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

Composition:

Active ingredient: diclofenac sodium;

3 ml of solution contain 75 mg of diclofenac sodium (25 mg/ml);

Excipients: mannite (E 421), sodium metabisulfite (E 223), benzyl alcohol, propylene glycol, water for injections, sodium hydroxide.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution ranging from colorless to slightly yellow.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.
Acetic acid derivatives and related compounds. ATC code M01A B05.

Pharmacological Properties.

Pharmacodynamics.

Voltaren® is a non-steroidal agent with pronounced analgesic and anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase (cyclooxygenase). Prostaglandins play a key role in the development of inflammation, pain, and fever. In vitro, at concentrations equivalent to those achieved in humans, sodium diclofenac does not suppress proteoglycan biosynthesis in cartilage tissue.

When administered concomitantly with opioids for postoperative pain relief, Voltaren® significantly reduces the need for opioids.

Pharmacokinetics.

Absorption.

After intramuscular injection of 75 mg of diclofenac, the mean maximum plasma concentration of approximately 2.5 µg/mL is reached within about 20 minutes. When 75 mg of diclofenac is administered by intravenous infusion over 2 hours, the mean maximum plasma concentration is approximately 1.9 µg/mL. Shorter infusion times result in higher peak plasma concentrations, while longer infusions lead to a concentration plateau proportional to the infusion rate after 3–4 hours. After intramuscular injection or oral administration of enteric-coated tablets or rectal suppositories, plasma concentrations decline rapidly immediately after peak levels are achieved. Following oral or rectal administration, approximately half of the absorbed diclofenac undergoes metabolism during its first pass through the liver (first-pass effect). The area under the concentration-time curve (AUC) after intramuscular or intravenous administration is approximately twice as high as that after oral or rectal administration.

Pharmacokinetic properties do not change following repeated dosing. With adherence to recommended dosing intervals, accumulation of the drug does not occur.

Distribution.

99.7% of diclofenac is bound to plasma proteins, primarily to albumin (99.4%).

The apparent volume of distribution is calculated to be 0.12–0.17 L/kg.

Diclofenac penetrates into synovial fluid, where maximum concentration is achieved 2–4 hours after peak plasma levels. The expected half-life in synovial fluid is 3 to 6 hours. Two hours after peak plasma concentration, the concentration of diclofenac in synovial fluid exceeds that in plasma and remains higher for up to 12 hours.

Diclofenac was detected at low concentrations (100 ng/mL) in breast milk in one breastfeeding woman. The estimated amount of drug transferred to the infant via breast milk is equivalent to 0.03 mg/kg/day.

Metabolism.

Biotransformation of diclofenac occurs partially via glucuronidation of the intact molecule, but primarily through single and multiple hydroxylations and methoxylations, leading to the formation of several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'-hydroxy-4'-methoxy-diclofenac), most of which are converted into glucuronide conjugates. Two of these phenolic metabolites are pharmacologically active, although their activity is significantly less than that of diclofenac.

Elimination.

Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean ± SD). The terminal half-life in plasma is 1–2 hours. Four metabolites, including two active ones, also have short plasma half-lives of 1–3 hours. One metabolite, 3'-hydroxy-4'-methoxydiclofenac, has a much longer half-life but is essentially inactive. Approximately 60% of the administered dose is excreted in urine as metabolites. Less than 1% is excreted unchanged. The remainder of the dose is eliminated as metabolites via bile into feces.

Linearity/Non-linearity.

Plasma concentrations demonstrate a linear relationship with dose.

Special patient groups.

Elderly patients. No age-related differences in absorption, metabolism, or excretion of the drug have been observed, except that in elderly patients, a 15-minute intravenous infusion resulted in a 50% higher plasma concentration compared to young healthy volunteers.

Patients with renal impairment. In patients with impaired renal function, accumulation of unchanged active substance is not expected with standard dosing regimens, based on pharmacokinetics after single-dose administration. However, with creatinine clearance less than 10 mL/min, theoretical steady-state levels of metabolites in plasma are approximately four times higher than in healthy volunteers.

