Novigan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOVIGAN® (NOVIGAN)

Composition:

Active substances: ibuprofen, p-piperidinoethoxy-o-carbomethoxybenzophenone hydrochloride, alpha-piperidinoethyl diphenylacetamide methobromide;

One film-coated tablet contains 400 mg of ibuprofen, 5 mg of p-piperidinoethoxy-o-carbomethoxybenzophenone hydrochloride, and 0.1 mg of alpha-piperidinoethyl diphenylacetamide methobromide;

Excipients: microcrystalline cellulose, corn starch, glycerin, colloidal anhydrous silicon dioxide, talc, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide (E 171), polysorbate 80, sorbic acid, dimethicone.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets with a smooth surface on one side and embossing "NOVIGAN" on the other side.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic drugs. Ibuprofen combinations. ATC code M01AE51.

Pharmacological properties.

Pharmacodynamics.

Novigan® is a combined drug belonging to the group of analgesic and spasmolytic agents. The drug contains the following components: ibuprofen – a nonsteroidal anti-inflammatory drug (NSAID), p-piperidinoethoxy-o-carbomethoxybenzophenone hydrochloride – a myotropic spasmolytic agent, and alpha-piperidinoethyl diphenylacetamide methobromide – a centrally and peripherally acting cholinolytic agent.

The main mechanism of pharmacological action of ibuprofen is inhibition of prostaglandin synthesis. Nonselective nonsteroidal anti-inflammatory drugs, including ibuprofen, act as systemic inhibitors (peripheral and central) of prostaglandin G/H synthase enzymes, also known as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These enzymes are responsible for the conversion of arachidonic acid into various tissue-specific prostaglandins and thromboxanes. COX-1 is constitutively expressed in all tissues and is responsible for the production of prostaglandins that maintain organ function, protect the integrity of the gastric mucosa, and generate thromboxane involved in platelet aggregation and vasoconstriction. COX-2 is induced during inflammation and produces prostaglandins that mediate pain and inflammatory processes.

p-Piperidinoethoxy-o-carbomethoxybenzophenone hydrochloride exerts a direct myotropic effect on smooth muscles of internal organs. It inhibits phosphodiesterase, leading to accumulation of cAMP and reduction of intracellular calcium levels, resulting in relaxation of smooth muscles of blood vessels and internal organs.

Alpha-piperidinoethyl diphenylacetamide methobromide, due to its ganglion-blocking and anticholinergic effects, reduces the tone and motility of smooth muscles of the stomach, intestines, biliary and urinary tracts.

Pharmacokinetics.

Ibuprofen is well absorbed in the gastrointestinal tract following oral administration. Maximum plasma concentration is reached within 1–2 hours after administration. Approximately 99% of ibuprofen is bound to plasma proteins. It is primarily excreted in urine either unchanged or as oxidized inactive metabolites. It is completely eliminated from the body within 24 hours.

The combination of the three components of the drug results in mutual enhancement of their pharmacological effects, leading to pain relief, relaxation of smooth muscles, and reduction of elevated body temperature.

Clinical characteristics.

Indications.

Mild to moderate pain associated with smooth muscle spasms of internal organs – renal or hepatic colic, biliary tract dyskinesia, intestinal spasms, spastic dysmenorrhea, and other spastic conditions of the smooth musculature of internal organs. Headache, including migraine-type headache. Short-term symptomatic treatment of joint pain, neuralgia, sciatica, myalgia. For reduction of elevated body temperature in colds and infectious-inflammatory diseases.

Contraindications.

