Sinris

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SİNRAİZ (CINRYZE)

Composition:

Active substance: C1 esterase inhibitor (human);

1 vial of powder contains 500 IU of human C1 esterase inhibitor, which after reconstitution corresponds to a concentration of 100 IU/mL;

total protein content in the reconstituted solution is 15 ± 5 mg/mL;

Excipients: trisodium citrate dihydrate; sodium chloride; L-valine; L-alanine;
L-threonine; sucrose;

1 vial of solvent contains 5 mL of water for injections.

Pharmaceutical form. Powder and solvent for solution for injection.

Main physicochemical characteristics: white powder; after reconstitution – a clear colorless or slightly bluish solution practically free from mechanical particles.

Pharmacotherapeutic group. Medicinal products used in hereditary angioneurotic edema. Plasma-derived C1 inhibitor.

ATC code B06AC01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

C1 inhibitor belongs to the superfamily of serine protease inhibitor proteins, or serpins. The primary function of serpins is to regulate the activity of serine proteases. C1 inhibitor is a single-chain glycoprotein found in plasma, which in its mature form consists of 478 amino acids with a molecular weight of approximately 105 kDa.

C1 inhibitor inhibits the complement system by binding to C1r and C1s, the two enzymatically active subunits of the first component of the complement system (C1) in the classical pathway, as well as to mannose-binding lectin-associated serine proteases in the lectin pathway. The primary substrate of activated C1 enzyme is C4; lack of C1 inhibition leads to decreased C4 levels. C1 inhibitor is the main inhibitor of the contact activation system and regulates the contact system and intrinsic coagulation pathway by binding and inactivating kallikrein and factor XIIa. Since these pathways are part of amplified enzymatic cascades, in the absence of C1 inhibitor, spontaneous or triggered activation of these pathways may lead to uncontrolled activation and edema.

Pharmacodynamic Effects

In clinical studies, intravenous administration of Cinryze resulted in a significant increase in systemic levels of antigenic and functional C1 inhibitor within 1 hour after administration.

Administration of C1 inhibitor increases serum C1 inhibitor activity and temporarily restores natural regulation of the contact, complement, and fibrinolytic systems, thereby controlling edema or predisposition to edema.

Low serum C4 levels often correlate with attacks of hereditary angioedema (HAE). Treatment with Cinryze led to an increase in C4 levels within 12 hours. A statistically significant (p = 0.0017) difference in mean change from baseline between treatment groups was observed at 12 hours, indicating a relationship between Cinryze treatment and increased C4 activity (Cinryze +2.9 mg/dL vs placebo +0.1 mg/dL).

Clinical Efficacy and Safety

Results from two randomized, double-blind, placebo-controlled studies (LEVP 2005-1/A and LEVP 2005-1/B), data from two open-label studies (LEVP 2006-1 and LEVP 2006-4), and two clinical studies involving children (0624-203 and 0624-301) demonstrated the efficacy of Cinryze in the treatment and prevention of angioedema attacks in patients with HAE.

Cinryze for Treatment of HAE Attacks

In the randomized, double-blind, placebo-controlled, parallel-group study LEVP 2005-1/A, 71 patients with acute HAE attacks were enrolled (36 patients receiving Cinryze, 35 patients in the placebo group). The study demonstrated that treatment with Cinryze within 4 hours of the onset of an HAE attack resulted in more than a 2-fold reduction in time to unequivocal relief of the index symptom compared to placebo (median 2 hours for Cinryze vs >4 hours for placebo, p = 0.048).

Treatment with Cinryze also resulted in more than a 2-fold reduction in time to complete resolution of the HAE attack compared to placebo (median 12.3 hours vs 31.6 hours, p = 0.001). The percentage of patients achieving unequivocal relief of the index symptom within 4 hours after dosing was 60% for patients receiving Cinryze and 42% for the placebo group (p = 0.062). Fifteen patients treated with Cinryze during laryngeal HAE attacks did not require tracheal intubation.

In the open-label study LEVP 2006-1, 101 subjects were treated for 609 acute HAE attacks (median 3 attacks per subject; range: 1–57). Within 4 hours after administration of Cinryze, unequivocal relief of the index symptom was achieved in 87% of attacks. Clinical improvement and/or discharge home occurred within 4 hours in 95% of cases. In patients with >1 attack, the number of attacks within 4 hours after dosing and time to response were comparable regardless of the number of treated attacks. Of 84 separate laryngeal HAE attacks, none required intubation after treatment with Cinryze.

