Diphtheria antitoxin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIPHTHERIA ANTITOXIN

Composition:

Active substance: diphtheria antitoxin, purified equine;

1 ml of solution contains not less than 1000 IU of diphtheria antitoxin, purified equine;

Excipients: cresol (0.25%), glycine (22.5 mg/ml), sodium chloride, water for injections.

Pharmaceutical form. Solution for injection

Main physicochemical properties: clear, colorless or slightly yellowish liquid, free from suspended particles.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Immune sera.

ATC code J06A A01.

Immunological and biological properties.

The active substance of the medicinal product Diphtheria Antitoxin exerts a specific neutralizing effect against the toxin produced by the causative agent of diphtheria, Corynebacterium diphtheriae. Diphtheria antitoxin is produced from the blood of horses hyperimmunized with diphtheria toxin. Plasma with a high content of antibodies against diphtheria toxin, obtained from hyperimmunized horses, is enzymatically purified, isolated, and concentrated.

Pharmacodynamics. Not applicable.

Pharmacokinetics. Not applicable.

Clinical characteristics.

Indications.

Diphtheria antitoxin is used to establish passive immunity against diphtheria.

Contraindications.

The use of antitoxin is contraindicated in patients with a history of allergic reactions to horse proteins, as well as in individuals with asthma and infantile eczema. Epinephrine and other supportive agents should be readily available in case of anaphylactic reaction.

Interaction with other medicinal products and other forms of interaction.

Immunoglobulins may affect the ability of live vaccines to induce an immune response. An appropriate interval should be maintained when administering these two medicinal products.

Special precautions for use.

A sensitivity test for Diphtheria antitoxin should be performed every time Diphtheria antitoxin is administered. Sensitivity to Diphtheria antitoxin is recommended to be assessed by two methods: (1) skin test, i.e. scarification skin test or prick test, and (2) intradermal test (hereinafter referred to as ID-test). The ID-test should be performed if the skin test result is negative.

This sequence is recommended because the skin test is considered safe, whereas there have been reports that the intradermal test has caused anaphylactic reactions with fatal outcomes.

For conducting sensitivity tests, along with Diphtheria antitoxin, histamine solution (histamine phosphate solution 2.75 mg/mL or histamine dihydrochloride solution 10 mg/mL, or a similar medicinal product intended for skin diagnosis; used as a reagent producing an acute allergic reaction on the skin) and physiological saline (a reagent that does not produce allergic reactions in skin tests) are recommended.

Skin tests should be performed on the right and left forearms of the patient. The left forearm is usually used for control (physiological saline and histamine solution are applied). The right forearm is used for the test (Diphtheria antitoxin is applied).

• Physiological saline is used as an example of absence of sensitivity or negative control test (usually performed on the left arm).
• Histamine solution (histamine dihydrochloride solution 10 mg/mL or histamine phosphate solution 2.75 mg/mL, or a similar medicinal product intended for skin diagnosis) is used as an example of positive control test (usually performed on the left arm).
• Diluted Diphtheria antitoxin 1:100* (0.1 mL of Diphtheria antitoxin diluted in 10 mL of physiological saline) is applied to the right arm.

* Diluted Diphtheria antitoxin 1:1000 should be used for patients with documented history of allergic manifestations and confirmed data on reactions to animal-derived sera.

(1). Skin tests, i.e. scarification skin test, prick test, or skin scratch test.

The skin area on the inner surface of the right and left forearms of the patient should be cleaned with alcohol or alcohol-containing antiseptic and dried.

• Example of negative test (physiological saline / left arm): using a sterile needle or other sharp sterile instrument, a scratch 2–4 mm long is made on the skin without bleeding. Then a drop of normal physiological saline is applied to the scratch site. The result is evaluated after 15 minutes; no skin sensitivity reaction should be observed.
• Example of positive test (histamine / left arm): using a sterile needle or other sharp sterile instrument, a scratch 2–4 mm long is made on the skin without bleeding, at least 5 cm away from the site of another test. Then a drop of histamine solution (histamine dihydrochloride solution 10 mg/mL or histamine phosphate solution 2.75 mg/mL, or a similar medicinal product intended for skin diagnosis) is applied to the scratch site. The result is evaluated after 15 minutes. A positive test is considered to be the formation of a papule with surrounding erythema measuring more than 3 mm exceeding the result of the negative control test obtained after 15–20 minutes. If a significant papule forms earlier than the specified time, the remaining histamine solution at the scratch site should be wiped off with a swab.
• Skin sensitivity test to diluted Diphtheria antitoxin. Dilute 0.1 mL of Diphtheria antitoxin injection solution in 10 mL of normal physiological saline (for patients with documented history of allergic manifestations and confirmed data on reactions to animal-derived sera, diluted Diphtheria antitoxin 1:1000 should be used). Using a sterile needle or other sharp sterile instrument, a scratch 2–4 mm long is made on the skin without bleeding, at least 5 cm away from the site of another test. Then a drop of Diphtheria antitoxin diluted in the appropriate proportion is applied to the scratch site. The result is evaluated after 15 minutes. A positive test is considered to be the formation of a papule with surrounding erythema measuring more than 3 mm exceeding the result of the negative control test obtained after 15–20 minutes.