Nevertheless, metabolites are ultimately eliminated via bile.

Patients with hepatic disease. In patients with chronic hepatitis or compensated cirrhosis of the liver, the pharmacokinetics and metabolism of diclofenac are similar to those in patients without liver disease.

Clinical characteristics.

Indications.

The drug is indicated for intramuscular administration in the treatment of:

Inflammatory and degenerative forms of rheumatism, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondyloarthritis, vertebral pain syndrome, non-articular rheumatism;
Acute gout attacks;
Renal and biliary colic;
Pain and swelling following injuries and surgeries;
Severe migraine attacks.

The drug is indicated for intravenous infusion in the treatment or prevention of postoperative pain.

Contraindications.

Known hypersensitivity to the active substance, sodium metabisulfite, or any other components of the drug.
Gastrointestinal bleeding or perforation in medical history associated with previous treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
Active peptic ulcer of the stomach or duodenum/bleeding, or recurrent peptic ulcer/bleeding in medical history (two or more separate episodes of confirmed ulcer or bleeding).
Third trimester of pregnancy.
As with other NSAIDs, diclofenac is contraindicated in patients in whom administration of ibuprofen, acetylsalicylic acid, or other nonsteroidal anti-inflammatory drugs triggers attacks of bronchial asthma, bronchospasm, angioneurotic edema, urticaria, or rhinitis/nasal polyps, or allergy-like symptoms.
Inflammatory bowel diseases (e.g., Crohn’s disease or ulcerative colitis).
Hepatic failure.
Renal failure (glomerular filtration rate (GFR) < 15 mL/min/1.73 m²).
Heart failure (NYHA II–IV).
High risk of postoperative bleeding, coagulation disorders, hemostasis disorders, hematopoietic disorders, or cerebrovascular bleeding.
Treatment of postoperative pain following coronary artery bypass grafting (or use of cardiopulmonary bypass machine).
Ischemic heart disease in patients with angina pectoris or history of myocardial infarction.
Cerebrovascular diseases in patients with history of stroke or transient ischemic attacks.
Peripheral arterial disease.

This drug formulation is contraindicated in children.

Regarding intravenous use only.

Concomitant use of NSAIDs or anticoagulants (including low-dose heparin).
History of hemorrhagic diathesis, confirmed or suspected cerebrovascular bleeding.
Surgeries associated with high risk of bleeding.
History of bronchial asthma.
Moderate or severe renal impairment (serum creatinine >160 µmol/L).
Hypovolemia or dehydration of any cause.

Interaction with other medicinal products and other types of interactions.

The interactions listed below have been observed during the use of Voltaren® injection solution and/or other diclofenac formulations.

Lithium. When used concomitantly, diclofenac may increase plasma lithium concentrations. Monitoring of serum lithium levels is recommended.

Digoxin. When used concomitantly, diclofenac may increase digoxin plasma concentrations. Monitoring of serum digoxin levels is recommended.

Diuretics and antihypertensive agents. As with other NSAIDs, concomitant use of diclofenac with diuretics and antihypertensive agents (e.g., beta-blockers, angiotensin-converting enzyme (ACE) inhibitors) may reduce their antihypertensive effect. Therefore, such combinations should be used with caution, and patients—especially elderly patients—should be closely monitored for blood pressure. Adequate hydration is recommended, and renal function should be monitored after initiation and on a regular basis during concomitant therapy, particularly with diuretics and ACE inhibitors, due to increased risk of nephrotoxicity (see section "Special precautions for use").

Medicinal products known to cause hyperkalemia. Concomitant use with potassium-sparing diuretics, cyclosporine, tacrolimus, or trimethoprim may lead to increased serum potassium levels; therefore, more frequent monitoring of patients is recommended (see section "Special precautions for use").

