Theraflex advans®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT THERAFLEX ADVANCE®

Composition:

Active substances: glucosamine sulfate, sodium chondroitin sulfate, ibuprofen;

1 capsule contains 250 mg glucosamine sulfate (as D-glucosamine sulfate potassium chloride), 200 mg sodium chondroitin sulfate, 100 mg ibuprofen;

Excipients: PROSOLV SMCC® (microcrystalline cellulose, colloidal anhydrous silicon dioxide), sodium starch glycolate (type A), crospovidone, povidone, silicon dioxide, pregelatinized starch, magnesium stearate, stearic acid, capsule shell (gelatin, FD&C Blue No. 1, titanium dioxide (E 171)).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules of size 0, consisting of a blue cap and a white body printed with "THERAFLEX ADVANCE", containing a white to almost white powder with a slight odor.

Pharmacotherapeutic group. Anti-inflammatory/antirheumatic agents in combination.

ATC code M01B.

Pharmacological Properties.

Pharmacodynamics.

This medicinal product stimulates regeneration of cartilage tissue. It exerts anti-inflammatory action at the cellular level, promotes synthesis of both endogenous proteoglycans and endogenous hyaluronic acid, reduces catabolic activity of chondrocytes by inhibiting certain enzymes that degrade cartilage, such as collagenase, esterase, proteoglycanase, phospholipase A2, N-acetylglucosaminidase, etc., and also inhibits formation of other substances that may damage cartilage tissues (in vitro), such as superoxide radicals, as well as activity of lysosomal enzymes.

Chondroitin and glucosamine are effective in osteoarthritis.

Chondroitin is one of the main components of cartilage. It reduces inflammatory activity at early stages and thus slows down degeneration of cartilage tissue. It helps reduce pain, improves joint function, and decreases the need for nonsteroidal anti-inflammatory drugs in knee and hip osteoarthritis.

Glucosamine is physiologically present in the human body and has chondroprotective properties. In vitro and in vivo studies have shown that glucosamine hydrochloride stimulates synthesis of physiological glycosaminoglycans and proteoglycans by chondrocytes, as well as synthesis of hyaluronic acid by synoviocytes.

Ibuprofen exerts antipyretic, analgesic, and anti-inflammatory effects. Its mechanism of action is related to non-selective inhibition of cyclooxygenase (COX)-1 and COX-2 (the key enzyme in arachidonic acid metabolism), leading to reduced synthesis of prostaglandins, decreased prostaglandin concentrations in cerebrospinal fluid, and diminished excitation of the thermoregulatory center. It reduces morning stiffness and improves range of motion in joints and spine.

Concomitant use of glucosamine and ibuprofen results in increased analgesic activity of the latter.

Pharmacokinetics.

After single oral administration of a therapeutic dose, maximum plasma concentration of chondroitin sulfate is reached within 3–4 hours. The oral bioavailability is 12%.

In blood, 85% of chondroitin and its depolymerized derivatives bind to several plasma proteins.

At least 90% of the administered chondroitin dose is initially metabolized by lysosomal phosphatases, followed by depolymerization via hyaluronidase, β-glucuronidase, and β-N-acetylhexosaminidase in the liver, kidneys, and other organs.

Chondroitin and its depolymerized derivatives are primarily eliminated via renal excretion. The elimination half-life ranges from 5 to 15 hours.

After oral administration, glucosamine hydrochloride is rapidly and almost completely absorbed from the intestine. The pharmacokinetics of glucosamine are linear when administered at doses up to 1500 mg once daily, and higher doses do not result in proportionally higher increases in maximum glucosamine concentration.

More than 25% of the administered glucosamine dose transfers from plasma to cartilage tissue and synovial membrane.

Due to first-pass metabolism in the liver, over 70% of glucosamine is metabolized into urea, carbon dioxide, and water.

It is excreted unchanged primarily via the kidneys into urine and partially in feces. The elimination half-life is 68 hours.

After oral administration, ibuprofen is almost completely absorbed from the gastrointestinal tract. Concomitant food intake delays absorption. Ibuprofen is metabolized in the liver (90%). The elimination half-life is 2–3 hours. About 80% of the dose is excreted in urine, primarily as metabolites.

Clinical characteristics.

Indications.

