Novigan^® Lady (Tablets) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Contact Information

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

M01AE51 (Ibuprofen in combination with other drugs)

Active Substances

Ibuprofen (Rec.INN registered by WHO)

Drotaverine (Rec.INN registered by WHO)

Dosage Form

Novigan® Lady

Film-coated tablets 80 mg+400 mg: 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light pink to pink in color, biconvex, oblong in shape; on the cross-section – a light yellow core.

Excipients: pregelatinized starch, microcrystalline cellulose (Avicel PH101), colloidal silicon dioxide, crospovidone, sodium lauryl sulfate, lactose monohydrate, povidone (PVP K-30), ascorbic acid, citric acid monohydrate, microcrystalline cellulose (Grade 102), stearic acid.

Film coating composition Opadry II pink 32K540017: lactose monohydrate, hypromellose 15 cP, titanium dioxide (E171), triacetin, Allura Red AC dye (E129), Sunset Yellow FCF dye (E110), Indigo Carmine (E132).

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

NSAIDs of combined composition

Pharmacotherapeutic Group

Anti-inflammatory and antirheumatic drugs; non-steroidal anti-inflammatory and antirheumatic drugs; propionic acid derivatives

Pharmacological Action

Drotaverine

An isoquinoline derivative that has a powerful antispasmodic effect on smooth muscle by inhibiting the enzyme phosphodiesterase type 4 (PDE 4). Inhibition of the PDE 4 enzyme leads to an increase in the concentration of cyclic adenosine monophosphate (cAMP), inactivation of myosin light chain kinase, which subsequently causes relaxation of smooth muscle. The antagonistic effect of drotaverine on Ca²⁺ ions is explained by its effect, mediated through cAMP, leading to a decrease in the concentration of Ca²⁺ ions.

In vitro, Drotaverine inhibits the PDE 4 enzyme (most important for suppressing the contractile activity of smooth muscle), without inhibiting PDE 3 and PDE 5 enzymes. Therefore, the efficacy of drotaverine depends on the concentration of PDE 4 in different tissues.

The hydrolysis of cAMP in the myocardium and vascular smooth muscle occurs mainly with the participation of PDE 3, which explains the fact that with high antispasmodic activity, drotaverine lacks serious adverse reactions from the heart and blood vessels and pronounced effects on the cardiovascular system.

Drotaverine is effective for spasms of smooth muscle of both neurogenic and muscular origin. Regardless of the type of autonomic innervation, Drotaverine relaxes the smooth muscles of the gastrointestinal tract, biliary tract, genitourinary system, and blood vessels.

Due to its vasodilating action, Drotaverine improves tissue blood supply. The described mechanisms of action of drotaverine eliminate smooth muscle spasm, which leads to a reduction in pain.

Ibuprofen

The mechanism of action of ibuprofen, a propionic acid derivative from the NSAID group, is due to inhibition of the synthesis of prostaglandins – mediators of pain, inflammation and hyperthermic reaction. It non-selectively blocks COX-1 and COX-2, thereby inhibiting the synthesis of prostaglandins. It has a rapid targeted action against pain (analgesic), antipyretic and anti-inflammatory effects. In addition, Ibuprofen reversibly inhibits platelet aggregation. The analgesic effect of the drug lasts up to 8 hours.

Pharmacokinetics

Drotaverine

Absorption

After oral administration, Drotaverine is rapidly and completely absorbed from the gastrointestinal tract. After presystemic metabolism, 65% of the administered dose of drotaverine enters the systemic circulation. C_max in blood plasma is reached after 45-60 minutes.

Distribution

In vitro, Drotaverine has a high degree of binding to plasma proteins (95-98%), especially to albumin, β- and γ-globulins. Drotaverine is evenly distributed in tissues, penetrates into smooth muscle cells. It does not penetrate the blood-brain barrier. Drotaverine and/or its metabolites are able to slightly penetrate the placental barrier.

Metabolism

In humans, Drotaverine is almost completely metabolized by O-desethylation in the liver.

Excretion

T_1/2 is 8-10 hours. Within 72 hours, Drotaverine is almost completely eliminated from the body, more than 50% of the drug is excreted by the kidneys (mainly in the form of metabolites) and about 30% through the gastrointestinal tract (excretion in bile). Unchanged Drotaverine is not detected in the urine.

Ibuprofen

Absorption

Absorption is high, rapidly and almost completely absorbed from the gastrointestinal tract. After administration on an empty stomach, C_max of ibuprofen in blood plasma is reached after 45 minutes. Taking the drug with food may increase the time to reach maximum concentration T_Cmax to 1-2 hours.