Anticoagulants and antithrombotic agents. Precautions are advised, as concomitant administration may increase the risk of bleeding (see section "Special precautions for use"). Although clinical studies do not indicate an effect of diclofenac on anticoagulant activity, there are individual reports of increased bleeding risk in patients receiving diclofenac and anticoagulants simultaneously. Therefore, careful monitoring of such patients is recommended.

Other NSAIDs and corticosteroids. Concomitant administration of diclofenac with other systemic NSAIDs or corticosteroids may increase the frequency of gastrointestinal adverse effects (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs). Concomitant use of systemic NSAIDs and SSRIs may increase the risk of gastrointestinal bleeding (see section "Special precautions for use").

Antidiabetic agents. Clinical studies have shown that diclofenac can be used together with oral antidiabetic agents without affecting their clinical efficacy. However, isolated cases of both hypoglycemic and hyperglycemic effects have been reported after diclofenac administration, requiring dosage adjustments of antidiabetic agents during diclofenac treatment. Monitoring of blood glucose levels is necessary in such cases and is recommended as a precaution during concomitant therapy.

There are also isolated reports of metabolic acidosis occurring with concomitant use of diclofenac, particularly in patients with pre-existing renal impairment.

Methotrexate. Caution is recommended when administering NSAIDs, including diclofenac, less than 24 hours before methotrexate treatment, as this may increase methotrexate blood concentrations and enhance its toxicity.

Cyclosporine and tacrolimus. Diclofenac, like other NSAIDs, may increase the nephrotoxicity of cyclosporine and tacrolimus due to effects on renal prostaglandins. Therefore, it should be administered at lower doses than in patients not receiving cyclosporine or tacrolimus.

Quinolone antibiotics. There are isolated reports of seizures that may result from concomitant use of quinolones and NSAIDs.

Phenytoin. When phenytoin is used concomitantly with diclofenac, monitoring of plasma phenytoin concentrations is recommended due to expected increased phenytoin exposure.

Cholestyramine and colestipol. These agents may delay or reduce absorption of diclofenac. Therefore, diclofenac should be administered at least one hour before or 4–6 hours after cholestyramine/colestipol administration.

Cardiac glycosides. Concomitant use of cardiac glycosides and NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase glycoside levels in plasma.

Mifepristone. NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce its efficacy.

CYP2C9 inhibitors. Caution is required when co-administering diclofenac with CYP2C9 inhibitors (e.g., voriconazole). This may lead to a significant increase in maximum plasma concentration and exposure to diclofenac.

CYP2C9 inducers. Caution is required when co-administering diclofenac with CYP2C9 inducers (e.g., rifampicin). This may lead to a significant increase in plasma concentration and exposure to diclofenac.

Special precautions for use.

General

Gastrointestinal ulcers, bleeding, or perforation may occur at any time during treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), regardless of COX-2 selectivity, even in the absence of warning signs or predisposing history. Concomitant use of Voltaren® with systemic NSAIDs, including selective COX-2 inhibitors, should be avoided due to the potential for increased adverse effects (see section "Interaction with other medicinal products and other forms of interaction").

Adverse effects can be minimized by using the lowest effective dose for the shortest possible duration required to control symptoms.

Placebo-controlled trials have shown an increased risk of thrombotic cardiovascular and cerebrovascular complications with certain selective COX-2 inhibitors. A direct correlation between this risk and the COX-1/COX-2 selectivity of individual NSAIDs has not been established. Due to the lack of comparable clinical trial data on long-term, high-dose diclofenac therapy, the possibility of a similar increased risk cannot be excluded. In the absence of such data, a careful benefit-risk assessment should be performed before using diclofenac in patients with clinically confirmed ischemic heart disease, cerebrovascular disorders, peripheral arterial occlusive disease, or significant risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking). Because of this risk, the lowest effective dose should be used for the shortest possible duration.

Effects of NSAIDs on the kidneys include fluid retention with edema and/or arterial hypertension. Therefore, diclofenac should be used with caution in patients with impaired cardiac function and other conditions predisposing to fluid retention. Caution is also advised in patients taking concomitant diuretics or angiotensin-converting enzyme (ACE) inhibitors, or those prone to hypovolemia.