• Hypersensitivity to the components of the drug or to other nonsteroidal anti-inflammatory drugs (NSAIDs).
• Hypersensitivity reactions (e.g., bronchial asthma, rhinitis, angioedema, or urticaria) previously observed after administration of ibuprofen, acetylsalicylic acid (aspirin), or other NSAIDs.
• Novigan® is contraindicated in patients with a history of erosive-ulcerative gastrointestinal lesions, gastrointestinal bleeding, or perforation following NSAID use.
• Severe impairment of liver or kidney function, heart failure.
• Concomitant use of ibuprofen, especially at high doses, with other nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided due to the potential for additive effects and development of adverse cardiovascular events, including myocardial infarction and stroke.
• The drug is also contraindicated in hepatic porphyria, hereditary glucose-6-phosphate dehydrogenase deficiency, tachyarrhythmia, optic nerve damage, disorders of hematopoiesis or blood coagulation, blood disorders, closed-angle glaucoma, heart failure, benign prostatic hyperplasia, mechanical gastrointestinal obstruction or megacolon.
• Cerebrovascular or other bleeding conditions.
• Severe dehydration.
• Third trimester of pregnancy and lactation period.
• Age under 16 years.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Novigan® with other nonsteroidal anti-inflammatory drugs (NSAIDs) or non-opioid analgesics may lead to a doubled increase in toxic effects.

Concomitant use of Novigan® with the following medicinal products should be avoided:

Acetylsalicylic acid: concomitant use of ibuprofen and acetylsalicylic acid is generally not recommended due to the potential for increased adverse effects. Data suggest that ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when used concomitantly. Therefore, a reduction in the cardioprotective effect of low-dose acetylsalicylic acid may occur during prolonged ibuprofen use.

Novigan® should be used with caution in combination with the following medicinal products:

Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin.

Antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics: NSAIDs may reduce the therapeutic effect of these drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II antagonist with drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, such combinations should be used with caution, especially in elderly patients. Adequate hydration should be ensured if long-term treatment is necessary, and monitoring of renal function should be considered at the beginning of combined therapy and periodically thereafter.

Diuretics may increase the risk of nephrotoxic effects of NSAIDs.

Corticosteroids: increased risk of gastrointestinal ulcers and bleeding.

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

Cardiac glycosides: concomitant use with NSAIDs may lead to exacerbation of heart failure, decreased glomerular filtration rate, and increased plasma concentrations of cardiac glycosides.

Lithium preparations: concomitant use reduces lithium elimination, increasing its toxicity and plasma concentration.

Methotrexate: concomitant use reduces methotrexate elimination, increasing its toxicity and plasma concentration.

Cyclosporine: concomitant use with NSAIDs increases nephrotoxicity.

Mifepristone: NSAIDs may be used only 8–12 days after discontinuation of mifepristone, as NSAIDs reduce the effect of mifepristone.

Quinolone antibiotics: NSAIDs may increase the risk of convulsions associated with quinolone use.

Zidovudine: evidence exists of increased risk of hemarthrosis and hematoma in HIV-infected patients receiving concomitant treatment with zidovudine and ibuprofen.

Tacrolimus: increased risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus.

The herbal preparation Ginkgo biloba may potentiate the risk of bleeding when used with nonsteroidal anti-inflammatory drugs.

Special precautions for use.

The drug should be used with caution and under medical supervision in patients with moderate impairment of liver or kidney function, predisposition to arterial hypertension or bronchospasm, systemic lupus erythematosus and other systemic connective tissue diseases – due to increased risk of aseptic meningitis; and in patients with a history of heart failure associated with fluid retention and edema during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).

Effect on cardiovascular and cerebrovascular systems.

Clinical trial data and epidemiological evidence suggest that use of ibuprofen, particularly at high doses (2400 mg per day) and with prolonged administration, may lead to a small increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological data do not indicate that low-dose ibuprofen (e.g., ≤ 1200 mg per day) increases the risk of myocardial infarction. Long-term treatment in patients with uncontrolled arterial hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be prescribed by a physician only after careful consideration. Patients with significant cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) should exercise caution and consult a physician before initiating treatment, as fluid retention, hypertension, and edema have been reported during NSAID therapy.

Cases of Kounis syndrome (cardiovascular symptoms arising from an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction) have been reported in patients receiving ibuprofen therapy.

Effect on the respiratory system.

