Naklofen Protect (Capsule kit) Instructions for Use

Marketing Authorization Holder

Krka-Rus, LLC (Russia)

ATC Code

M01AB55 (Diclofenac in combination with other drugs)

Active Substances

Diclofenac (Rec.INN registered by WHO)

Lansoprazole (Rec.INN registered by WHO)

Dosage Form

Naklofen Protect

Set of capsules: 75 mg prolonged-release caps. and 15 mg enteric-soluble caps., 5 pcs. of each type in a blister; 2, 4, or 6 blisters

Dosage Form, Packaging, and Composition

Prolonged-release capsules No. 2, capsule body white, cap blue; capsule contents – enteric-coated pellets and prolonged-release pellets from white to cream-colored.

Enteric-soluble capsules No. 3, capsule body white, cap red-brown; capsule contents – pellets from white to white with a slightly yellowish or slightly pinkish tint.

10 pcs. (5+5) – blister packs (2) – cardboard packs.
10 pcs. (5+5) – blister packs (4) – cardboard packs.
10 pcs. (5+5) – blister packs (6) – cardboard packs.

Clinical-Pharmacological Group

NSAID

Pharmacotherapeutic Group

NSAID + Gastric iron secretion reducing agent – proton pump inhibitor

Pharmacological Action

Diclofenac – NSAID, a phenylacetic acid derivative. It has anti-inflammatory, analgesic, antipyretic, and antiplatelet effects. By non-selectively inhibiting cyclooxygenase 1 and 2, it disrupts arachidonic acid metabolism, reduces the amount of prostaglandins (Pg) at the site of inflammation, and suppresses the exudative and proliferative phases of inflammation. In rheumatic diseases, the anti-inflammatory and analgesic effects of diclofenac contribute to a significant reduction in the severity of pain, morning stiffness, and joint swelling, which improves the condition of the joint.

Lansoprazole – a drug from the group of proton pump inhibitors. It does not exhibit anticholinergic or antihistamine properties, specifically binds to H⁺/K⁺-ATPase (also called the proton pump) on the secretory surface of gastric parietal cells and prevents the final stage of gastric juice secretion.

Lansoprazole reduces basal, daytime, and nighttime gastric juice secretion, which prevents food-stimulated gastric juice secretion and increased secretion caused by other factors, such as gastrin and pentagastrin, and also prevents insulin-receptor-mediated increase in gastric juice volume and acidity. It lowers the acidity of gastric juice and the duration of time during which the pH value is >4. The effect is proportional to the dose.

After discontinuation of lansoprazole therapy, the pH of gastric juice decreases gradually and returns to normal within 2-4 days. No cases of significant increase in gastric juice secretion after treatment cessation were identified.

Lansoprazole increases the activity of pepsinogen in the blood serum and reduces the activity of pepsin below basal values after food stimulation.

During treatment with lansoprazole, the average gastrin activity in the blood serum increases by 1.5-2 times. The concentration increases during the first 8 weeks of treatment, after which it reaches a plateau and returns to initial values after therapy completion within 4 weeks.

Pharmacokinetics

Absorption

Absorption is rapid and complete; food slows the rate of absorption. Maximum concentration is noted 30-60 minutes after oral administration. Plasma concentration is linearly dependent on the orally administered dose. No changes in diclofenac pharmacokinetics with repeated use are noted. Bioavailability is 50%.

Distribution

Does not accumulate when the recommended interval between doses is observed. Plasma protein binding is more than 99% (most binds to albumin).

Metabolism

50% undergoes metabolism during the first-pass effect through the liver. Metabolism occurs as a result of multiple or single hydroxylation and conjugation with glucuronic acid. The isoenzyme CYP2C9 is also involved in the metabolism of diclofenac. The pharmacological activity of metabolites is lower than that of diclofenac.