Hypersensitivity reactions may progress to Kounis syndrome, a serious allergic reaction that may lead to myocardial infarction. Symptoms of such reactions may include chest pain occurring in combination with an allergic reaction to diclofenac.

Consequences are generally more severe in elderly patients. Caution is required when prescribing the drug to elderly individuals. In particular, for frail elderly patients and those with low body weight, the lowest effective doses are recommended. If gastrointestinal bleeding or ulceration occurs in patients receiving Voltaren®, treatment should be discontinued.

Like other NSAIDs, Voltaren® may mask signs and symptoms of infection due to its pharmacodynamic properties.

Sodium metabisulfite in the injectable solution may also cause rare but severe hypersensitivity reactions.

Gastrointestinal effects

When using all NSAIDs, including diclofenac, cases of gastrointestinal bleeding (hematemesis, melena), ulceration, or perforation have been reported. These may be fatal and may occur at any time during treatment, with or without preceding symptoms, and may be associated with a history of serious gastrointestinal events. These events generally have more serious consequences in elderly patients. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the drug should be discontinued.

As with all NSAIDs, including diclofenac, careful medical monitoring is required; particular caution should be exercised when prescribing diclofenac to patients with symptoms suggesting gastrointestinal disorders or with a history of gastric or intestinal ulcers, bleeding, or perforation (see section "Adverse reactions"). The risk of gastrointestinal bleeding increases with higher NSAID doses, in patients with a history of ulcers (especially complicated by bleeding or perforation), and in elderly patients.

Elderly patients have an increased frequency of adverse reactions when using NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal.

To reduce the risk of gastrointestinal toxicity in patients with a history of ulcers (especially complicated by bleeding or perforation) and in elderly patients, treatment should be initiated and maintained at the lowest effective doses.

For such patients, as well as those requiring concomitant use of low-dose acetylsalicylic acid (ASA) or other medicinal products that may increase the risk of gastrointestinal adverse effects, consideration should be given to combination therapy with protective agents (e.g., proton pump inhibitors or misoprostol).

Patients with a history of gastrointestinal toxicity, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding). Caution is also required in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as systemic corticosteroids, anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), or selective serotonin reuptake inhibitors (see section "Interaction with other medicinal products and other forms of interaction").

NSAIDs, including diclofenac, may be associated with an increased risk of gastrointestinal anastomotic insufficiency. Careful medical monitoring and caution are recommended when using Voltaren® after gastrointestinal surgery.

Hepatic effects

Close medical supervision is required when Voltaren® is prescribed to patients with impaired liver function, as their condition may worsen (see section "Adverse reactions").

As with other NSAIDs, including diclofenac, the levels of one or more liver enzymes may increase. This has been very commonly observed in clinical trials with diclofenac (approximately 15% of patients), but very rarely associated with clinical symptoms. Most cases involve borderline elevations. Moderate increases (≥ 3 to < 8 times the upper limit of normal) have been frequently observed (in 2.5% of cases), while marked elevations (≥ 8 times the upper limit of normal) occurred in approximately 1% of cases. Clinically evident liver injury occurred in 0.5% of cases in the aforementioned clinical trials. Elevated enzyme levels were generally reversible upon discontinuation of the drug. In patients receiving diclofenac, the course of diseases such as hepatitis may occur without prodromal symptoms.

Caution is required when Voltaren® is used in patients with hepatic porphyria due to the potential to provoke an attack.

Renal effects

Because prostaglandins are important for maintaining renal blood flow, prolonged high-dose treatment with NSAIDs, including diclofenac, frequently (1–10%) leads to edema and arterial hypertension.

Since fluid retention and edema have been reported with NSAID treatment, including diclofenac, particular attention should be paid to patients with impaired cardiac or renal function, a history of arterial hypertension, elderly patients, those receiving concomitant diuretic therapy or drugs significantly affecting renal function, and patients with significant extracellular fluid volume depletion due to any cause, such as before or after major surgery (see section "Contraindications"). As a precautionary measure, monitoring of renal function is recommended when using Voltaren® in such patients. Discontinuation of therapy usually leads to return to the pre-treatment state.