Treatment of pain syndrome in primary and secondary osteoarthritis of limb joints and intervertebral discs.

Contraindications.

This medicinal product is contraindicated in the following cases:

• Hypersensitivity to the active substances or to any of the excipients;
• History of allergic reactions (such as bronchospasm, asthma, rhinitis or skin rash, angioedema, urticaria) associated with the use of acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs);
• History of gastrointestinal bleeding or perforation following the use of NSAIDs;
• Active or past peptic ulcer disease / gastrointestinal bleeding (two or more distinct episodes of peptic ulcer exacerbation and bleeding);
• Optic nerve disorders;
• Hematopoietic disorders;
• Severe renal, cardiac or hepatic insufficiency;
• Phenylketonuria;
• Cerebrovascular or other bleeding disorders;
• Diabetes mellitus;
• Tendency to bleeding;
• Thrombophlebitis;
• Third trimester of pregnancy.

Concomitant use of this drug with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Medicinal products with which interactions may occur when used concomitantly with Teraflex Advance®, capsules:

Ibuprofen

Combinations with ibuprofen that should be avoided:

Acetylsalicylic acid

May lead to an increased risk of adverse effects. Due to specific pharmacodynamic properties, ibuprofen may competitively inhibit the antiplatelet effect of low-dose acetylsalicylic acid when used concomitantly. The clinical relevance of this interaction has not been fully established. The possibility that long-term use of ibuprofen may reduce the protective effect of low-dose acetylsalicylic acid in patients at high cardiovascular risk cannot be excluded. No clinically significant interaction is expected with short-term ibuprofen use.

Other NSAIDs, including selective COX-2 inhibitors

Increased risk of erosive-ulcerative gastrointestinal lesions and gastrointestinal bleeding (see section "Contraindications").

Combinations with ibuprofen that should be used with caution:

Cyclosporine

May increase the risk of nephrotoxic effects.

Lithium

Plasma lithium levels may increase.

Methotrexate

Plasma methotrexate concentration may increase, increasing the risk of methotrexate toxicity.

Anticoagulants

NSAIDs may enhance the effects of anticoagulants such as warfarin.

Glucocorticoids

Increased risk of gastrointestinal bleeding or ulceration.

Antihypertensive and diuretic agents

Nonsteroidal anti-inflammatory drugs may reduce the therapeutic effect of these agents.

In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists and agents that inhibit cyclooxygenase may lead to further deterioration of renal function, including potentially reversible acute renal failure. This interaction should be considered in patients taking coxibs concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, this combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and monitoring of renal function should be considered at the start of concomitant therapy and periodically thereafter. Diuretics may increase the risk of NSAID-induced nephrotoxicity.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding.

Cardiac glycosides

NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase blood levels of glycosides.

Zidovudine

Concomitant use of NSAIDs with zidovudine may increase the risk of hematological toxicity. Evidence suggests an increased risk of hemarthrosis and hematoma in HIV-infected patients receiving concomitant treatment with zidovudine and ibuprofen.

Mifepristone

NSAIDs should not be used earlier than 8–12 days after mifepristone administration, as they may reduce its efficacy.

Tacrolimus

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

Potassium-sparing diuretics

Hyperkalemia may occur.

Alcohol

Increased risk of gastrointestinal tract damage and prolonged bleeding time.

Quinolone antibiotics

Concomitant use of NSAIDs and quinolone antibiotics may increase the risk of seizures.

Sulfonylurea derivatives and phenytoin

Possible potentiation of drug effects.

Chondroitin and glucosamine

Tetracycline

Absorption of tetracycline from the gastrointestinal tract may be increased.

Penicillin

Absorption of penicillin may be reduced.

Chloramphenicol

Absorption of chloramphenicol may be reduced.

Cyclosporine

May affect cyclosporine blood concentration.

Physicochemical and pharmacokinetic properties of chondroitin and glucosamine suggest a low potential for drug interactions; however, specific interaction studies have not been conducted. Chondroitin and glucosamine are compatible with NSAIDs.

According to some data, concomitant use of glucosamine and warfarin may potentiate the effect of warfarin and lead to bleeding. Therefore, coagulation parameters should be monitored when these agents are used together.