The presence of a positive reaction indicates that the patient has increased sensitivity to Diphtheria antitoxin. In such cases, the patient requires desensitization according to a defined protocol.

A doubtful result is considered when a papule of significant size is formed, but less than 3 mm in diameter, within 15–20 minutes.

A mandatory condition for correct interpretation of the skin test result is a pronounced reaction at the site of the positive control using histamine solution (usually left arm / positive control example).

If skin tests show a negative result, intradermal sensitivity tests should be performed.

If skin tests show a positive or doubtful result (the site of application of diluted Diphtheria antitoxin resembles the site of histamine solution application), the patient requires desensitization according to the scheme described below.

If the patient develops systemic reactions (hypotension, respiratory disturbances, urticaria), adrenaline should be administered.

(2) Intradermal test (ID-test).

The intradermal sensitivity test is recommended to be performed only after a negative result of skin tests, as there have been reports that the intradermal test has caused anaphylactic reactions with fatal outcomes.

To perform the ID-test, the skin area on the inner surface of the right and left forearms of the patient should be cleaned with alcohol or alcohol-containing antiseptic and dried.

• Example of negative control (physiological saline / left arm): intradermally, using a syringe with a needle for intradermal injection, 0.02 mL of normal physiological saline (0.9% NaCl) is administered. As a result of injection, a small intradermal papule should form. The result is evaluated after 15 minutes; no skin sensitivity reaction should be observed.
• Example of positive control (histamine / left arm): intradermally, using a syringe with a needle for intradermal injection, 0.02 mL of histamine solution (histamine dihydrochloride solution 10 mg/mL or histamine phosphate solution 2.75 mg/mL or a similar medicinal product intended for skin diagnosis) is administered. As a result of injection, a small intradermal papule should form. The result is evaluated after 15 minutes. A positive test is considered to be the formation of a papule with surrounding erythema measuring more than 3 mm exceeding the result of the negative control test obtained after 15–20 minutes. If a significant papule forms earlier than the specified time, the remaining histamine solution at the injection site should be wiped off with a swab.
• Sensitivity test to diluted Diphtheria antitoxin. Dilute 0.1 mL of Diphtheria antitoxin injection solution in 10 mL of normal physiological saline (0.9% NaCl). For patients with documented history of animal allergy and confirmed data on reactions to animal-derived sera, diluted Diphtheria antitoxin 1:1000 should be used. Determine the site for intradermal injection at least 5 cm away from the site of another test. Inject 0.02 mL of diluted 1:100 Diphtheria antitoxin intradermally using a syringe with a needle for intradermal injection. As a result of injection, a small intradermal papule should form. For patients with documented history of animal allergy and confirmed data on reactions to animal-derived sera, 0.02 mL of diluted Diphtheria antitoxin in physiological saline 1:1000 should be administered. If administration of diluted 1:1000 Diphtheria antitoxin shows a negative sensitivity result, repeat intradermal administration of 0.02 mL of diluted 1:100 Diphtheria antitoxin and monitor the result.
• The result is evaluated after 15 minutes. There should be no pronounced reaction. A positive ID-test is considered to be the formation of a papule with surrounding erythema measuring more than 3 mm exceeding the result of the negative control test obtained after 15–20 minutes. The presence of a positive reaction indicates that the patient has increased sensitivity to Diphtheria antitoxin. In such cases, the patient requires desensitization according to a defined protocol.

A doubtful result is considered when a papule of significant size, but less than 3 mm in diameter, is formed within 15–20 minutes.

If the intradermal test shows a negative result (the site of administration of diluted Diphtheria antitoxin resembles the site of physiological saline administration), Diphtheria antitoxin may be administered according to the indications and doses specified in the section "Administration and dosage".

