Kiovig

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KIOVIG (KIOVIG)

Composition:

Active substance: human normal immunoglobulin (IVIg)*;

solution for infusion at 100 mg/ml:

1 vial of 10 ml contains 1 g of human normal immunoglobulin (IVIg);

1 vial of 25 ml contains 2.5 g of human normal immunoglobulin (IVIg);

1 vial of 50 ml contains 5 g of human normal immunoglobulin (IVIg);

1 vial of 100 ml contains 10 g of human normal immunoglobulin (IVIg);

1 vial of 200 ml contains 20 g of human normal immunoglobulin (IVIg);

1 vial of 300 ml contains 30 g of human normal immunoglobulin (IVIg).

* corresponds to total human protein content, of which at least 98% is IgG

distribution of IgG immunoglobulin subclasses:

IgG1 ≥ 56.9 %;

IgG2 ≥ 26.6 %;

IgG3 ≥ 3.4 %;

IgG4 ≥ 1.7 %;

maximum content of immunoglobulin A (IgA) – 0.14 mg/ml;

Excipients: glycine, water for injections.

Pharmaceutical form. Solution for infusion.

Main physicochemical properties: clear or slightly opalescent, colorless or pale yellow solution.

Pharmacotherapeutic group. Immune sera and immunoglobulins. Normal human immunoglobulin for intravenous administration. ATC code J06BA02.

Pharmacological properties.

Pharmacodynamics.

Normal human immunoglobulin contains predominantly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Normal human immunoglobulin contains IgG antibodies present in the body of most healthy individuals. It is typically manufactured from a pooled plasma derived from at least 1,000 donor blood units. The distribution of IgG subclasses corresponds to that found in natural human plasma. Appropriate doses of this medicinal product are capable of increasing abnormally low levels of immunoglobulin G to normal levels.

The mechanism of action for indications other than replacement therapy is not fully understood, but is believed to involve an immunomodulatory effect.

Children

There is no theoretical or observed difference in the effect of immunoglobulins in children compared to adults.

Pharmacokinetics.

After intravenous administration, normal human immunoglobulin becomes immediately and completely bioavailable in the recipient's circulatory system. It distributes relatively rapidly between plasma and extravascular fluid; equilibrium between intravascular and extravascular compartments is reached approximately 3–5 days after administration.

The pharmacokinetic parameters of KIOVIG were determined in two clinical studies in patients with primary immunodeficiency (PID), conducted in Europe and the United States. Overall, 83 subjects aged 2 years and older participated in these studies, receiving doses of 300–600 mg/kg body weight every 21–28 days for 6–12 months. The median half-life of IgG following administration of KIOVIG was 32.5 days. This value may vary among individual patients, particularly in those with primary immunodeficiency. The pharmacokinetic parameters of the product are presented in Table 1 according to three age groups: children under 12 years of age (n = 5), adolescents aged 13–17 years (n = 10), and adults aged 18 years and older (n = 64). The data obtained in these studies are comparable to those reported for other human immunoglobulins.

Table 1

* CI – confidence interval.

IgG and IgG complexes are degraded in cells of the reticuloendothelial system.

Preclinical safety data

Immunoglobulins are normal components of the human body.

The safety of KIOVIG administration has been demonstrated in several preclinical studies. Preclinical data obtained from traditional safety pharmacology and toxicity studies revealed no special risk for humans.

Toxicity studies of repeated doses, genotoxicity, and reproductive toxicity in animals have limited practical relevance due to induction and interference with antibody production against heterologous proteins. Since clinical experience provides no evidence of the carcinogenic potential of immunoglobulins, no experimental studies involving heterologous species have been conducted.

Clinical characteristics.

Indications.

Replacement therapy in adults and children (aged 0–18 years) in the following conditions:

• primary immunodeficiency (PID) with impaired antibody production (see section "Special precautions for use");
• secondary immunodeficiencies (SID) in patients with severe or recurrent infections, ineffective antibacterial therapy, proven specific antibody deficiency (PSAD)* or serum IgG level < 4 g/L.

*PSAD − inability to achieve at least a two-fold increase in IgG antibody titers against pneumococcal polysaccharide vaccine and polypeptide antigen.