Skin effects

Serious skin reactions (some of which have been fatal), including exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and cutaneous drug embolism, also known as Nicolau syndrome (especially after improper subcutaneous injection), have been very rarely reported with NSAIDs, including Voltaren®. Appropriate needle selection and injection technique should be observed when administering Voltaren® (see section "Incompatibilities").

The highest risk of these reactions appears to occur early in treatment, mostly within the first month of therapy. Voltaren® should be discontinued at the first appearance of skin rash, mucosal lesions, or any other signs of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, may rarely occur even without prior exposure to diclofenac.

Systemic lupus erythematosus (SLE) and mixed connective tissue diseases

Patients with SLE and mixed connective tissue diseases may have an increased risk of aseptic meningitis.

Cardiovascular and cerebrovascular effects

Diclofenac should be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful clinical evaluation.

Treatment with NSAIDs, including diclofenac, particularly at high doses and for prolonged periods, may be associated with a slightly increased risk of serious cardiovascular thrombotic events (including myocardial infarction and stroke).

Voltaren® is generally not recommended for patients with diagnosed cardiovascular diseases (heart failure, ischemic heart disease, peripheral arterial disease) or uncontrolled arterial hypertension. If such treatment is necessary in patients with diagnosed cardiovascular diseases, uncontrolled hypertension, or significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking), Voltaren® should be prescribed only after careful evaluation and only at doses up to 100 mg daily if treatment exceeds 4 weeks.

Since cardiovascular risks of diclofenac may increase with dose and duration of treatment, it should be used for the shortest possible duration and at the lowest effective dose. The patient's need for diclofenac and response to therapy should be periodically reviewed, especially if treatment exceeds 4 weeks. Use with caution in patients aged 65 years and older.

Patients with a history of arterial hypertension and/or mild to moderate congestive heart failure require appropriate monitoring and advice, as fluid retention and edema have been reported with NSAID use, including diclofenac.

Clinical and epidemiological data suggest that diclofenac use, particularly at high doses (150 mg/day) and for prolonged periods, may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Diclofenac is not recommended for patients with uncontrolled arterial hypertension, congestive heart failure, stable ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. If use is necessary, it may be considered only after careful benefit-risk assessment and at a dose not exceeding 100 mg daily. A similar assessment should be performed before initiating long-term treatment in patients with risk factors for cardiovascular events (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Patients should be informed about signs and symptoms of serious arterial thromboembolic events (e.g., chest pain, dyspnea, weakness, speech disturbances), which may occur without warning signs. In such cases, immediate medical attention is required.

Hematological effects

With prolonged use of the drug, as with other NSAIDs, monitoring of blood parameters is recommended.

Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Careful monitoring is required in patients with coagulation disorders, hemorrhagic diathesis, or hematological disorders.

Respiratory effects (asthma history)

Patients with bronchial asthma, seasonal allergic rhinitis, nasal mucosal edema (nasal polyps), chronic obstructive lung diseases, or chronic respiratory infections (especially those associated with allergic, rhinitis-like symptoms) are more likely than others to experience NSAID-related reactions resembling asthma exacerbation (so-called analgesic intolerance/analgesic-induced asthma), Quincke's edema, or urticaria. Therefore, special precautionary measures (readiness for emergency intervention) are recommended for these patients. This also applies to patients with allergies to other substances manifesting as skin reactions, pruritus, or urticaria.

Particular caution is recommended when administering Voltaren® parenterally to patients with bronchial asthma, as symptoms may worsen.

Like other drugs that inhibit prostaglandin synthetase activity, sodium diclofenac and other NSAIDs may provoke bronchospasm in patients with bronchial asthma or a history of bronchial asthma.