Bronchospasm may occur in patients with bronchial asthma or allergic diseases, or those with such conditions in their medical history.

Other NSAIDs.

Concomitant use of ibuprofen with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided, as this increases the risk of adverse reactions.

Effect on the kidneys.

Risk of renal impairment due to worsening kidney function: prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and provoke the development of renal failure. Patients with pre-existing kidney dysfunction, heart disorders, liver dysfunction, those taking diuretics, and elderly patients are at higher risk. Renal function should be monitored in such patients. Patients who are dehydrated have an increased risk of kidney damage.

Effect on female fertility.

Limited data suggest that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis may affect ovulation. This effect is reversible upon discontinuation of treatment. Long-term use of ibuprofen (referring to a daily dose of 2400 mg and treatment duration exceeding 10 days) may impair female fertility and is not recommended for women attempting to conceive. This medication should be discontinued in women experiencing difficulty conceiving or undergoing infertility investigations.

Effect on the gastrointestinal tract.

NSAIDs should be used with caution in patients with chronic inflammatory bowel diseases (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated. Cases of gastrointestinal bleeding, perforation, and ulcers, which may be fatal, have been reported at any stage of NSAID treatment, regardless of warning symptoms or history of severe gastrointestinal disorders.

Higher NSAID doses, advanced age, and history of peptic ulcer disease increase the risk of gastrointestinal adverse reactions. In such cases, the lowest effective dose for the shortest possible duration is recommended.

The drug should be used with caution in patients receiving concomitant therapy with medications that may increase the risk of gastric or duodenal ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid. Patients who experience gastrointestinal disturbances, especially elderly individuals, should discontinue treatment and consult a physician if any adverse symptoms occur (particularly gastrointestinal bleeding).

Severe skin adverse reactions.

Exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported during treatment with ibuprofen-containing medications (see section "Adverse reactions"). These severe skin reactions may be life-threatening and/or lead to fatal outcomes. Most such reactions occur within the first month of treatment.

At the first signs or symptoms of skin adverse reactions (skin rash, blistering, mucosal lesions, or any other signs of hypersensitivity), ibuprofen should be discontinued immediately, and alternative therapy should be considered if necessary.

The use of the drug should be avoided in chickenpox, as concomitant use of NSAIDs may worsen the course of the disease. NSAIDs may promote the development of complications such as serious skin and soft tissue infections.

During prolonged use (more than one week), monitoring of peripheral blood parameters and liver function is required.

The drug may affect the psychophysiological state of patients when used concomitantly with alcohol or central nervous system (CNS) depressants.

Prolonged and uncontrolled use of analgesics, especially combinations of different analgesic active substances, may lead to chronic kidney damage with risk of renal failure (analgesic nephropathy).

The drug should not be used in patients with hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Masking symptoms of underlying infections

As with other NSAIDs, administration of ibuprofen-containing drugs may mask symptoms of infectious diseases, potentially delaying appropriate treatment and thereby complicating disease progression. This has been observed in community-acquired bacterial pneumonia and bacterial complications of chickenpox.

When Novigan® is used to reduce fever or relieve pain associated with infection, monitoring of the infectious condition is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Use during pregnancy or breastfeeding.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and congenital malformations following use of prostaglandin synthesis inhibitors in early pregnancy. The risk is considered to increase with higher doses and longer duration of therapy.

From the 20th week of pregnancy, use of the drug may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of fetal arterial duct constriction after treatment during the second trimester, which in most cases resolved after stopping the drug. Therefore, Novigan® should not be prescribed during the first and second trimesters of pregnancy unless clearly necessary. If the drug is used by a woman trying to conceive or during the first or second trimester of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Prenatal monitoring for oligohydramnios and fetal arterial duct constriction may be advisable if the drug has been used for several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios or arterial duct constriction is detected.

During the third trimester of pregnancy, use of any prostaglandin synthesis inhibitor carries the following risks:

for the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the fetal arterial duct with pulmonary hypertension);
• impaired kidney function, which may progress to renal failure manifesting as oligohydramnios (see above);

for the mother at the end of pregnancy and for the newborn:

• prolonged bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding should be discontinued during treatment with this drug.

