Nurofen^® Plus N (Tablets) Instructions for Use

Marketing Authorization Holder

Reckitt Benckiser Healthcare International, Ltd. (United Kingdom)

ATC Code

N02AA59 (Codeine in combination with other drugs)

Active Substances

Ibuprofen (Rec.INN registered by WHO)

Codeine (Ph.Eur. European Pharmacopoeia)

Dosage Form

Nurofen® Plus N

Film-coated tablets, 200 mg+10 mg: 5, 6, 10, 12, 15, 18, 20, 24, 30, or 36 pcs.

Dosage Form, Packaging, and Composition

5 pcs. – blisters (1) – carton packs.
5 pcs. – blisters (2) – carton packs.
5 pcs. – blisters (3) – carton packs.
6 pcs. – blisters (1) – carton packs.
6 pcs. – blisters (2) – carton packs.
6 pcs. – blisters (3) – carton packs.
10 pcs. – blisters (1) – carton packs.
10 pcs. – blisters (2) – carton packs.
10 pcs. – blisters (3) – carton packs.
12 pcs. – blisters (1) – carton packs.
12 pcs. – blisters (2) – carton packs.
12 pcs. – blisters (3) – carton packs.

Clinical-Pharmacological Group

NSAIDs of combined composition

Pharmacotherapeutic Group

Analgesic agent (opioid analgesic + NSAID)

Pharmacological Action

Nurofen^® Plus N is a combined drug that has analgesic, antipyretic, anti-inflammatory, and antitussive effects.

The mechanism of action of ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) that non-selectively blocks COX-1 and COX-2, is due to the inhibition of prostaglandin synthesis – mediators of pain, inflammation, and hyperthermic reaction.

Codeine is an analgesic that acts on opioid receptors in the CNS, causing a change in the emotional perception of pain and having an antitussive effect.

Pharmacokinetics

Ibuprofen

Absorption is high, plasma protein binding is 90%. It slowly penetrates into the joint cavity, is retained in the synovial tissue, creating higher concentrations in it than in plasma. After absorption, about 60% of the pharmacologically inactive R-form is slowly transformed into the active S-form. The half-life is 2 hours. It undergoes metabolism. It is excreted by the kidneys (unchanged no more than 1%) and, to a lesser extent, with bile.

Codeine

After oral administration, it is rapidly absorbed. Plasma protein binding is 30%. The time to reach maximum plasma concentration is 2-4 hours. It is metabolized in the liver to active metabolites – 10% is converted to morphine by demethylation. It is excreted by the kidneys (5-15% unchanged and 10% as morphine and its metabolites) and with bile. T_1/2 is 2.5-4 hours.

Indications

• Headache and toothache;
• Migraines;
• Painful menstruation;
• Neuralgia;
• Back pain;
• Muscular and rheumatic pains;
• Febrile condition in influenza and colds.

ICD codes

Dosage Regimen

Take orally for adults and children over 12 years 1-2 tablets every 4-6 hours, with water.

To achieve a rapid therapeutic effect, a single dose can be increased to 400 mg (ibuprofen dose) – 2 tablets 3 times/day. Do not take more than 6 tablets in 24 hours. The maximum daily dose is 1200 mg (6 tablets). The maximum daily dose for children from 12-17 years is 1000 mg (5 tablets).

If symptoms persist when taking the drug for 2-3 days, it is necessary to stop treatment and consult a doctor.

Adverse Reactions

When using the drug, the following side effects may occur.

From the digestive system: NSAID-gastropathy (abdominal pain, nausea, vomiting, heartburn, loss of appetite, diarrhea, flatulence, constipation; rarely – ulceration of the gastrointestinal mucosa, which in some cases is complicated by perforation and bleeding); irritation or dryness of the oral mucosa, mouth pain, ulceration of the gum mucosa, aphthous stomatitis, pancreatitis, hepatitis.

From the respiratory system: shortness of breath, bronchospasm, respiratory depression.

From the sensory organs: hearing impairment: hearing loss, ringing or noise in the ears; visual impairment: toxic damage to the optic nerve, blurred vision or double vision, scotoma, dryness and irritation of the eyes, swelling of the conjunctiva and eyelids (of allergic origin).