Female fertility

Use of Voltaren® may impair fertility in women and is not recommended for women attempting to conceive. For women experiencing difficulties conceiving or undergoing infertility evaluation, discontinuation of Voltaren® should be considered.

Use during pregnancy or breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and/or congenital heart defects and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%.

In animal studies, prostaglandin synthesis inhibitors have been shown to increase pre- and post-implantation loss and embryonic/fetal mortality. Additionally, in animals treated with a prostaglandin synthesis inhibitor during organogenesis, an increased incidence of various developmental abnormalities, including cardiovascular defects, has been observed.

First/second trimester

During the first and second trimesters of pregnancy, Voltaren® should be prescribed only if the expected benefit to the woman outweighs the potential risk to the fetus. If Voltaren® is used by a woman attempting to conceive or by a pregnant woman during the first or second trimester, the dose should be as low as possible and the duration of treatment as short as possible.

Oligohydramnios / renal dysfunction in newborns / constriction of the arterial duct

Use of NSAIDs from the 20th week of pregnancy may lead to fetal renal dysfunction, causing oligohydramnios and, in some cases, renal dysfunction in the newborn. These adverse effects are observed on average after several days or weeks of treatment, although in rare cases oligohydramnios developed within 48 hours of starting NSAID therapy. Oligohydramnios often, but not always, resolves after discontinuation of NSAID treatment. Complications of prolonged oligohydramnios may include, for example, limb contractures and pulmonary hypoplasia. In some post-marketing clinical observations, renal dysfunction in newborns required invasive procedures such as exchange transfusion or dialysis.

Additionally, constriction of the arterial duct has been reported after second-trimester treatment, which resolves in most cases after discontinuation of therapy.

If treatment with Voltaren® lasts longer than 48 hours, consideration should be given to ultrasound monitoring of amniotic fluid volume and fetal heart. In case of oligohydramnios or constriction of the arterial duct, Voltaren® should be discontinued and appropriate treatment initiated according to clinical practice.

Third trimester

During the third trimester of pregnancy, use of Voltaren® is contraindicated.

All prostaglandin synthesis inhibitors may:

expose the fetus to the following risks:
- cardiopulmonary toxicity (with premature closure of the arterial duct and pulmonary hypertension);
- renal dysfunction, which may progress to renal failure with oligohydramnios;
expose the mother and child to the following risks:
- possible prolongation of bleeding time – due to inhibition of platelet aggregation, which may occur even with very low doses;
- inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding period

Like other nonsteroidal anti-inflammatory drugs, diclofenac passes into breast milk in small amounts. Therefore, to avoid potential adverse effects on the infant, Voltaren® should not be used during breastfeeding. If treatment is considered necessary, the infant should be switched to artificial feeding.

Fertility

Voltaren® may affect female fertility. The drug is not recommended for women planning to become pregnant. Women experiencing difficulties with conception or undergoing infertility evaluation should discontinue use of Voltaren®.

Based on relevant animal studies, impairment of male reproductive function cannot be excluded. The relevance of these findings to humans has not been established.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience visual disturbances, dizziness, vertigo, somnolence, or other central nervous system effects during treatment with Voltaren® should refrain from driving or operating machinery.

Method of Administration and Dosage

The general recommendation is to determine the dose individually. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Adults

VOLTAREN®, solution for injection, should not be used for more than 2 days. If further treatment is required, therapy may be continued with gastro-resistant tablets or suppositories of VOLTAREN®.

Intramuscular Injection

To prevent nerve or other tissue damage at the site of intramuscular injection, the following instructions must be followed. Such damage may lead to muscle weakness, paralysis, hypoesthesia, or cutaneous medication embolism (Nicolau syndrome).

The usual dose is 75 mg (one ampoule) per day administered by deep injection into the upper outer quadrant of the gluteus maximus muscle using an aseptic technique. In severe cases (e.g., colic), the daily dose may be increased to two injections of 75 mg each, administered several hours apart (one injection into each buttock). As an alternative to the 75 mg injection solution, other dosage forms of VOLTAREN® (e.g., tablets or suppositories) may be used in combination, up to a maximum total daily dose of 150 mg of sodium diclofenac.