If the intradermal test shows a positive or doubtful result (the site of administration of diluted Diphtheria antitoxin resembles the site of histamine solution administration), the patient requires desensitization according to the scheme described below.

If the patient develops systemic reactions (hypotension, respiratory disturbances, urticaria), adrenaline should be administered.

Healthcare personnel should be aware that a negative result of skin tests does not exclude the possibility of an adverse reaction. Therefore, Diphtheria antitoxin should be administered cautiously even if the ID-test result is negative. Furthermore, antihistamine medications (and possibly other drugs such as tricyclic antidepressants) previously used by the patient may affect the results of skin tests for a period of one day or longer, depending on the antihistamine used.

Desensitization.

For patients with positive sensitivity test results or patients with confirmed history indicating an increased risk associated with the use of Diphtheria antitoxin injection solution, the desensitization measures described below should be implemented.

Healthcare personnel involved in patient desensitization should have experience in treating anaphylaxis and shock therapy and should be equipped with necessary equipment and medications.

Tables 1 and 2 describe the desensitization procedures. Table 1 specifies the intravenous route of desensitization, Table 2 specifies intramuscular, subcutaneous, and intradermal routes.

Table 1. Desensitization to Diphtheria antitoxin – intravenous route of administration.

*Administered at 15-minute intervals.

**1 ml DAT + 9 ml of physiological solution = 1:10 dilution;
1 ml (1:10 dilution) + 9 ml of physiological solution = 1:100 dilution;
0.1 ml (1:10 dilution) + 9.9 ml of physiological solution = 1:1000 dilution
or 1 ml (1:100 dilution) + 9 ml of physiological solution = 1:1000 dilution.

Table 2. Desensitization to Diphtheria Antitoxin – Intramuscular (IM), Subcutaneous (SC), and Intradermal (ID) Administration Routes.

*Administered at 15-minute intervals.

**1 ml DAT + 9 ml of physiological saline = 1:10 dilution;
1 ml (1:10 dilution) + 9 ml of physiological saline = 1:100 dilution;
0.2 ml (1:10 dilution) + 9.9 ml of physiological saline = 1:1000 dilution,
or 1 ml (1:100 dilution) + 9 ml of physiological saline = 1:1000 dilution.

In case of anaphylactic shock following administration of Diphtheria Antitoxin, 1 ml of adrenaline must be administered intramuscularly immediately.

Before administering Diphtheria Antitoxin, it is necessary to inquire about the patient’s history of prior serum administration and the presence of personal or hereditary allergies, such as asthma, eczema, or drug allergies.

In case of an allergic reaction to Diphtheria Antitoxin within 15–30 minutes, antihistamine agents such as pheniramine maleate or hydrocortisone should be administered intramuscularly. 1 ml of adrenaline (1:1000) may be administered intramuscularly simultaneously with diphtheria antitoxin. Administration of hydrocortisone or adrenaline may be repeated if necessary.

Adrenaline and other anti-shock therapy agents must be readily available in case of anaphylactic reaction.

The product contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy is not a contraindication for the use of diphtheria antitoxin; see section "Contraindications".

Breastfeeding is not a contraindication for the use of diphtheria antitoxin unless specifically stated otherwise. It is not known whether antibodies are excreted in breast milk.

Ability to affect reaction speed when driving or operating machinery.

There is no information available regarding the effect on reaction speed when driving or operating machinery.

Administration and Dosage

In cases of mild to moderate severity of diphtheria, Diphtheria Antitoxin should be administered intramuscularly to adults and children at a dose of 20,000 to 60,000 IU, and up to a maximum of 100,000 IU in severe cases.

Intravenous administration should be chosen as the most effective route in severe cases. For intravenous use, Diphtheria Antitoxin is mixed with 250 to 500 ml of 0.9% sodium chloride solution and administered by slow infusion over 2–4 hours. Careful monitoring for anaphylactic reactions is required throughout the infusion.

Prior to administration, the antitoxin should be warmed to 32–34°C. The medicinal product should be heated carefully, avoiding temperatures above the recommended range, as proteins in Diphtheria Antitoxin may denature.

Antibiotics and corticosteroids may be administered if necessary. After recovery, active immunization with adsorbed diphtheria or adsorbed diphtheria-tetanus vaccine is recommended for long-term protection against reinfection, using two doses administered at an interval of 1 to 2 months.

Before administering Diphtheria Antitoxin according to clinical indications, sensitivity testing must be performed, and desensitization carried out if necessary (see section "Special Warnings and Precautions for Use").