Elimination

Systemic clearance is 260 ml/min. T_1/2 from plasma is 2 hours. Elimination from synovial fluid is slower than from plasma. 70% of the administered dose is excreted as metabolites by the kidneys; less than 1% is excreted unchanged, the remainder of the dose is excreted as metabolites with bile. In patients with severe renal impairment, the excretion of metabolites with bile increases, but no increase in their blood concentration is observed. In patients with chronic hepatitis or compensated liver cirrhosis, the pharmacokinetic parameters are the same as in patients without liver disease. Diclofenac penetrates into breast milk.

Lansoprazole

Absorption

Absorption is high, bioavailability 80%. Food intake reduces absorption and bioavailability (by 50%), but the inhibitory effect on gastric secretion remains the same, regardless of food intake. Time to reach maximum concentration (0.75-1.15 mg/l) is 1.7 hours. Maximum plasma concentration and area under the concentration/time curve (AUC) are approximately proportional to the administered dose of the drug.

Distribution

No accumulation occurs. Plasma protein binding is 97%. Penetrates well into tissues, including the parietal cells of the gastric mucosa. Volume of distribution 0.5 l/kg.

Metabolism

Extensively metabolized during the first pass through the liver with the participation of the isoenzyme CYP2C19 to form sulfonyl, sulfone, and hydroxyl derivatives. Inhibits the activity of CYP2C19.

Elimination

T_1/2 of lansoprazole is less than 2 hours and does not reflect the duration of gastric secretion suppression. In case of impaired liver function, T_1/2 increases 3-4 times. Lansoprazole is excreted as metabolites; approximately one third of lansoprazole is excreted by the kidneys and two thirds – with bile through the intestine (renal failure does not significantly affect the excretion rate).

Indications

Symptomatic therapy of inflammatory and degenerative diseases of the musculoskeletal system in patients at risk of developing gastric and/or duodenal ulcers associated with NSAID use: rheumatoid arthritis; psoriatic arthritis; juvenile chronic arthritis; ankylosing spondylitis; gouty arthritis; rheumatic soft tissue lesions; osteoarthritis of peripheral joints and spine (including with radicular syndrome); tenosynovitis; bursitis.

ICD codes

Dosage Regimen

Take orally. The regimen is individual, based on the specific indication, patient age, and clinical situation.

For adult patients, the typical daily dose is one 75 mg diclofenac prolonged-release capsule and one 15 mg lansoprazole enteric-soluble capsule.

Take both capsules once daily, in the morning, before a meal. Swallow the capsules whole with a sufficient amount of water; do not chew or crush.

Use the lowest effective dose for the shortest duration necessary to control symptoms. Do not exceed the maximum daily dose of 150 mg diclofenac.

For long-term therapy, periodically re-evaluate the need for continued treatment. Monitor liver enzymes and perform regular blood counts and fecal occult blood tests.

In elderly patients and those with mild to moderate hepatic or renal impairment, use at the minimum effective dose with increased monitoring.

The duration of treatment is determined by the physician. Do not stop taking the medication without consulting your doctor.

Adverse Reactions

Diclofenac

From the digestive system: frequently – epigastric pain, nausea, vomiting, diarrhea, dyspepsia, flatulence, anorexia, increased activity of aminotransferases; rarely – gastritis, proctitis, gastrointestinal bleeding (hematemesis, melena, diarrhea with blood), gastrointestinal ulcers (with or without bleeding or perforation), hepatitis, jaundice, impaired liver function; very rarely – stomatitis, glossitis, esophagitis, nonspecific hemorrhagic colitis, exacerbation of ulcerative colitis or Crohn’s disease, constipation, pancreatitis, fulminant hepatitis.

From the nervous system: frequently – headache, dizziness; rarely – drowsiness; very rarely – sensory disturbances (including paresthesia), memory disorders, tremor, convulsions, anxiety, cerebrovascular disorders, aseptic meningitis, disorientation, depression, insomnia, nightmares, irritability, mental disorders.

From the sensory organs: frequently – vertigo; very rarely – visual impairment (blurred vision, diplopia), hearing impairment, tinnitus, taste disturbance.

From the urinary system: very rarely – acute renal failure, hematuria, proteinuria, interstitial nephritis, nephrotic syndrome, papillary necrosis.