Immunomodulation in adults and children (aged 0–18 years) in the following conditions:

• primary immune thrombocytopenia (ITP) in patients with a high risk of bleeding or prior to surgical intervention to correct platelet count;
• Guillain-Barré syndrome;
• Kawasaki disease (in combination with acetylsalicylic acid; see section "Method of administration and dosage");
• chronic inflammatory demyelinating polyradiculoneuropathy (CIDP);
• multifocal motor neuropathy (MMN).

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the product. Hypersensitivity to human immunoglobulins, particularly in patients with antibodies to IgA.

Administration of products containing IgA may lead to anaphylaxis in patients with selective IgA deficiency who have developed antibodies against IgA.

Interaction with other medicinal products and other forms of interaction.

Live attenuated viral vaccines

Administration of immunoglobulin may reduce the efficacy of live attenuated viral vaccines such as measles, rubella, mumps, and varicella for a period ranging from at least 6 weeks to 3 months. An interval of 3 months should be ensured after administration of this medicinal product before vaccination with live attenuated viral vaccines. In the case of measles, this negative effect may persist for up to one year. Therefore, antibody testing should be performed in patients receiving measles vaccine.

Dilution of KIOVIG 5% solution with glucose solution may lead to increased blood glucose levels.

Loop diuretics

Concomitant use of loop diuretics should be avoided.

Children

The above-mentioned interactions apply both to treatment of adults and children.

Special precautions for use.

Before administration, the medicinal product should be warmed to room temperature or body temperature.

If dilution is required, 5 % glucose solution is recommended. To obtain an immunoglobulin solution with a concentration of 50 mg/ml (5 %), KIOVIG 100 mg/ml (10 %) should be diluted with an equal volume of glucose solution. During dilution, the risk of microbial contamination should be minimized.

Before administration, the preparation should be visually inspected for the presence of particulate matter and discoloration. The solution should be clear or slightly opalescent, colorless or pale yellow. Solutions that are cloudy or contain a precipitate must not be used.

KIOVIG should be administered only by intravenous infusion. Other routes of administration of this medicinal product have not been studied.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Infusion-related reactions

Some severe adverse reactions (e.g., headache, facial flushing, chills, myalgia, wheezing, tachycardia, back pain, nausea, and arterial hypotension) may be related to the rate of infusion. The recommended infusion rate described in the section "Dosage and administration" must be strictly followed. Patients should be closely monitored for the appearance of any symptoms throughout the entire period of drug administration.

Some adverse reactions may occur more frequently:

• with a high rate of infusion;
• when human normal immunoglobulin is administered for the first time, or rarely when switching from one human normal immunoglobulin preparation to another, or after a prolonged interval since the previous infusion;
• in patients with untreated infection or underlying chronic inflammation.

Precautions for use

Potential complications can often be avoided by ensuring that patients:

• are not sensitive to human normal immunoglobulin by initially administering the product slowly (0.5 ml/kg body weight per hour);
• are under close monitoring for the appearance of any symptoms throughout the entire infusion period. In particular, patients should be carefully observed during the first infusion and for the first hour thereafter to detect signs of a potential adverse reaction, when human normal immunoglobulin is administered for the first time, or when switching to alternative intravenous immunoglobulins (IVIG), or after a prolonged interval since the previous infusion. Other patients should be observed for at least 20 minutes after administration of this medicinal product.

For all patients receiving IVIG, the following measures are required:

• adequate hydration should be ensured before starting IVIG infusion;
• urine output should be monitored;
• serum creatinine levels should be monitored;
• patients should be observed for signs and symptoms of thrombosis;
• blood viscosity should be assessed in patients at risk of hyperviscosity;
• concomitant use of loop diuretics should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

If an adverse reaction occurs, the infusion rate should be reduced or the infusion stopped.

Treatment depends on the nature and severity of the adverse reaction.

If KIOVIG needs to be diluted to lower concentrations for treatment of patients with diabetes mellitus, the recommendation to use 5 % glucose solution for dilution should be reconsidered.

Hypersensitivity

Hypersensitivity reactions are rare.

Anaphylaxis may develop in patients:

• with undetermined IgA who have antibodies to IgA;
• who have previously been treated with human normal immunoglobulin.

In case of shock, standard medical treatment for shock should be administered.