Ability to affect reaction speed when driving or operating machinery.

Caution is required when driving vehicles or engaging in other potentially hazardous activities requiring increased attention and rapid psychomotor reactions.

Dosage and Administration

The lowest effective dose required to treat symptoms should be used for the shortest possible duration. If symptoms persist for more than 5 days after starting treatment or worsen, medical advice should be sought.

It is advisable to take Novigan® either 1 hour before or 3 hours after a meal. Tablets should be swallowed whole with water and not chewed. To prevent gastric irritation, the drug should be taken immediately after food or with milk.

The recommended dose is 1 tablet up to 3 times daily. The maximum recommended daily dose is 3 tablets.

Repeat doses may be taken as needed every 4–6 hours. Do not exceed the daily dose of 1200 mg of ibuprofen.

Elderly patients do not require special dosage adjustments.

Children. Do not administer the drug to children under 16 years of age.

Overdose.

Symptoms. Overdose manifests as gastrointestinal disturbances (diarrhea, nausea, vomiting (vomit may contain blood streaks), anorexia, epigastric pain), and signs of hepatotoxicity.

Weakness, dizziness, tinnitus, headache, confusion, nystagmus, and gastrointestinal bleeding may occur. In severe poisoning, toxic effects on the central nervous system may develop, presenting as chest pain, tachycardia, respiratory disturbances, drowsiness, occasionally agitation and disorientation, or coma. Seizures may occur in some patients. In more severe cases, metabolic acidosis and prolonged prothrombin time/INR (likely due to interaction with circulating blood coagulation factors) may develop. Acute renal failure (hematuria) and liver damage may also occur. In patients with bronchial asthma, an exacerbation of asthma may be observed.

Treatment. Symptomatic and supportive therapy is indicated, including maintaining airway patency and monitoring cardiac function and vital signs until the patient stabilizes. Gastric lavage and activated charcoal administration are recommended within 1 hour after ingestion of a large dose. Adequate urine output should be maintained, and renal and hepatic functions should be monitored. Patients who have ingested potentially toxic doses should be observed for at least 4 hours. In case of seizures, intravenous diazepam or lorazepam may be administered. In cases of bronchial asthma, bronchodilators should be used.

Side effects

The occurrence of adverse reactions can be minimized by using the lowest effective dose for the shortest duration possible.

The following adverse reactions have been observed with short-term use of ibuprofen at doses not exceeding 1200 mg/day. Other adverse reactions may occur during treatment of chronic conditions or with long-term use.

Adverse reactions associated with ibuprofen use are classified by system organ class and frequency. Frequency is defined as follows: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1000 to <1/100; rare: ≥1/10,000 to <1/1000; very rare: <1/10,000; frequency not known (cannot be estimated from available data).

Gastrointestinal system.

Possible: abdominal pain, dyspepsia, nausea.

Rare: diarrhea, flatulence, constipation, vomiting.

Very rare: peptic ulcers, gastrointestinal perforation or hemorrhage, heartburn, melena, hematemesis (sometimes fatal), ulcerative stomatitis, exacerbation of ulcerative colitis and Crohn's disease, gastritis, esophagitis.

Blood and lymphatic system.

Very rare: blood disorders¹.

¹ Includes anemia, leukopenia, thrombocytopenia, pancytopenia, and agranulocytosis. Initial signs of such disorders include malaise, sore throat, superficial oral ulcers, flu-like symptoms, severe exhaustion, bleeding, and unexplained bruising.

Cardiovascular system.

Rare: tachycardia, dyspnea, cerebrovascular complications, arterial hypotension, palpitations.

Very rare: edema, arterial hypertension, heart failure.

With long-term use and at high doses (2400 mg/day), there may be an increased risk of arterial thrombotic events (e.g., stroke or myocardial infarction), and reduced effectiveness of antihypertensive medications.