From the hematopoietic organs: very rarely – thrombocytopenia, leukopenia, hemolytic and aplastic anemia, agranulocytosis.

Allergic reactions: very rarely – angioedema (including facial), anaphylactic/anaphylactoid reactions, including severe hypotension and shock.

From the cardiovascular system: very rarely – palpitations, chest pain, increased blood pressure, vasculitis, heart failure, myocardial infarction.

From the respiratory system: rarely – exacerbation of bronchial asthma (including shortness of breath); very rarely – pneumonitis.

From the skin: frequently – skin rash; rarely – urticaria; very rarely – bullous rash, erythema, including multiforme and Stevens-Johnson syndrome, Lyell’s syndrome, exfoliative dermatitis, itching, hair loss, photosensitivity, purpura, including allergic.

Lansoprazole

From the digestive system: frequently – constipation; infrequently – abdominal pain, diarrhea, nausea, dry oral mucosa, dyspepsia, taste disturbances, flatulence; very rarely – colitis, ulcerative colitis, gastrointestinal candidiasis, increased activity of liver enzymes, hyperbilirubinemia; rarely – jaundice, hepatitis.

From the nervous system: frequently – headache; infrequently – dizziness, anxiety, fear, confusion, depression, confusion.

From the respiratory system: rarely – cough, pharyngitis, rhinitis, upper respiratory tract infections.

From the hematopoietic system: very rarely – leukopenia, thrombocytopenia, eosinophilia, pancytopenia or agranulocytosis.

Allergic reactions: rarely – urticaria, angioedema, photosensitivity; very rarely – anaphylactic reactions.

From metabolism: rarely – anorexia, increased appetite.

From the sensory organs: very rarely – visual impairment (blurred vision), tinnitus.

From the skin: frequently – skin rash; rarely – purpura, petechiae, hair loss; very rarely – toxic epidermal necrolysis, Stevens-Johnson syndrome, multiforme erythema.

From the musculoskeletal system: rarely – pain in joints, muscles, and bones.

From the genitourinary system: infrequently – increased creatinine concentration; very rarely – interstitial nephritis, renal failure, urogenital disorders, impotence, gynecomastia.

Other: infrequently – feeling of fatigue; rarely – flu-like syndrome; very rarely – peripheral edema.

Contraindications

Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nasal mucosa, paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including in history); inflammatory bowel diseases (ulcerative colitis, Crohn’s disease) in the acute phase; condition after coronary artery bypass grafting; active gastrointestinal bleeding; decompensated heart failure; hematopoietic disorders, hemostasis disorders (including hemophilia); severe hepatic insufficiency or active liver disease; renal failure (creatinine clearance less than 30 ml/min), progressive kidney diseases, hyperkalemia; pregnancy, breastfeeding period; children under 18 years of age; hypersensitivity to diclofenac (including to other NSAIDs) or to lansoprazole.

With caution

Erosive-ulcerative lesions of the gastric or duodenal mucosa (Diclofenac should be used only after careful assessment of the need for use, in a dose not exceeding 75 mg/day), malignant neoplasms of the gastrointestinal tract.

History of ulcerative disease of the gastrointestinal tract, presence of Helicobacter pylori infection, elderly age, long-term use of NSAIDs, alcoholism, severe somatic diseases.

Anemia, bronchial asthma, cerebrovascular diseases, coronary artery disease, arterial hypertension, peripheral artery diseases, edematous syndrome, hepatic and/or renal insufficiency (creatinine clearance 30-60 ml/min), history of liver disease, dyslipidemia/hyperlipidemia, diabetes mellitus, smoking, inflammatory bowel diseases, significant reduction in circulating blood volume (including after extensive surgical intervention), inducible porphyria, diverticulitis, systemic connective tissue diseases.

Concomitant use of corticosteroids (e.g., prednisolone), anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid, clopidogrel), selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine, sertraline).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency or active liver disease.

Use in Renal Impairment

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

Pediatric Use

Contraindicated in children under 18 years of age.

Special Precautions

Long-term use of diclofenac can very rarely cause serious adverse effects on the liver, which requires periodic monitoring of liver enzymes.