Distribution

Plasma protein binding – 90%. It slowly penetrates into the joint cavity, is retained in the synovial fluid, creating higher concentrations in it than in blood plasma. Lower concentrations of ibuprofen are found in the cerebrospinal fluid compared to blood plasma.

Metabolism

After absorption, about 60% of the pharmacologically inactive R-form of ibuprofen is slowly transformed into the active S-form. It undergoes metabolism in the liver.

Excretion

T_1/2 is 2 hours. It is excreted by the kidneys (unchanged no more than 1%) and, to a lesser extent, with bile.

In limited studies, Ibuprofen was detected in breast milk in very low concentrations.

Indications

• For the relief of pain and spasms in menstrual cycle disorders (algodysmenorrhea) in the absence of other diseases of the reproductive system (primary dysmenorrhea).

ICD codes

Dosage Regimen

The drug is intended for oral administration. The tablets should be taken with water. It is recommended to take the drug after meals to reduce the risk of adverse effects from the gastrointestinal tract.

1 tablet of 80 mg + 400 mg (single dose) not more than 3 times/day (maximum daily dose 240 mg for drotaverine and 1200 mg for ibuprofen).

The interval between doses of the drug is at least 4 hours.

It is recommended to take the drug in a short course, at the minimum effective dose. Do not use the drug for more than 3 days without consulting a doctor.

If no improvement is seen within 2-3 days or symptoms worsen, or new symptoms appear, it is necessary to consult a doctor.

The drug should be used only according to the indication, method of administration and doses specified in the instructions for use.

Special patient groups

Patients with impaired liver or kidney function

The use of the drug is contraindicated in patients with severe hepatic insufficiency and/or severe renal insufficiency (creatinine clearance less than 30 ml/min).

Children

The drug is contraindicated in children (there is no data on the efficacy and safety of the Drotaverine + Ibuprofen combination in children under 18 years of age).

Adverse Reactions

The risk of side effects can be minimized by taking the drug in a short course, at the minimum effective dose necessary to relieve symptoms.

Elderly people have an increased frequency of side effects while using NSAIDs, especially gastrointestinal bleeding and perforations. Side effects are dose-dependent. In particular, the risk of gastrointestinal bleeding depends on the dose range and the duration of treatment.

Side effects expected based on the experience of using drotaverine and ibuprofen are grouped by system-organ classes with an indication of the frequency of their occurrence according to the WHO classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency unknown (cannot be estimated from the available data). When grouped by frequency, adverse reactions are listed in order of decreasing severity.

Drotaverine

If the side effects listed in the instructions occur, or they worsen, or any other side effects not listed in the instructions occur, the use of the drug should be discontinued and a doctor should be consulted.

Contraindications

• Hypersensitivity to ibuprofen, drotaverine or to any of the excipients included in the drug;
• Complete or incomplete combination of bronchial asthma, recurrent nasal and paranasal sinus polyposis, and intolerance to acetylsalicylic acid or other NSAIDs (including in history);
• Erosive and ulcerative diseases of the gastrointestinal tract (including peptic ulcer of the stomach and duodenum, Crohn’s disease, ulcerative colitis) or ulcerative bleeding in the active phase or in history (2 or more confirmed episodes of peptic ulcer or ulcerative bleeding, including those provoked by the use of NSAIDs);
• Severe heart failure, class IV according to NYHA (New York Heart Association classification);
• Severe hepatic insufficiency or active liver disease;
• Severe renal insufficiency (creatinine clearance less than 30 ml/min), confirmed hyperkalemia;
• Decompensated heart failure;
• Period after coronary artery bypass grafting;
• Severe degree of dehydration caused by prolonged vomiting, diarrhea or insufficient fluid intake;
• Malignant hypertension;
• Use of anticoagulants;
• History of chronic respiratory tract infections;
• Parkinson’s disease;
• Epilepsy;
• Systemic lupus erythematosus (SLE);
• Cerebrovascular or other bleeding;
• Hemophilia and other blood clotting disorders (including hypocoagulation), hemorrhagic diatheses;
• Lactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age (no data on the efficacy and safety of the Drotaverine + Ibuprofen combination in children under 18 years of age).