Thromboembolism

There is clinical evidence of an association between IVIG administration and the development of thromboembolic complications such as myocardial infarction, acute cerebrovascular accident (including stroke), pulmonary embolism, and deep vein thrombosis, which are believed to be related to relative increases in blood viscosity due to the infusion of a large amount of immunoglobulin in patients at risk. Caution should be exercised when prescribing and administering IVIG to patients with obesity and patients at risk of thrombotic events (such risk factors include a history of atherosclerosis; multiple cardiovascular risk factors; advanced age; impaired cardiac output; arterial hypertension; estrogen therapy; diabetes mellitus and vascular disease or history of thrombosis; acquired or inherited thrombophilic disorders; hypercoagulable states; prolonged immobilization; severe hypovolemic shock; conditions increasing blood viscosity; presence of a central catheter, administration in high doses and at high infusion rates).

In patients undergoing IVIG therapy, hyperproteinemia, increased serum viscosity, and subsequent relative pseudohyponatremia may occur. This should be taken into account by physicians, as initiating treatment for true hyponatremia (i.e., restricting intake of sodium-free water) in such patients may lead to further increase in serum viscosity and possible predisposition to thromboembolic complications.

IVIG preparations should be administered at the minimum possible rate and in the smallest effective doses to patients at risk of thromboembolic adverse reactions.

Acute renal failure

Cases of acute renal failure, including acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis, have been reported in patients receiving IVIG therapy. In most cases, risk factors were identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, obesity, concomitant use of nephrotoxic drugs, age over 65 years, sepsis, hyperviscosity, or paraproteinemia.

Renal function parameters should be evaluated before IVIG administration, especially in patients who potentially have an increased risk of developing acute renal failure, and repeated at appropriate intervals.

IVIG preparations should be administered at the minimum infusion rate and in the lowest possible dose to patients at risk of acute renal failure. If renal function impairment occurs, discontinuation of IVIG should be considered.

Although cases of renal function impairment and acute renal failure have been associated with many licensed IVIG preparations containing various excipients such as sucrose, glucose, and maltose, the proportion of medicinal products containing sucrose as a stabilizer was quite significant. For treatment of patients at increased risk, the possibility of using IVIG preparations not containing these excipients may be considered. KIOVIG does not contain sucrose, maltose, or glucose.

Acute transfusion-related lung injury (ATRLI)

Acute non-cardiogenic pulmonary edema (acute transfusion-related lung injury (ATRLI)) has been reported in patients receiving IVIG (including KIOVIG). ATRLI is characterized by marked hypoxia, dyspnea, tachypnea, cyanosis, fever, and arterial hypotension. Symptoms of ATRLI usually develop during or within 6 hours after transfusion, most commonly within 1–2 hours. Therefore, recipients of IVIG should be monitored, and IVIG infusion should be immediately stopped in case of pulmonary adverse reactions. ATRLI is a potentially life-threatening reaction requiring immediate treatment in an intensive care unit.

Aseptic meningitis syndrome (AMS)

Cases of aseptic meningitis syndrome associated with IVIG administration have been reported. The syndrome usually develops within several hours to two days after IVIG administration. Cerebrospinal fluid analysis often shows positive results with pleocytosis up to several thousand cells per 1 mm³, predominantly granulocytic, and elevated protein levels up to several hundred mg/dl. AMS may occur more frequently with high-dose (2 g/kg) IVIG treatment.

Patients presenting with these signs and symptoms should undergo a thorough neurological examination, including cerebrospinal fluid analysis, to exclude other causes of meningitis.

Discontinuation of IVIG treatment led to remission of AMS within several days without sequelae.

Post-marketing data on the use of KIOVIG do not show a clear correlation between AMS and high doses of this medicinal product. The incidence of AMS was higher in women.

Hemolytic anemia

IVIG preparations may contain blood group antibodies capable of acting as hemolysins and inducing in vivo coating of erythrocytes with immunoglobulin, leading to a positive direct antiglobulin reaction (Coombs test) and rarely hemolysis. Hemolytic anemia may develop after IVIG treatment due to enhanced erythrocyte sequestration. Patients receiving IVIG should be monitored for clinical signs and symptoms of hemolysis (see section "Adverse reactions").

Neutropenia/leukopenia

Transient decreases in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after IVIG treatment. This usually occurs within hours or days after IVIG administration and resolves spontaneously within 7–14 days.

Serological testing

After immunoglobulin infusion, passive transfer of antibodies may temporarily increase antibody levels in the patient's blood, potentially leading to false-positive results in serological testing.

Passive transfer of antibodies to erythrocyte antigens such as A, B, D may affect results of certain serological tests for antibodies to red blood cells, e.g., the direct antiglobulin test (direct Coombs test).