In the case of a migraine attack, clinical experience is limited to cases where one 75 mg ampoule is administered initially, preferably immediately after administration of a 75 mg suppository on the same day (if necessary). The total daily dose should not exceed 150 mg on the first day.

There are no available data on the use of VOLTAREN® for the treatment of migraine attacks for more than one day. If the patient requires further therapy in subsequent days, the maximum daily dose should be up to 150 mg (in divided doses administered as suppositories).

Intravenous Infusion

Immediately before starting intravenous infusion, VOLTAREN® should be diluted in 100–500 mL of 0.9% sodium chloride solution or 5% glucose solution. Both solutions must first be buffered with sodium bicarbonate solution (0.5 mL of 8.4% solution or 1 mL of 4.2% solution). Only clear solutions should be used. If crystals or precipitate are present in the solution, it must not be used.

VOLTAREN®, solution for injection, must not be administered as an intravenous bolus injection.

Recommended alternative dosing regimens for VOLTAREN® solution for injection:

For the treatment of moderate to severe postoperative pain: 75 mg should be administered continuously over 30 minutes to 2 hours; if necessary, treatment may be repeated after several hours, but the dose must not exceed 150 mg per day;
For the prophylaxis of postoperative pain: a loading dose of 25–50 mg should be administered 15 minutes to 1 hour after surgery, followed by continuous infusion at approximately 5 mg/hour up to a maximum daily dose of 150 mg.

Special Patient Groups

Elderly Patients (65 years and older)

Dose adjustment is generally not required for elderly patients. However, caution is recommended based on the patient's condition, particularly in frail elderly patients or those with low body weight (see section "Special Warnings and Precautions for Use").

Paediatric Population (under 18 years)

VOLTAREN® in the form of solution for injection is contraindicated for use in children and adolescents.

Established Cardiovascular Disease or Serious Cardiovascular Risk Factors

Treatment with VOLTAREN® is generally not recommended in patients with cardiovascular disease or uncontrolled arterial hypertension. If necessary, patients with cardiovascular disease, uncontrolled arterial hypertension, or significant cardiovascular risk factors should only be treated with VOLTAREN® after careful assessment and only at doses up to 100 mg per day if treatment duration exceeds 4 weeks (see section "Special Warnings and Precautions for Use").

Renal Impairment

VOLTAREN® is contraindicated in patients with renal impairment (GFR < 15 mL/min/1.73 m²; see section "Contraindications").

Specific studies in patients with impaired renal function have not been conducted; therefore, no dosage recommendations can be made. VOLTAREN® should be used with caution in patients with impaired renal function (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

VOLTAREN® is contraindicated in patients with hepatic impairment (see section "Contraindications").

Specific studies in patients with impaired liver function have not been conducted; therefore, no dosage recommendations can be made. VOLTAREN® should be used with caution in patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

VOLTAREN® in the form of solution for injection is contraindicated for use in children and adolescents.

Overdose

Symptoms. There is no typical clinical picture of diclofenac overdose. Overdose may cause symptoms such as vomiting, gastrointestinal bleeding, diarrhea, dizziness, tinnitus, or convulsions. In severe poisoning, acute renal failure and liver damage may occur.

Treatment.

Management of acute poisoning with NSAIDs, including diclofenac, consists primarily of supportive measures and symptomatic treatment. Supportive care and symptomatic treatment are necessary to manage complications such as hypotension, renal failure, convulsions, gastrointestinal disturbances, and respiratory depression.

Specific interventions such as forced diuresis, dialysis, or hemoperfusion cannot reliably remove NSAIDs, including diclofenac, due to their high plasma protein binding and extensive metabolism.

Adverse Reactions

Adverse reactions to the medicinal product are listed according to the following frequency categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

The adverse effects listed below are associated with administration of Voltaren® under both short-term and long-term use.