Special precautions for use

This medicinal product is not intended for the treatment of pain associated with the gastrointestinal tract. Concomitant use of the medicinal product Teraflex Advance® with other NSAIDs, including selective COX-2 inhibitors, should be avoided due to an increased risk of gastrointestinal ulceration or bleeding, as well as other adverse reactions. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal bleeding, ulceration, or perforation, which may be fatal and may occur with or without preceding symptoms, have been reported with all NSAIDs at any time during treatment, regardless of a history of serious gastrointestinal complications.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, a history of ulcers (particularly those complicated by bleeding or perforation), and in elderly patients. Such patients should begin treatment with the lowest available dose. For these patients, consideration should be given to concomitant therapy with protective agents (e.g., misoprostol or proton pump inhibitors), as well as for patients requiring concomitant use of low-dose acetylsalicylic acid or other medicinal products that may increase the risk of gastrointestinal adverse reactions.

Patients with a history of gastrointestinal disorders, especially elderly patients, should inform their physician of any unusual abdominal symptoms (including gastrointestinal bleeding), particularly in the early stages of treatment. Caution should be exercised when treating patients who are concurrently receiving medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, and antiplatelet agents such as acetylsalicylic acid.

If gastrointestinal bleeding or ulceration occurs in patients receiving ibuprofen, treatment should be discontinued.

NSAIDs should be used with caution in patients with a history of ulcerative colitis or Crohn’s disease, as their condition may worsen.

If acetylsalicylic acid is used for the inhibition of platelet aggregation, consultation with a physician is recommended before initiating treatment with Teraflex Advance®.

Results from clinical trials and epidemiological data suggest that the use of ibuprofen, particularly at high doses (2400 mg daily) and during long-term treatment, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Overall, epidemiological studies do not indicate that low doses of ibuprofen (≤ 1200 mg daily) are associated with an increased risk of myocardial infarction.

Long-term treatment may be prescribed by a physician only after careful evaluation for patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Long-term NSAID treatment should be prescribed for patients with significant cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking) only after careful consideration.

Severe skin reactions, some with fatal outcomes, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, have very rarely been observed with NSAID use. These reactions appear to have the highest risk during the initial stages of treatment: onset typically occurs within the first month of therapy. Treatment with ibuprofen should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Ibuprofen may cause bronchospasm and asthma attacks or other hypersensitivity reactions. Risk factors for such reactions include pre-existing bronchial asthma, hay fever, nasal polyps, sensitivity to acetylsalicylic acid, or chronic respiratory diseases. This also applies to patients who experience allergic reactions to ibuprofen or other NSAIDs (e.g., skin reactions, pruritus, urticaria).

Alcohol consumption is not recommended during treatment with Teraflex Advance®.

The medicinal product should be used with caution in patients with:

• systemic lupus erythematosus and connective tissue disorders, due to an increased risk of aseptic meningitis;
• a history of hypertension and/or heart failure associated with fluid retention and edema during NSAID use;
• impaired renal and/or hepatic function; hepatic dysfunction increases the risk of renal toxicity and injury, as well as severe and potentially fatal hepatic reactions. For patients with liver or kidney disease, additional examinations are recommended before initiating treatment: monitoring of liver and kidney function and peripheral blood tests.

Prolonged use of NSAIDs may lead to dose-dependent reduction in prostaglandin synthesis and may provoke the development of renal failure. Patients at high risk include those taking diuretics; patients with hepatic, renal, and/or cardiac dysfunction.

Adverse reactions are more frequently observed in elderly patients during NSAID use, particularly gastrointestinal bleeding and perforation, which may be fatal.

Ibuprofen may mask symptoms of infection, potentially delaying the initiation of appropriate treatment and thus contributing to a worsening of infection outcomes. This has been observed in community-acquired bacterial pneumonia and bacterial complications of varicella. If symptoms persist or worsen, medical advice should be sought.

Special considerations for use of glucosamine sulfate and chondroitin sulfate

The product should not be used in patients with hypersensitivity (allergy) to seafood.

Exacerbation of asthma symptoms may occur in patients with a history of bronchial asthma after starting treatment with glucosamine. Therefore, patients with asthma should be warned about the possible worsening of symptoms before initiating treatment.