Administration of KIOVIG may lead to false-positive results in tests based on detection of beta-D-glucans for diagnosis of fungal infections. This effect may persist for weeks after infusion of the product.

Infectious agents

KIOVIG is manufactured from human plasma. Standard measures to prevent transmission of infections with medicinal products manufactured from human blood or plasma include donor selection, screening of individual donor samples and plasma pools for specific infection markers, and implementation of effective manufacturing steps aimed at inactivation/removal of viruses. Nevertheless, the possibility of transmitting infectious agents with medicinal products manufactured from human blood or plasma cannot be completely excluded. This also applies to unknown or new viruses and other pathogens.

The measures applied are considered effective against enveloped viruses such as HIV, hepatitis B, and hepatitis C, as well as against non-enveloped viruses such as hepatitis A virus and parvovirus B19.

There is clinical evidence of absence of transmission of hepatitis A or parvovirus B19 with immunoglobulins. In addition, the antibodies present in the preparations are considered to play an important role in ensuring viral safety.

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded in the patient's treatment record.

Children

There is no specific pediatric risk for any of the adverse reactions mentioned above. Pediatric patients may be more susceptible to volume overload (see section "Overdose").

Use during pregnancy and breastfeeding.

Pregnancy

The safety of this medicinal product in pregnant women has not been established in controlled clinical trials; therefore, it should be prescribed to pregnant women and women who are breastfeeding only with caution. It has been shown that IVIG preparations cross the placenta, particularly actively during the third trimester of pregnancy. Clinical experience with immunoglobulins indicates no harmful effects on pregnancy, the fetus, or the newborn.

Breastfeeding

Immunoglobulins are excreted in breast milk and can contribute to protecting the newborn from pathogenic microorganisms entering the child's body through the oral mucosa. There are no negative consequences for newborns/infants.

Fertility

Clinical experience with immunoglobulins indicates no harmful effect on fertility.

Ability to drive and use machinery.

The ability to drive or operate machinery may be impaired due to some adverse reactions caused by the use of KIOVIG. Patients who experience adverse reactions during treatment should wait until these reactions have subsided before driving or operating machinery.

Administration and Dosage

Replacement therapy must be administered under the supervision of a physician experienced in the treatment of immunodeficiency.

Dosage

The dose and regimen depend on the indication.

In replacement therapy, it may be necessary to determine the dose on an individual basis for each patient according to pharmacokinetics and clinical response. The dose calculated based on body weight may require adjustment in patients with low or excessive body weight. The treatment regimens below are provided as general guidance.

Replacement therapy in primary immunodeficiency syndrome

The treatment regimen should aim to achieve a minimum IgG level (measured immediately before the next infusion) of at least 5–6 g/L. Treatment should be continued for three to six months to reach equilibrium (stable IgG level). The recommended initial dose is 0.4–0.8 g/kg as a single dose, followed by at least 0.2 g/kg every three to four weeks.

The dose required to achieve a minimum level of 5–6 g/L is approximately 0.2–0.8 g/kg per month. After a stable condition is achieved, the interval between administrations ranges from 3 to 4 weeks.

The minimum residual drug concentration should be measured and evaluated in relation to the frequency of infections. To reduce the frequency of infections, it may be necessary to increase the dose to achieve a higher minimum residual drug concentration.

Secondary immunodeficiencies (as indicated in the section "Indications")

The recommended dose is 0.2–0.4 g/kg every three to four weeks.

The minimum residual drug concentration should be measured and evaluated according to the frequency of infections. The dose should be adjusted as needed to achieve optimal protection against infections: an increase may be necessary for patients with persistent infections, while dose reduction may be considered when the patient remains free of infections.

Primary immune thrombocytopenia

Two alternative treatment regimens are available:

• 0.8–1 g/kg on day 1, with this dose repeatable once within 3 days;
• 0.4 g/kg daily for 2–5 days.

In case of relapse, the treatment course may be repeated.

Guillain-Barré syndrome

0.4 g/kg/day for 5 days (re-administration of the dose may be considered in case of relapse).

Kawasaki disease

2 g/kg should be administered as a single dose.

Patients should also receive acetylsalicylic acid concurrently.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Initial dose – 2 g/kg, administered over 2–5 days.

Maintenance doses – 1 g/kg over 1–2 days every 3 weeks.

Therapeutic response should be evaluated after each cycle; treatment should be discontinued if no response is observed within 6 months.