The full therapeutic dose of Diphtheria Antitoxin should be administered in a single infusion (intramuscularly or intravenously). The only exception may be a series of injections required for desensitization.

Table 3. Recommended Dosages of Diphtheria Antitoxin for Children and Adults

Children should be given the same doses as adults.

Repeated doses of Diphtheria Antitoxin should not be administered after the initial recommended dose has been given, as this may increase the risk of adverse reactions.

Appropriate antimicrobial agents in full therapeutic doses should be initiated immediately upon suspicion of respiratory diphtheria (ideally, after specimen collection).

Diphtheria Antitoxin is rarely used in cutaneous diphtheria. In such cases, emphasis should be placed on wound hygiene and the use of antimicrobial agents. Erythromycin or penicillin are the antibiotics of first choice for the treatment of cutaneous diphtheria.

Any individual with clinical symptoms suggestive of diphtheria should receive Diphtheria Antitoxin as soon as possible, even before bacteriological confirmation of the diagnosis. Supportive therapy should be continued until all local and systemic symptoms are under control.

Children.

Diphtheria Antitoxin is used in pediatric practice; see information in the sections "Dosage and Administration" and "Special Warnings and Precautions for Use".

Overdose.

The dose usually depends on the severity of the infection. In case of overdose, symptomatic treatment is required and supportive therapy is recommended.

Side effects

Anaphylactic reaction.

Although the onset and severity vary greatly, anaphylaxis usually begins within minutes after administration of Diphtheria Antitoxin in susceptible patients. In general, the faster the onset, the more severe the reaction. The main manifestations are:

1. Skin manifestations, including itching, hyperemia, urticaria, and Quincke's edema (angioedema);
2. Respiratory manifestations, including hoarseness and stridor, wheezing, dyspnea, and cyanosis;
3. Cardiovascular manifestations, including rapid and weak pulse, hypotension, and arrhythmias.

Anaphylaxis requires immediate medical intervention.

In case of an anaphylactic reaction, treatment will depend on the nature and severity of the reaction. Parenterally administered epinephrine (adrenaline) is the primary drug for all types of reactions. Antihistamines should also be administered. Additionally, depending on the severity of the reaction, corticosteroids, alpha-adrenergic blockers, aminophylline, and beta-2 agonists may be used.

Febrile reaction.

Fever usually develops within 20 minutes to 1 hour after administration of Diphtheria Antitoxin. It is characterized by chills, mild dyspnea, and rapid rise in body temperature. Most febrile reactions are mild and can be managed with antipyretics alone; severe reactions may require additional measures (such as cool water baths, etc.) to reduce body temperature.

Serum sickness.

Symptoms of serum sickness include fever, maculopapular skin rash, or urticaria in milder forms (90% of cases), accompanied by arthritis, arthralgia, and lymphadenopathy; more severe forms may also occur. Rarely, angioneurotic edema, glomerulonephritis, Guillain-Barré syndrome, peripheral neuritis, or myocarditis may develop. Symptoms typically appear 7–10 days (range 5–24 days) after initial administration of Diphtheria Antitoxin. Onset may occur within several hours to 3 days after administration in individuals previously exposed to animal serum; serum sickness also occurs more frequently in these individuals. Mild cases of serum sickness often resolve spontaneously within a few days to 2 weeks. Medications that may be helpful include antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids.

Febrile reactions and serum sickness are not mediated by IgE and therefore cannot be predicted by skin testing. The incidence of anaphylaxis and serum sickness partially depends on the prevalence of prior animal serum exposure in the population; currently, this incidence is low.

Due to the potential risk of serious adverse reactions associated with administration of Diphtheria Antitoxin, it should be administered under close medical supervision and with immediate availability of appropriate medical intervention if needed.

The clinical decision to treat with Diphtheria Antitoxin should be based on an assessment of risks and benefits and the patient's clinical status. Given the life-threatening nature of respiratory diphtheria and the specific neutralizing action of Diphtheria Antitoxin against the toxin produced by Corynebacterium diphtheriae, administration of Diphtheria Antitoxin may potentially reduce disease severity and improve survival in diphtheria patients.

Shelf life: 2 years.

After the first opening of the vial, the product should be used immediately.

Storage conditions: Store at a temperature of 2 to 8°C. Do not freeze.

Packaging: 10 ml in vials. 1 vial per cardboard box.

Prescription status: Prescription only.

Manufacturer: VINS BIOPRODUCTS LIMITED.

Manufacturer's address and location of business operations:
No. 117, Timmapur, Kothur Mandal, Ranga Reddy District, Telangana State, India.