observed for signs of bleeding. Nurofen (Ibuprofen Sodium Dihydrate) has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. This effect may be exaggerated in patients with underlying hemostatic defects.

5.4 Bilirubin Displacement

Nurofen (Ibuprofen Sodium Dihydrate) has been shown to displace bilirubin from albumin binding-sites; therefore, it should be used with caution in patients with elevated total bilirubin.

5.5 Administration

Nurofen (Ibuprofen Sodium Dihydrate) should be administered carefully to avoid extravascular injection or leakage, as solution may be irritating to tissue.

• Nurofen (Ibuprofen Sodium Dihydrate) has not been assessed for neurodevelopmental outcome and growth (5.1)
• Nurofen (Ibuprofen Sodium Dihydrate) may alter the usual signs of infection (5.2)
• Nurofen (Ibuprofen Sodium Dihydrate) can inhibit platelet aggregation, and has been shown to prolong bleeding time in normal adult subjects (5.3)
• Nurofen (Ibuprofen Sodium Dihydrate) has been shown to displace bilirubin from albumin binding-sites (5.4)
• Nurofen (Ibuprofen Sodium Dihydrate) should be administered carefully to avoid extravascular injection or leakage (5.5)

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

The most frequently reported adverse events with Nurofen (Ibuprofen Sodium Dihydrate) were as shown in Table 1.

6.2 Renal Function

Compared to placebo, there was a small decrease in urinary output in the Nurofen (Ibuprofen Sodium Dihydrate) group on days 2-6 of life, with a compensatory increase in urine output on day 9. In other studies, adverse events classified as renal insufficiency including oliguria, elevated BUN, elevated creatinine, or renal failure were reported in Nurofen (Ibuprofen Sodium Dihydrate) treated infants.

6.3 Additional Adverse Events

The adverse events reported in the multicenter study and of unknown association include tachycardia, cardiac failure, abdominal distension, gastroesophageal reflux, gastritis, ileus, inguinal hernia, injection site reactions, cholestasis, various infections, feeding problems, convulsions, jaundice, hypotension, and various laboratory abnormalities including neutropenia, thrombocytopenia, and hyperglycemia.

6.4 Post-marketing Experience

The following adverse reactions have been identified from spontaneous post-marketing reports or published literature: gastrointestinal perforation, necrotizing enterocolitis, and pulmonary hypertension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency, or establish a causal relationship to drug exposure.

Most common adverse reactions (≥10%) are sepsis, anemia, intraventricular bleeding, apnea, gastrointestinal disorders, impaired renal function, respiratory infection, skin lesions, hypoglycemia, hypocalcemia, respiratory failure. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Table 1

7 DRUG INTERACTIONS

Drug interactions of Nurofen (Ibuprofen Sodium Dihydrate) in neonates have not been assessed.

Drug interactions in neonates have not been assessed. (7)

10 OVERDOSAGE

The following signs and symptoms have occurred in individuals (not necessarily in premature infants) following an overdose of oral Nurofen (Ibuprofen Sodium Dihydrate): breathing difficulties, coma, drowsiness, irregular heartbeat, kidney failure, low blood pressure, seizures, and vomiting. There are no specific measures to treat acute overdosage with Nurofen (Ibuprofen Sodium Dihydrate). The patient should be followed for several days because gastrointestinal ulceration and hemorrhage may occur.

11 DESCRIPTION

Nurofen (Ibuprofen Sodium Dihydrate) ^® is a clear sterile preservative-free solution of the L-lysine salt of (±)-ibuprofen which is the active ingredient. (±)-Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAID). L-lysine is used to create a water-soluble drug product salt suitable for intravenous administration. Each mL of Nurofen (Ibuprofen Sodium Dihydrate) contains 17.1 mg of Nurofen (Ibuprofen Sodium Dihydrate) lysine (equivalent to 10 mg of (±)-ibuprofen) in Water for Injection, USP. The pH is adjusted to 7.0 with sodium hydroxide or hydrochloric acid.

The structural formula is:

Nurofen (Ibuprofen Sodium Dihydrate) is designated chemically as α-methyl-4-(2-methyl propyl) benzeneacetic acid lysine salt. Its molecular weight is 352.48. Its empirical formula is C ₁₉H ₃₂N ₂O ₄. It occurs as a white crystalline solid which is soluble in water and slightly soluble in ethanol.

Structural Formula

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action through which Nurofen (Ibuprofen Sodium Dihydrate) causes closure of a patent ductus arteriosus (PDA) in neonates is not known. In adults, Nurofen (Ibuprofen Sodium Dihydrate) is an inhibitor of prostaglandin synthesis.

12.2 Pharmacokinetics and Bioavailability Studies

The pharmacokinetic data were obtained from 54 NeoProfen-treated premature infants included in a double-blind, placebo-controlled, randomized, multicenter study. Infants were less than 30 weeks gestational age, weighed between 500 and 1000 g, and exhibited asymptomatic PDA with evidence of echocardiographic documentation of ductal shunting. Dosing was initially 10 mg/kg followed by 5 mg/kg at 24 and 48 hours.

The population average clearance and volume of distribution values of racemic Nurofen (Ibuprofen Sodium Dihydrate) for premature infants at birth were 3 mL/kg/h and 320 mL/kg, respectively. Clearance increased rapidly with post-natal age (an average increase of approximately 0.5 mL/kg/h per day). Inter-individual variability in clearance and volume of distribution were 55% and 14%, respectively. In general, the half-life in infants is more than 10 times longer than in adults.

The metabolism and excretion of Nurofen (Ibuprofen Sodium Dihydrate) in premature infants have not been studied.