Frequency not known: Cozzarelli syndrome.

General disorders.

Very rare: nonspecific allergic reactions and anaphylactic shock, asthma or worsening of asthma, bronchospasm, rash, pruritus, urticaria, purpura, angioedema.

Nervous system.

Uncommon: headache.

Very rare: optic neuritis, paresthesia, nervousness, dizziness, somnolence, irritability, tinnitus, depression, insomnia, anxiety, psychomotor agitation, emotional instability, convulsions.

Frequency not known: hallucinations, confusion.

Immune system.

Uncommon: hypersensitivity reactions accompanied by urticaria and pruritus².

Very rare: severe hypersensitivity reactions, symptoms of which may include facial, tongue, and laryngeal swelling, dyspnea, tachycardia, arterial hypotension (anaphylaxis, angioedema, or severe shock).

² Hypersensitivity reactions may include: (a) nonspecific allergic reactions and anaphylaxis, (b) respiratory tract reactivity including asthma, asthma exacerbation, bronchospasm, and dyspnea, or (c) various skin reactions including pruritus, urticaria, purpura, angioedema, and less commonly exfoliative and bullous dermatoses including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.

In patients with systemic lupus erythematosus and mixed connective tissue diseases, ibuprofen use may rarely lead to symptoms of aseptic meningitis, including nuchal rigidity, headache, vomiting, high fever, or disorientation.

Blood and lymphatic system organs.

Very rare: blood disorders (hemolytic anemia, aplastic anemia, thrombocytopenia, neutropenia, eosinophilia, decreased hematocrit and hemoglobin levels, pancytopenia, agranulocytosis). Initial signs include high fever, sore throat, oral ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding, and bruising. Reversible platelet aggregation, alveolitis, pulmonary eosinophilia.

Eye organs.

Very rare: blurred vision, color vision disturbances, toxic amblyopia.

Frequency not known: visual disturbances.

Hepatobiliary system.

Very rare: liver function abnormalities, hepatitis, jaundice, duodenitis, pancreatitis, hepatorenal syndrome, liver failure, hepatonecrosis.

Skin and subcutaneous tissue.

Rare: skin desquamation, alopecia, photosensitivity, various skin rashes.

Very rare: severe skin adverse reactions (including erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis).

Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP), skin and soft tissue infections (in rare cases, varicella may lead to complications such as severe skin and soft tissue infections).

If a widespread red scaly rash with subcutaneous nodules and blisters, predominantly localized in skin folds, trunk, and upper limbs, accompanied by fever at the beginning of treatment, appears, the medication should be discontinued immediately and medical advice sought, as these signs may indicate acute generalized exanthematous pustulosis (see section "Special precautions").

Renal and urinary system.

Very rare: papillary necrosis, cystitis, hematuria, nephrotic syndrome, oliguria, polyuria, tubular necrosis, glomerulonephritis, renal function impairment, toxic nephropathy in various forms including interstitial nephritis, nephrotic syndrome and renal failure, acute kidney injury.³

³ Particularly with long-term use of NSAIDs, associated with increased serum urea levels and edema. Also includes papillary necrosis.

Other effects.

Rare: dryness of mucous membranes of eyes and mouth, stomatitis, fever, malaise, weakness, fatigue, hearing disturbances, ulcerative stomatitis.

Very rare: endocrine system and metabolic changes, decreased appetite.

Laboratory tests.

Very rare: decreased hemoglobin levels.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions. Store in a dry, light-protected place, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 10 tablets per blister, 1 blister per cardboard box.

Availability category. Over-the-counter.

Manufacturer.

Dr. Reddy’s Laboratories Limited.

Manufacturer’s address and location of operations.

Manufacturing site – VI, Village Khol, Nalagarh Road, Baddi, District Solan, Himachal Pradesh, 173205, India.

To report an adverse reaction or lack of efficacy during use of this medicinal product, please call (24/7):
+380 44 207 51 97 or +380 50 414 39 39; or email: [email protected]