Rarely, edema and/or fluid retention have been observed in patients with cardiac and/or renal insufficiency. This may be related to the osmotic effect of chondroitin sulfate.

Medical advice should be sought if symptoms worsen after starting treatment with this medicinal product.

Use during pregnancy or breastfeeding

Pregnancy

Ibuprofen

Inhibition of prostaglandin synthesis may adversely affect the course of pregnancy and/or embryonic/fetal development. Epidemiological data suggest a possible increased risk of miscarriage and congenital malformations (particularly cardiac defects and gastroschisis) following the use of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors increase pre- and post-implantation loss and embryofetal mortality. Animal studies have also reported an increased incidence of various developmental abnormalities, including cardiovascular malformations, when prostaglandin synthesis inhibitors are administered during organogenesis.

Ibuprofen should not be used during the first and second trimesters of pregnancy.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following effects on the fetus:

• cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios.

In the mother and neonate at the end of pregnancy:

• prolonged bleeding time; antiplatelet effects may occur even with very low doses;
• inhibition of uterine contractions, leading to delayed onset or prolonged duration of labor.

Therefore, ibuprofen is contraindicated during the third trimester of pregnancy.

Chondroitin sulfate and glucosamine sulfate: clinical data on the efficacy and safety of glucosamine sulfate during pregnancy are lacking or limited. Therefore, Teraflex Advance® should not be used during the first and second trimesters of pregnancy. Teraflex Advance® is contraindicated during the third trimester of pregnancy.

Breastfeeding

Ibuprofen may pass into breast milk in small amounts, but when used at therapeutic doses, the risk of effects on the infant is considered unlikely.

There is insufficient information on the excretion of chondroitin sulfate and glucosamine sulfate and their metabolites in breast milk. Therefore, this medicinal product should not be used by women during lactation.

Fertility

There is evidence that medicinal products which inhibit cyclooxygenase/prostaglandin synthesis may impair fertility in women by affecting ovulation. This effect is reversible upon discontinuation of these drugs. Data on the effects of chondroitin sulfate and glucosamine are lacking.

Ability to influence reaction speed when driving or operating machinery. Patients should monitor changes in their reaction speed before driving or operating machinery. If any adverse neurological effects occur, driving or operating machinery should be avoided.

Method of administration and dosage.

The medicine should be taken after food, with a glass of water.

For adults: take 2 capsules 3 times daily.

Do not exceed the maximum daily dose of 12 capsules (1.2 g of ibuprofen).

The total duration of treatment at the recommended dose should not exceed 10 days. If symptoms persist or worsen, or if prolonged treatment is required, consult a physician. The lowest effective dose should be used for the shortest necessary duration of treatment. After the pain subsides, the patient may continue treatment with Terafлекс® in capsule form.

Children.

This medicinal product should not be used in children (under 18 years of age) due to lack of data on efficacy and safety.

Overdose.

There are no data on overdose with this medicinal product, chondroitin, and/or glucosamine. Administration of doses exceeding 400 mg/kg of ibuprofen in children may lead to overdose. In adults, the dose-dependent effect is less defined. The half-life of ibuprofen in overdose is 1.5–3 hours.

In case of overdose, symptoms may include abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, dizziness, headache, sleep disturbances, and tinnitus. In severe cases, nervous system symptoms may occur: drowsiness, lethargy, apnea (especially in young children), rarely excitement and disorientation, loss of consciousness, or coma; arterial hypertension, arterial hypotension, liver and kidney dysfunction, or hepatonecrosis, acute renal failure, rhabdomyolysis, and hypothermia may develop; respiratory failure and cyanosis are possible. Seizures may rarely occur with overdose. In patients with bronchial asthma, asthma exacerbation is possible. In severe overdose, metabolic acidosis (including renal tubular acidosis) and hypokalemia may develop, and prothrombin time/INR (international normalized ratio) may be prolonged, likely due to interaction with blood coagulation factors.

Treatment is symptomatic and aimed at maintaining airway patency, monitoring cardiac activity and other vital functions until the condition normalizes. Gastric lavage and oral administration of activated charcoal are recommended within 1 hour after ingestion of a potentially toxic dose (over 400 mg/kg), along with hospitalization in a toxicology unit. Inpatient management includes infusion therapy, forced diuresis, and symptomatic treatment. There are no specific antidotes. Frequent or prolonged seizures should be treated with intravenous diazepam or lorazepam. Bronchodilators should be used in patients with bronchial asthma.