During long-term therapy, it is necessary to monitor the peripheral blood picture and stool analysis for occult blood.

Like all medicines, Diclofenac should be used in elderly patients at the minimum effective dose.

Symptomatic improvement during therapy with lansoprazole does not exclude the possible development of neoplasms in the gastrointestinal tract. Caution is required in case of sudden onset or exacerbation of dyspeptic symptoms, especially in patients over 45 years of age.

The use of diclofenac, especially in high doses (150 mg/day), may cause a slight increase in the risk of arterial thrombosis (e.g., myocardial infarction or stroke).

Patients with uncontrolled arterial hypertension, chronic heart failure, coronary artery disease, peripheral vascular disease, and/or cerebrovascular disorders should take Diclofenac only after thorough examination. A thorough examination should be performed before starting long-term therapy in patients at risk of cardiovascular diseases (arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Concomitant use of lansoprazole and atazanavir is not recommended. Endoscopic control before and after treatment is mandatory to exclude a malignant neoplasm, because treatment may mask symptoms and delay correct diagnosis. In patients taking Lansoprazole, ulcerative colitis may develop.

Effect on ability to drive vehicles and mechanisms

Caution should be exercised when driving vehicles and other technical devices requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Diclofenac

Concomitant use of diclofenac with

• lithium or digoxin may increase their plasma concentration;
  – with some diuretics may reduce their diuretic effect;
  – potassium-sparing diuretics may cause hyperkalemia;
  – acetylsalicylic acid, glucocorticosteroids and other non-steroidal anti-inflammatory drugs – increases the risk of adverse effects (gastrointestinal bleeding);
  – cyclosporine increases the nephrotoxicity of cyclosporine;
  – methotrexate increases the toxicity of methotrexate;
  – antihypertensive agents – reduces their effectiveness.

It reduces the effect of hypoglycemic agents.

With concurrent use with anticoagulants, antiplatelet and thrombolytic drugs (alteplase, streptokinase, urokinase), the risk of bleeding (more frequently gastrointestinal) increases. It reduces the effect of hypnotic drugs. Acetylsalicylic acid decreases the concentration of diclofenac in the blood.

Paracetamol increases the risk of nephrotoxic effects of diclofenac. Cefamandole, cefoperazone, cefotetan, valproic acid, and plicamycin increase the frequency of hypoprothrombinemia.

Gold preparations enhance the effect of diclofenac on prostaglandin synthesis in the kidneys, which is manifested by increased nephrotoxicity.

Selective serotonin reuptake inhibitors increase the risk of gastrointestinal bleeding.

Concomitant use with ethanol, colchicine, corticotropin, and St. John’s wort preparations increases the risk of gastrointestinal bleeding. Drugs causing photosensitization increase the sensitizing effect of diclofenac to UV radiation.

Drugs that block tubular secretion increase the plasma concentration of diclofenac, thereby increasing its efficacy and toxicity. Antibacterial drugs from the quinolone group increase the risk of seizures.

Lansoprazole

Lansoprazole reduces gastric acidity, which may lead to changes in the absorption of some substances; for example, the bioavailability of ketoconazole, ampicillin esters, and iron salts decreases. The bioavailability of digoxin increases by approximately 10%, which is clinically insignificant for most patients. Interaction with drugs metabolized in the liver by CYP3A and CYP2C19 isoenzymes may be observed. Thus, with the simultaneous use of lansoprazole and theophylline (metabolized by the CYP3A isoenzyme), a moderate increase in theophylline clearance (10%) was noted. This interaction is unlikely to be of clinical significance. Nevertheless, in some patients, additional titration of the theophylline dose at the beginning and end of lansoprazole therapy may be required to achieve clinically effective blood concentrations of lansoprazole.

Since interaction with phenytoin, theophylline, or warfarin may be significant in individual at-risk patients, the drug should be used with caution.

Sucralfate and antacids may reduce the absorption of lansoprazole. Since the interaction is not clinically significant, patients can take sucralfate or antacids at least 30 minutes before taking lansoprazole or 1 hour after.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.