With caution

• In patients with arterial hypotension;
• With simultaneous use with levodopa, with other NSAIDs;
• With a history of a single episode of duodenal ulcer or gastrointestinal ulcer bleeding, or conditions such as gastritis, enteritis, colitis, presence of Helicobacter pylori infection, ulcerative colitis;
• Bronchial asthma or allergic diseases in the acute stage or in history – bronchospasm may develop;
• SLE or mixed connective tissue disease (Sharp’s syndrome) – increased risk of aseptic meningitis;
• Chickenpox;
• Renal insufficiency, including with dehydration (creatinine clearance value less than 30-60 ml/min);
• Nephrotic syndrome;
• Hepatic insufficiency;
• Liver cirrhosis with portal hypertension;
• Hyperbilirubinemia;
• Arterial hypertension and/or heart failure;
• Cerebrovascular diseases;
• Diseases of the blood of unclear etiology (leukopenia and anemia);
• Severe somatic diseases;
• Dyslipidemia/hyperlipidemia;
• Diabetes mellitus;
• Peripheral arterial diseases;
• Smoking;
• Frequent alcohol consumption;
• Phenylketonuria or phenylalanine intolerance;
• Simultaneous use of drugs that may increase the risk of ulcers or bleeding, in particular:
  • Oral corticosteroids (including prednisolone);
  • Anticoagulants (including warfarin);
  • Selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline);
  • Antiplatelet agents (including acetylsalicylic acid, clopidogrel);
• Elderly age.

Use in Pregnancy and Lactation

Pregnancy

The use of the drotaverine and ibuprofen combination during pregnancy is contraindicated.

Breastfeeding period

The use of the drotaverine and ibuprofen combination during breastfeeding is contraindicated.

Fertility

The drug inhibits COX and prostaglandin synthesis, affects ovulation, disrupting it (reversible after discontinuation of treatment).

Use in Hepatic Impairment

The use of the drug is contraindicated in patients with severe hepatic insufficiency. With caution – hepatic insufficiency, liver cirrhosis with portal hypertension, hyperbilirubinemia.

Use in Renal Impairment

The use of the drug is contraindicated in patients with severe renal insufficiency (creatinine clearance less than 30 ml/min). With caution in renal insufficiency, including with dehydration (creatinine clearance value less than 30-60 ml/min).

Pediatric Use

Contraindicated for use in children under 18 years of age (no data on the efficacy and safety of the Drotaverine + Ibuprofen combination in children under 18 years of age).

Geriatric Use

Use with caution in elderly patients.

Special Precautions

It is recommended to take the drug for the shortest possible course and at the minimum effective dose necessary to relieve symptoms.

In patients with bronchial asthma or an allergic disease in the acute stage, as well as in patients with a history of bronchial asthma/allergic disease, the drug may provoke bronchospasm.

The use of the drug in patients with SLE or mixed connective tissue disease is associated with an increased risk of developing aseptic meningitis.

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.

Patients with renal insufficiency need additional consultation before using the drug, as there is a risk of worsening the functional state of the kidneys.

Patients with hypertension, including in history, and/or chronic heart failure also need additional consultation, since the drug can cause fluid retention, increased blood pressure and edema. Patients with uncontrolled arterial hypertension, congestive heart failure class II-III according to NYHA, coronary artery disease, peripheral arterial diseases and/or cerebrovascular diseases should be prescribed Ibuprofen only after a thorough assessment of the benefit/risk ratio, and the use of ibuprofen in high doses (≥2400 mg/day) should be avoided.

The use of NSAIDs in patients with chickenpox may be associated with an increased risk of developing severe purulent complications of infectious and inflammatory diseases of the skin and subcutaneous fat (for example, necrotizing fasciitis). In this regard, it is recommended to avoid the use of the drug for chickenpox.

Use in arterial hypotension requires increased caution.

Effect on laboratory tests

If it is necessary to determine 17-ketosteroids, the drug should be discontinued 48 hours before the study.

Effect on ability to drive vehicles and mechanisms

Adverse reactions such as dizziness, drowsiness, lethargy or visual impairment may develop during the use of the drug (see section “Adverse Reactions”). Patients who develop these adverse reactions should avoid driving vehicles and operating machinery.

Overdose

Symptoms

Drotaverine

Overdose has been associated with cardiac rhythm and conduction disorders, including complete bundle branch block and cardiac arrest, which may be fatal.

Ibuprofen

Nausea, vomiting, epigastric pain or, less commonly, diarrhea, tinnitus, headache, and gastrointestinal bleeding. In more severe cases, manifestations from the central nervous system are observed: drowsiness, rarely – agitation, convulsions, disorientation, coma. In cases of severe poisoning, metabolic acidosis and increased prothrombin time, renal failure, liver tissue damage, decreased blood pressure, respiratory depression and cyanosis may develop. In patients with bronchial asthma, an exacerbation of this disease is possible.