Adverse Reactions.

Most adverse effects following administration of Teraflex Advance® are due to ibuprofen and are dose-dependent. Since the recommended single dose of ibuprofen is moderate, and the usual daily dose in Teraflex Advance® (600 mg) is significantly lower than its maximum daily dose (1200 mg), it is unlikely that any adverse effects will occur if the medication is used according to the recommended dosing regimen. The frequency of adverse reactions to ibuprofen is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). The frequency of adverse reactions to Teraflex Advance® cannot be determined, as these data are derived from post-marketing reports. Therefore, the frequency of these reactions is listed as not known.

Gastrointestinal system. Uncommon: abdominal pain, dyspepsia, nausea. Rare: diarrhea, flatulence, constipation, vomiting. Very rare: ulcerative stomatitis, peptic ulcers, melena, hematemesis, gastritis, gastrointestinal perforation or bleeding, which in some cases may be fatal, particularly in elderly patients. Frequency not known: diaphragm-like intestinal strictures (especially with prolonged use), exacerbation of colitis and Crohn’s disease, heartburn.

Nervous system. Uncommon: headache. Very rare: aseptic meningitis (isolated cases have been reported). In patients with autoimmune disorders (particularly systemic lupus erythematosus, connective tissue diseases), isolated symptoms of aseptic meningitis have been observed during ibuprofen therapy, including nuchal rigidity, headache, nausea, vomiting, high fever, or disorientation.

Frequency not known: dizziness, somnolence, paresthesia, general weakness, and increased fatigue. With prolonged use only – depression, hallucinations, confusion, tinnitus.

Urinary system. Very rare: acute renal failure, papillary necrosis, particularly with prolonged use, associated with increased serum urea levels and edema. Frequency not known: ibuprofen may cause interstitial nephritis, nephrotic syndrome, nephrotoxicity.

Hepatobiliary system. Very rare: hepatic disorders, particularly with prolonged use, manifesting as hepatitis or jaundice.

Blood and lymphatic system. Very rare: disorders of the hematopoietic system (anemia, neutropenia, aplastic anemia, hemolytic anemia, eosinophilia, decreased hematocrit and hemoglobin levels, leukopenia, thrombocytopenia, 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.

Skin and subcutaneous tissue. In isolated cases, severe skin reactions (exfoliative and bullous dermatoses) such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis may occur. Skin desquamation, alopecia, photosensitivity, erythema, dermatitis, and eczema may also be observed.

Immune system. Uncommon: urticaria, pruritus, rash. Very rare: allergic reactions, including severe hypersensitivity reactions, facial, tongue, and laryngeal edema, dyspnea, Quincke’s edema, anaphylactic shock, anaphylaxis, anaphylactoid reactions. Frequency not known: respiratory tract reactivity, including bronchial asthma, asthma exacerbation, bronchospasm.

Cardiovascular system and cerebral circulation. Frequency not known: edema, arterial hypertension, decreased blood pressure, heart failure, tachycardia, palpitations have been reported during NSAID therapy. Long-term use of high-dose ibuprofen (2400 mg/day) may lead to a slight increase in the risk of arterial thrombosis (myocardial infarction or stroke). Complications related to cerebral circulation are possible.

Eye disorders. Frequency not known: with prolonged use – visual disturbances, optic neuritis.

Ear and labyrinth disorders. Frequency not known: tinnitus.

Laboratory test results. Increased ALT levels, increased serum creatinine, increased AST levels, increased blood urea levels, increased blood bilirubin levels.

Other. Endocrine system and metabolic changes, decreased appetite, dryness of the mucous membranes of the eyes and oral cavity, rhinitis, hearing disturbances.

Rare cases of extrasystoles with administration of 1200 mg chondroitin sulfate have been reported in the literature.

The use of Teraflex Advance® should be discontinued immediately upon the occurrence of any adverse reaction, and medical advice should be sought promptly.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

60 or 120 capsules in a bottle, 1 bottle in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

Contract Pharmacal Corporation.

Manufacturer’s address.

135 Adams Avenue, Hauppauge, New York 11788, USA.