Once a positive therapeutic effect is achieved, further duration of treatment should be determined by the physician based on the patient's response to the drug.

Dosing and intervals may need to be adjusted according to the individual course of the disease.

Multifocal motor neuropathy (MMN)

Initial dose – 2 g/kg over 2–5 days.

Maintenance dose – 1 g/kg every 2–4 weeks or 2 g/kg every 4–8 weeks over 2–5 days.

Therapeutic response should be evaluated after each cycle; treatment should be discontinued if no response is observed within 6 months.

Once a positive therapeutic effect is achieved, further duration of treatment should be determined by the physician based on the patient's response to therapy and maintenance dosing.

Dosing and intervals may need to be adjusted according to the individual course of the disease.

Recommended treatment regimens are provided in Table 2.

Table 2

Hepatic impairment

There are no data regarding the need for dose adjustment.

Renal impairment

Clinically, dose adjustment is not justified; see section "Special precautions for use".

Elderly patients

Clinically, dose adjustment is not justified; see section "Special precautions for use".

Route of administration

For intravenous use.

Normal human immunoglobulin should be administered intravenously at an initial infusion rate of 0.5 mL/kg body weight per hour for 30 minutes. If this infusion is well tolerated (see section "Special precautions for use"), the infusion rate may be gradually increased up to a maximum of 6 mL/kg body weight per hour. Clinical data from a limited number of patients indicate that adult patients with primary immunodeficiency may also tolerate infusion rates up to 8 mL/kg body weight per hour. For information on additional safety measures, see section "Special precautions for use".

If necessary, KIOVIG may be diluted with 5 % glucose solution to obtain a final concentration of 50 mg/mL (5 % immunoglobulin). Recommendations for dilution of the medicinal product prior to administration are provided in section "Special precautions for use".

If any infusion-related adverse reactions occur, the infusion rate should be reduced or the infusion stopped.

Children

Dosing for children (aged 0–18 years) does not differ from that for adults, as dosing for each indication is based on body weight and adjusted according to the clinical response to the conditions listed above.

Overdose.

Overdose may lead to fluid overload and hyperviscosity, particularly in patients at increased risk, including elderly patients or patients with cardiac or renal impairment (see section "Special precautions for use").

Children

Children under 5 years of age may be particularly sensitive to volume overload. Therefore, dosing must be carefully calculated in this population. In addition, children with Kawasaki disease have an especially high risk due to cardiovascular involvement; thus, dose and infusion rate must be carefully monitored.

Adverse reactions

Summary of safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure, and mild back pain may occur from time to time.

Rarely, human normal immunoglobulins may cause a sudden drop in blood pressure and, in individual cases, anaphylactic shock, even if no hypersensitivity reactions were observed during previous administrations.

Cases of reversible aseptic meningitis and rare cases of transient skin reactions (including cases of cutaneous lupus erythematosus, frequency unknown) have been observed with the use of human normal immunoglobulin. Reversible hemolytic reactions have been observed in patients, particularly those with blood groups A, B, and AB. Rarely, hemolytic anemia requiring blood transfusion may develop after treatment with high doses of IVIG (see also section "Special precautions for use").

Elevated serum creatinine levels and/or acute renal failure have been observed.

Very rare: thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis.

Cases of transfusion-related acute lung injury (TRALI) have been reported.

List of adverse reactions in tabular form

Tables 3 and 4 provide information according to MedDRA system organ class classification (using preferred terms). Table 3 lists adverse reactions observed in clinical trials, and Table 4 lists those reported during the post-marketing period.

The frequency of adverse reactions is classified as follows: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 3

Table 4

Description of individual adverse reactions

Muscle twitching and weakness were observed only in patients with ALS.

Children

The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.

Reporting of suspected adverse reactions

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

For safety regarding transmissible agents, see section "Special precautions for use".

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze. Keep in the original packaging to protect from light. Keep out of reach of children.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products or any other intravenous immunoglobulin preparations.

Packaging.

1 vial containing 1 g/10 ml, 2.5 g/25 ml, 5 g/50 ml, 10 g/100 ml, 20 g/200 ml or 30 g/300 ml of infusion solution per carton.

Prescription status.

Prescription only.

Manufacturers.

Baxter Belgium Manufacturing SA.

Manufacturer's address and place of business.

Boulevard Rene Grandmont 80, Lessines, 7860, Belgium.