Infections and infestations: very rare – injection site abscess.

Blood and lymphatic system disorders: very rare – thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.

Immune system disorders: rare – hypersensitivity, anaphylactic and anaphylactoid reactions (including arterial hypotension and shock); very rare – angioedema (including facial swelling).

Psychiatric disorders: very rare – confusion, depression, insomnia, nightmares, irritability, and other psychiatric disorders.

Nervous system disorders: common – headache, dizziness; rare – somnolence, fatigue; very rare – paraesthesia, memory impairment, convulsions, anxiety, tremor, aseptic meningitis, taste disturbances, stroke; frequency not known – confusion, hallucinations, sensory disturbances, malaise.

Eye disorders: very rare – visual disturbances, blurred vision, diplopia; frequency not known – optic neuritis.

Ear and labyrinth disorders: common – vertigo; very rare – tinnitus, hearing disturbances.

Cardiac disorders: uncommon* – palpitations, chest pain, heart failure, myocardial infarction; frequency not known – Kounis syndrome;

*Frequency reflects data from long-term treatment with high doses (150 mg/day).

Vascular disorders: common – arterial hypertension; very rare – arterial hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: rare – asthma (including dyspnoea); very rare – pneumonitis.

Gastrointestinal disorders: common – nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, decreased appetite; rare – gastritis, gastrointestinal haemorrhage, vomiting of blood, haemorrhagic diarrhoea, melena, gastric or intestinal ulcer (with or without bleeding, gastrointestinal stenosis or perforation (sometimes fatal, especially in elderly patients), which may lead to peritonitis); very rare – colitis (including haemorrhagic colitis, ischaemic colitis, and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis, glossitis, oesophageal disorders, membranous intestinal strictures, pancreatitis.

Hepatobiliary disorders: common – increased transaminase levels; rare – hepatitis, jaundice, liver function abnormalities; very rare – fulminant hepatitis, hepatonecrosis, liver failure.

Skin and subcutaneous tissue disorders: common – skin rashes; rare – urticaria; very rare – bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exfoliative dermatitis, alopecia, photosensitivity reaction, purpura, allergic purpura (Schönlein-Henoch purpura), pruritus.

Renal and urinary disorders: common – fluid retention, oedema; very rare – acute kidney injury (acute renal failure), haematuria, proteinuria, nephrotic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions: common – injection site reaction, injection site pain, induration; rare – swelling, injection site necrosis; very rare – injection site abscess.

Reproductive system and breast disorders: very rare – impotence.

Meta-analysis of clinical trial data and pharmacoepidemiological evidence indicate an increased risk of arterial thrombotic complications (e.g. myocardial infarction or stroke) associated with the use of diclofenac, particularly at high therapeutic doses (150 mg daily) and with prolonged treatment duration (see section "Special Warnings and Precautions for Use").

Visual disturbances

Visual disturbances such as blurred vision, visual impairment, and diplopia are class effects of NSAIDs and are generally reversible upon discontinuation of the drug. The most likely mechanism of visual disturbances is inhibition of prostaglandin synthesis and related compounds, which may disrupt retinal blood flow regulation and contribute to visual disturbances. If such symptoms occur during diclofenac treatment, an ophthalmological examination should be performed to exclude other potential causes.

Adverse reactions reported during the post-marketing period (frequency not known)

Injection site reactions: cutaneous medicinal embolism (Nicolau syndrome).

Shelf life. 2 years.

Reconstituted infusion solutions should be used immediately.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Incompatibilities.

Voltaren®, solution for injection, should generally not be mixed with other injectable solutions.

Solutions of 0.9% sodium chloride or 5% glucose for infusion without sodium bicarbonate as an additive carry a risk of supersaturation, which may lead to crystal or precipitate formation. Other infusion solutions besides those recommended must not be used.

Packaging.

3 ml in a vial; 5 vials in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Lek Pharmaceuticals d.d.

Manufacturer's address and place of business.

Verovskova 57, 1526 Ljubljana, Slovenia.