From the central and peripheral nervous system: headache, dizziness, insomnia, anxiety, nervousness and irritability, psychomotor agitation, drowsiness, depression, confusion, hallucinations, rarely – aseptic meningitis (more often in patients with autoimmune diseases).

From the cardiovascular system: heart failure, tachycardia, bradycardia, increased blood pressure.

From the urinary system: acute renal failure, allergic nephritis, nephrotic syndrome (edema), polyuria, cystitis.

Allergic reactions: skin rash (usually erythematous or urticarial), skin itching, angioedema, anaphylactoid reactions, anaphylactic shock, bronchospasm or dyspnea, fever, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), eosinophilia, allergic rhinitis.

From the hematopoietic organs: anemia (including hemolytic, aplastic), thrombocytopenia and thrombocytopenic purpura, agranulocytosis, leukopenia.

Other: increased sweating, opioid dependence (with long-term uncontrolled use).

Laboratory parameters: bleeding time (may increase), serum glucose concentration (may decrease), creatinine clearance (may decrease), hematocrit or hemoglobin (may decrease), serum creatinine concentration (may increase), activity of “hepatic” transaminases (may increase).

With long-term use, the likelihood of developing side effects increases, the frequency of developing allergic reactions does not depend on the duration of drug use.

If side effects occur, you should stop taking the drug and consult a doctor.

Contraindications

• Erosive and ulcerative diseases of the gastrointestinal tract in the acute stage (including gastric and duodenal ulcers, Crohn’s disease, ulcerative colitis);
• Hemophilia and other blood clotting disorders (including hypocoagulation), hemorrhagic diathesis;
• The period after coronary artery bypass grafting;
• Gastrointestinal bleeding and intracranial hemorrhages;
• Severe hepatic insufficiency or active liver disease;
• Severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney diseases, confirmed hyperkalemia;
• Acute depression of the respiratory center;
• Pregnancy;
• Lactation period;
• Children under 12 years of age;
• Toxic dyspepsia;
• Hypersensitivity to any of the ingredients that make up the drug. Hypersensitivity to acetylsalicylic acid or other NSAIDs in history, including anamnestic data on an attack of bronchial obstruction, rhinitis, urticaria after taking acetylsalicylic acid or another NSAID; complete or incomplete acetylsalicylic acid intolerance syndrome (rhinosinusitis, urticaria, nasal mucosal polyps, bronchial asthma).

With caution: drug dependence (including in history), smoking, frequent alcohol consumption, presence of Helicobacter pylori infection, bronchial asthma attack, chronic obstructive pulmonary disease, elderly age, heart failure, arrhythmias, arterial hypertension, coronary heart disease, cerebrovascular diseases, convulsions, hyperlipidemia, diabetes mellitus, peripheral arterial diseases, liver cirrhosis with portal hypertension, cholelithiasis, hepatic and/or renal failure (creatinine clearance from 30 to 60 ml/min), nephrotic syndrome, hyperbilirubinemia, gastric and duodenal ulcer (in history), gastritis, enteritis, colitis, diseases of the blood of unclear etiology (leukopenia and anemia), severe somatic diseases, surgical interventions on the gastrointestinal tract or urinary system, head trauma, intracranial hypertension, hypothyroidism, prostatic hyperplasia, urethral strictures, cachexia, long-term use of NSAIDs, simultaneous use of oral glucocorticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including acetylsalicylic acid, clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline), monoamine oxidase (MAO) inhibitors.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency or active liver disease.

With caution: liver cirrhosis with portal hypertension, hepatic insufficiency, hyperbilirubinemia.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney diseases, confirmed hyperkalemia.

With caution: renal failure (creatinine clearance from 30 to 60 ml/min), nephrotic syndrome.

Pediatric Use

Contraindicated in children under 12 years of age.

Geriatric Use

Take with caution in the elderly.

Special Precautions

During long-term treatment, monitoring of the peripheral blood picture and the functional state of the liver and kidneys is necessary. If symptoms of gastropathy appear, careful monitoring is indicated, including esophagogastroduodenoscopy, complete blood count (hemoglobin determination), stool test for occult blood. If it is necessary to determine 17-ketosteroids, the drug should be discontinued 48 hours before the study.

Patients should refrain from all activities requiring increased attention, rapid mental and motor reactions. The drug should not be taken for acute abdominal pain, as the drug may mask the symptoms of acute diseases (for example, acute appendicitis). During treatment, ethanol intake is not recommended.