In adults, renal elimination of unchanged Nurofen (Ibuprofen Sodium Dihydrate) accounts for only 10-15% of the dose. The excretion of Nurofen (Ibuprofen Sodium Dihydrate) and metabolites occurs rapidly in both urine and feces. Approximately 80% of the dose administered orally is recovered in urine as hydroxyl and carboxyl metabolites, respectively, as a mixture of conjugated and unconjugated forms. Nurofen (Ibuprofen Sodium Dihydrate) is eliminated primarily by metabolism in the liver where CYP2C9 mediates the 2- and 3-hydroxylations of R- and S-ibuprofen. Nurofen (Ibuprofen Sodium Dihydrate) and its metabolites are further conjugated to acyl glucuronides.

In neonates, renal function and the enzymes associated with drug metabolism are underdeveloped at birth and substantially increase in the days after birth.

14 CLINICAL STUDIES

In a double-blind, multicenter clinical study premature infants of birth weight between 500 and 1000 g, less than 30 weeks post-conceptional age, and with echocardiographic evidence of a PDA were randomized to placebo or Nurofen (Ibuprofen Sodium Dihydrate). These infants were asymptomatic from their PDA at the time of enrollment. The primary efficacy parameter was the need for rescue therapy (indomethacin, open-label Nurofen (Ibuprofen Sodium Dihydrate), or surgery) to treat a hemodynamically significant PDA by study day 14. An infant was rescued if there was clinical evidence of a hemodynamically significant PDA that was echocardiographically confirmed. A hemodynamically significant PDA was defined by three of the following five criteria ― bounding pulse, hyperdynamic precordium, pulmonary edema, increased cardiac silhouette, or systolic murmur ― or hemodynamically significant ductus as determined by a neonatologist.

One hundred and thirty-six premature infants received either placebo or Nurofen (Ibuprofen Sodium Dihydrate) (10 mg/kg on the first dose and 5 mg/kg at 24 and 48 hours). Mean birth age was 1.5 days (range: 4.6 – 73.0 hours), mean gestational age was 26 weeks (range: 23 – 30 weeks), and mean weight was 798 g (range: 530 – 1015 g). All infants had a documented PDA with evidence of ductal shunting. As shown in Table 2, 25% of infants on Nurofen (Ibuprofen Sodium Dihydrate) required rescue therapy versus 48% of infants on placebo (p=0.003 from logistic regression controlling for site).

Of the infants requiring rescue within the first 14 days after the first dose of study drug, no statistically significant difference was observed between the Nurofen (Ibuprofen Sodium Dihydrate) and placebo groups for mean age at start of first rescue treatment (8.7 days, range 4-15 days, for the Nurofen (Ibuprofen Sodium Dihydrate) group and 6.9 days, range 2-15 days, for the placebo group).

The groups were similar in the number of deaths by day 14, the number of patients on a ventilator or requiring oxygenation at day 1, 4 and 14, the number of patients requiring surgical ligation of their PDA (12%), the number of cases of Pulmonary Hemorrhage and Pulmonary Hypertension by day 14, and Bronchopulmonary Dysplasia at day 28. In addition, no significant differences were noted in the incidences of Stage 2 and 3 Necrotizing Enterocolitis, Grades 3 and 4 Intraventricular Hemorrhage, Periventricular Leukomalacia and Retinopathy of Prematurity between groups as determined at 36±1 weeks adjusted gestational age.

Two supportive studies also determined that Nurofen (Ibuprofen Sodium Dihydrate), either prophylactically (n=433, weight range: 400 – 2165 g) or as treatment (n=210, weight range: 400 – 2370 g), was superior to placebo (or no treatment) in preventing the need for rescue therapy for a symptomatic PDA.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Nurofen (Ibuprofen Sodium Dihydrate) (ibuprofen lysine) Injection is dispensed in clear glass single-use vials, each containing 2 mL of sterile solution (NDC 55292-122- 52). The solution is not buffered and contains no preservatives. Each milliliter contains 17.1 mg/mL (±)-ibuprofen L-lysine [equivalent to 10 mg/mL (±)-ibuprofen] dissolved in Water for Injection, USP. Nurofen (Ibuprofen Sodium Dihydrate) is supplied in a carton containing 3 single-use vials.

Storage and Handling

Store at 20 – 25°C (68 – 77°F); excursions permitted 15 – 30°C (59 – 86°F). Protect from light. Store vials in carton until contents have been used.

17 PATIENT COUNSELING INFORMATION

17.1 General

Patients’ caregivers should be informed that the effects of Nurofen (Ibuprofen Sodium Dihydrate) on infants’ neurodevelopmental outcome, growth and disease process with prematurity have not been assessed in long-term studies.

17.2 Infection

Nurofen (Ibuprofen Sodium Dihydrate) may alter signs of infection. Patients’ caregivers should be informed that the infant will be carefully monitored for any signs of infection.

17.3 Platelet Aggregation

Patients’ caregivers should be informed that like other NSAIDS, Nurofen (Ibuprofen Sodium Dihydrate) can inhibit clot formation therefore their infant will be monitored for any signs of bleeding.

17.4 Bilirubin Displacement

Patients’ caregivers should be informed that the infants’ blood will be tested for increased levels of total bilirubin.

17.5 Administration

Patients’ caregivers should be informed that the infants’ skin and tissues will be monitored as leakage from administration may be irritating to tissue.

Manufactured by: AAIPharma Services, Charleston, SC 29405, U.S.A.

For: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.

RECORDATI RARE DISEASES GROUP

® Trademark of Recordati Rare Diseases Inc.

Revised: January 2016 PC4477D