Cinryze for Routine Prophylaxis of HAE Attacks

In the randomized, double-blind, placebo-controlled, crossover study LEVP 2005-1/B, 22 patients were included in the efficacy analysis (randomized and treated in both crossover periods). The study demonstrated that prophylaxis with Cinryze led to more than a 2-fold reduction in the number of HAE attacks compared to placebo (mean 6.3 attacks in the Cinryze group vs 12.8 attacks in the placebo group, p < 0.0001). Angioedema attacks were also less severe during prophylactic therapy with Cinryze compared to placebo (mean severity score 1.3 vs 1.9, a 32% reduction, p = 0.0008) and shorter in duration (mean 2.1 days vs 3.4 days, a 38% reduction, p = 0.0004). The total number of edema days during prophylactic therapy with Cinryze was lower compared to placebo (mean 10.1 days vs 29.6 days, a 66% reduction, p < 0.0001). Additionally, fewer infusions of Cinryze were required to treat HAE attacks during therapy with this medicinal product compared to placebo (mean 4.7 infusions vs 15.4 infusions, a 70% reduction, p < 0.0001).

In the open-label study LEVP 2006-4, 146 patients received Cinryze as HAE prophylaxis for periods ranging from 8 days to approximately 32 months (median 8 months). Prior to enrollment, patients reported a mean monthly HAE attack rate of 3.0 (range: 0.08–28.0); during prophylactic treatment with Cinryze, this rate was 0.21 (range: 0–4.56), and 86% of patients experienced a mean of ≤1 attack per month. In patients receiving prophylactic treatment with Cinryze for at least 1 year, the monthly attack rate per patient remained consistently low (0.34 attacks per month) compared to pre-study levels.

Cinryze for Prophylaxis of HAE Attacks Prior to Procedures

Cinryze was administered within 24 hours prior to a total of 91 medical, dental, or surgical procedures within the clinical program (40 procedures in children and 51 in adults). In 98% of cases, no HAE attacks were reported within 72 hours after administration of Cinryze.

Pediatrics

Age Group 6–11 Years

Treatment

Study LEVP 2006-1. Twenty-two pediatric patients were treated for 121 acute HAE attacks. The proportion of HAE attacks achieving unequivocal relief of the index symptom within 4 hours after administration of Cinryze was comparable between the 22 children included in the study (age range: 2–17 years) and adults, with symptom relief in 89% and 86% of cases, respectively.

Study 0624-203. Nine patients (age range: 6–11 years) were enrolled and received a single dose of Cinryze: 3 patients (body weight 10–25 kg) received 500 units*; 3 patients (body weight >25 kg) received 1000 units*, and 3 patients (body weight >25 kg) received 1500 units*. All 9 (100%) patients achieved unequivocal onset of relief of the index symptom within 4 hours after initiation of Cinryze administration. The median time to onset was 0.5 hours (range: 0.25–2.5 hours): 1.25, 0.25, and 0.5 hours in the 500 units*, 1000 units*, and 1500 units* groups, respectively. The median time to complete resolution of the HAE attack for the 9 patients was 13.6 hours (range: 1.6–102.3 hours).

Prophylaxis

Study LEVP 2006-4. Prior to enrollment, 23 children (age range: 3–17 years) reported a mean monthly HAE attack rate of 3.0 (range: 0.5–28.0). During the study, with prophylactic administration of Cinryze (1000 units* every 3–7 days; except for a 3-year-old child who received 500 units* every 3–7 days), the median monthly attack rate across pediatric subgroups was 0.4 (range: 0–3.4), and 87% of children reported a mean of ≤1 attack per month; these results are comparable to those observed in adults.

Study 0624-301. Six pediatric patients (ages 6 to 11 years) were enrolled and randomized to receive weekly administration of the drug for 12 weeks in two treatment sequences (500/1000 units* or 1000/500 units* of Cinryze).

Both doses resulted in similar reductions in attack frequency and demonstrated clinical benefit regarding attack severity, duration, and need for emergency treatment.

Age Group < 6 Years

In 3 patients under 6 years of age, administration of Cinryze (500 units* or 1000 units*) was associated with increased C1 INH levels and clinical efficacy in both emergency treatment and prophylaxis of attacks. Overall, Cinryze was well tolerated.