T_1/2 of the drug in case of overdose is 1.5-3 hours.

Treatment

Symptomatic, with mandatory maintenance of airway patency, ECG monitoring, and monitoring of vital signs until the patient’s condition normalizes. Oral administration of activated charcoal or gastric lavage within 1 hour after ingestion of a potentially toxic dose of ibuprofen is recommended. Alkaline fluids may be prescribed to promote the renal excretion of the acidic ibuprofen metabolite, along with forced diuresis.

Frequent or prolonged seizures should be controlled by intravenous administration of diazepam or lorazepam. In case of worsening bronchial asthma, the use of bronchodilators is recommended.

Drug Interactions

Contraindicated Combinations

Acetylsalicylic acid (ASA) (except for low doses not exceeding 75 mg/day)

When used concomitantly, Ibuprofen reduces the anti-inflammatory and antiplatelet effects of ASA.

Other NSAIDs, particularly selective COX-2 inhibitors

The concomitant use of two or more drugs from the NSAID group should be avoided due to the possible increased risk of adverse reactions.

Interactions Requiring Caution

Anticoagulants and thrombolytic drugs

NSAIDs may enhance the effect of anticoagulants (e.g., warfarin) and thrombolytic drugs.

Antihypertensive agents (ACE inhibitors and angiotensin II antagonists) and diuretics

NSAIDs may reduce the effectiveness of drugs in these groups. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), the concomitant use of ACE inhibitors or angiotensin II antagonists and agents that inhibit COX may lead to deterioration of renal function, including the development of acute renal failure (usually reversible).

These interactions should be considered in patients taking coxibs concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, caution should be exercised when using the aforementioned agents concomitantly, especially in the elderly. Dehydration should be prevented in such patients, and consideration should be given to monitoring renal function after initiation of such combined therapy and periodically thereafter.

Diuretics and ACE inhibitors may increase the nephrotoxicity of NSAIDs.

Glucocorticoids

Increased risk of gastrointestinal ulcers or bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors

Increased risk of gastrointestinal bleeding.

Cardiac glycosides

Concomitant use of NSAIDs and cardiac glycosides may lead to worsening of heart failure, reduced glomerular filtration rate, and increased plasma concentrations of cardiac glycosides.

Lithium preparations

There is evidence of a probable increase in plasma lithium concentrations during the use of NSAIDs.

Methotrexate

There is evidence of a probable increase in plasma methotrexate concentrations during the use of NSAIDs.

Cyclosporine

Increased risk of nephrotoxicity with concomitant use of NSAIDs and cyclosporine.

Mifepristone

NSAIDs should be started no earlier than 8-12 days after taking mifepristone, as NSAIDs may reduce the effectiveness of mifepristone.

Tacrolimus

Concomitant use of NSAIDs and tacrolimus may increase the risk of nephrotoxicity.

Zidovudine

Concomitant use of NSAIDs and zidovudine may lead to increased hematotoxicity.

Quinolone antibiotics

In patients receiving NSAIDs and quinolone antibiotics concomitantly, there may be an increased risk of seizures.

Myelotoxic drugs

Increased hematotoxicity.

Cefamandole, cefoperazone, cefotetan, valproic acid, plicamycin

Increased incidence of hypoprothrombinemia.

Drugs that block tubular secretion

Reduced excretion and increased plasma concentration of ibuprofen.

Inducers of microsomal oxidation (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants)

Increased production of hydroxylated active metabolites, increased risk of severe intoxication.

Inhibitors of microsomal oxidation

Reduced risk of hepatotoxic effects.

Oral hypoglycemic drugs and insulin, sulfonylurea derivatives

Enhanced effect of the drugs.

Antacids and cholestyramine

Reduced absorption of ibuprofen.

Uricosuric drugs

Reduced effectiveness of the drugs.

Caffeine

Enhanced analgesic effect of ibuprofen.

Levodopa

Phosphodiesterase (PDE) inhibitors, like papaverine, reduce the antiparkinsonian effect of levodopa. When drotaverine is prescribed concomitantly with levodopa, increased rigidity and tremor may occur.

Other antispasmodic agents, including m-cholinoblockers

Mutual enhancement of the antispasmodic action of drotaverine.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is available without a prescription.

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.