Overdose

Symptoms: abdominal pain, nausea, vomiting, lethargy, drowsiness, depression, headache, tinnitus, metabolic acidosis, coma, acute renal failure, decreased blood pressure, bradycardia, tachycardia, atrial fibrillation, respiratory arrest.

Treatment: gastric lavage (only within an hour after ingestion), activated charcoal, alkaline drinking, forced diuresis, symptomatic therapy. For respiratory depression, a specific opioid antagonist – naloxone – is used.

Drug Interactions

Simultaneous administration of Nurofen^® Plus N tablets with acetylsalicylic acid and other NSAIDs is not recommended. With simultaneous administration, Ibuprofen reduces the anti-inflammatory and antiplatelet effect of acetylsalicylic acid (an increase in the frequency of acute coronary insufficiency is possible in patients receiving small doses of acetylsalicylic acid as an antiplatelet agent after starting ibuprofen). When prescribed with anticoagulant and thrombolytic drugs (alteplase, streptokinase, urokinase) simultaneously, the risk of bleeding increases. Simultaneous administration with serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline) increases the risk of serious gastrointestinal bleeding.

Cefamandole, cefoperazone, cefotetan, valproic acid, plicamycin increase the incidence of hypoprothrombinemia. Cyclosporine and gold preparations enhance the effect of ibuprofen on prostaglandin synthesis in the kidneys, which is manifested by increased nephrotoxicity. Ibuprofen increases the plasma concentration of cyclosporine and the likelihood of developing its hepatotoxic effects. Drugs that block tubular secretion reduce the excretion and increase the plasma concentration of ibuprofen. Inducers of microsomal oxidation (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) increase the production of hydroxylated active metabolites, increasing the risk of severe intoxications. Inhibitors of microsomal oxidation reduce the risk of hepatotoxic action. It reduces the hypotensive activity of vasodilators, the natriuretic effect of furosemide and hydrochlorothiazide. It reduces the effectiveness of uricosuric drugs, enhances the effect of indirect anticoagulants, antiplatelet agents, fibrinolytics. It enhances the side effects of mineralocorticoids, glucocorticoids, estrogens, ethanol. It enhances the effect of oral hypoglycemic drugs and insulin, sulfonylurea derivatives.

Antacids and cholestyramine reduce absorption. It increases the blood concentration of digoxin, lithium preparations, methotrexate. Myelotoxic drugs enhance the manifestations of hematotoxicity. Preparations and drinks containing caffeine enhance the analgesic effect.

Codeine enhances the inhibitory effect of ethanol on the speed of psychomotor reactions. With simultaneous use of ethanol, muscle relaxants, as well as drugs that depress the CNS, an increase in the sedative effect, suppression of the respiratory center and depression of the CNS is possible. With simultaneous administration with other opioid analgesics, it increases the risk of CNS depression, respiration, and decreased blood pressure. It enhances the effects of hypotensive and antipsychotic drugs (neuroleptics), anxiolytics (tranquilizers), barbiturates and drugs for general anesthesia. Naloxone and naltrexone are specific antagonists. Naloxone reduces the effect of opioid analgesics, as well as the respiratory and CNS depression caused by them, larger doses may be required to counteract the effects of butorphanol, nalbuphine and pentazocine, which were prescribed to eliminate the undesirable effects of other opioids, may accelerate the appearance of symptoms of “withdrawal syndrome” against the background of drug dependence. Naltrexone accelerates the appearance of symptoms of “withdrawal syndrome” against the background of drug dependence (symptoms may appear as early as 5 minutes after drug administration, last for 48 hours, are characterized by persistence and difficulty in their elimination), reduces the effect of opioid analgesics (analgesic, antidiarrheal, antitussive), does not affect symptoms caused by the histamine reaction of drugs with anticholinergic activity, antidiarrheal drugs (including loperamide) increase the risk of constipation up to intestinal obstruction, urinary retention and CNS depression.

It should be used with caution simultaneously with MAO inhibitors due to possible overexcitation or inhibition with the occurrence of hyper- or hypotensive crises (initially, to assess the interaction effect, the dose should be reduced to 1/4 of the recommended one). It reduces the effect of metoclopramide.

Storage Conditions

In a dry place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

Over the counter.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.