In all studies, administration of Cinryze resulted in increased levels of antigenic and functional C1 inhibitor after infusion compared to pre-infusion levels in both pediatric and adult patients.

Pharmacokinetics

A randomized, parallel-group, open-label pharmacokinetic study of Cinryze was conducted in patients with asymptomatic HAE. Patients received either a single intravenous dose of 1000 units*, or a dose of 1000 units* followed by a second dose of 1000 units* after 60 minutes. Mean pharmacokinetic parameters for functional C1 inhibitor, derived from concentration data adjusted to baseline, are presented in Table 1.

Table 1. Mean pharmacokinetic parameters for functional C1 inhibitor after administration of Cinryze

Parameters	Single dose (1000 units*)	Double dose (dose of 1000 units followed by a second dose of 1000 units after 60 minutes)
Baseline level (IU/mL)	0.31 ± 0.20 (n = 12)	0.33 ± 0.20 (n = 12)
Cmax (IU/mL)	0.68 ± 0.08 (n = 12)	0.85 ± 0.12 (n = 13)
Cmax corrected for baseline (IU/mL)	0.37 ± 0.15 (n = 12)	0.51 ± 0.19 (n = 12)
tmax (hours) [median (range)]	[1.2 (0.3 – 26.0)] (n = 12)	[2.2 (1.0 – 7.5)] (n = 13)
AUC(0-t) (IU×hour/mL)	74.5 ± 30.3 (n = 12)	95.9 ± 19.6 (n = 13)
AUC(0-t) corrected for baseline (IU×hour/mL)	24.5 ± 19.1 (n = 12)	39.1 ± 20.0 (n = 12)
CL (mL/min)	0.85 ± 1.07 (n = 7)	1.17 ± 0.78 (n = 9)
Elimination half-life (hours)	56 ± 35 (n = 7)	62 ± 38 (n = 9)

n – number of evaluated subjects.

*Historically assigned activity values are expressed in international units (IU).

After intravenous administration of a single dose of Cinryze to patients with HAE, serum concentration of functional C1 inhibitor doubled within 1–2 hours. Maximum serum concentration (Cmax) and area under the serum concentration–time curve (AUC) increased from single to double dose, although the increase was not proportional to the dose. The mean elimination half-life of functional C1 inhibitor following administration of Cinryze was 56 hours for a single dose and 62 hours for a double dose.

Since C1 inhibitor is an endogenous human plasma protein, it is not subject to metabolism by cytochrome P450 isoenzymes, excretion, or pharmacokinetic interactions with other drugs, typical for many low-molecular-weight compounds. The expected metabolic fate of this glycoprotein is its breakdown into small peptides and individual amino acids. Therefore, it is not expected that renal or hepatic impairment would affect the pharmacokinetics and excretion of Cinryze.

Children

Functional C1 inhibitor activity was measured in children in two open-label studies (see section "Pharmacodynamics. Children"). Mean increase from baseline in functional C1 inhibitor activity at 1 hour post-dose in children aged 2 to 18 years ranged from 20% to 88% in study LEVP 2006-1 (treatment) and from 22% to 46% in study LEVP 2006-4 (prophylaxis), compared to 21% to 66% and 25% to 32% in adults, respectively. Plasma levels were also evaluated in children (6–11 years) in two additional studies.

In study 624-203, plasma C1 INH antigen and functional activity were assessed in 9 patients after a single intravenous dose of 500 IU*, 1000 IU*, or 1500 IU* of Cinryze depending on body weight (see section "Pharmacodynamics. Children"). Increased levels of C1 INH antigen and functional activity above baseline were demonstrated at 1 hour and 24 hours after dose administration.

In study 0624-301, plasma C1 INH antigen and functional activity were measured in 6 patients before and at 1 hour after intravenous administration of two dose levels of Cinryze (500 IU* and 1000 IU*) administered every 3 or 4 days over 12 weeks. Both dose levels of Cinryze resulted in significant plasma levels of C1 INH antigen and functional activity.

Clinical characteristics

Indications.

Treatment and prevention of attacks of angioedema prior to procedures in adults and children (from 2 years of age) with hereditary angioedema (HAE).

Routine prophylaxis of angioedema attacks in adults and children (from 6 years of age) with severe and recurrent attacks of hereditary angioedema (HAE) who are intolerant of or insufficiently protected by oral prophylactic therapy, or in patients who do not adequately respond to repeated on-demand treatment.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

No interaction studies have been performed.

Special precautions for use.

Thrombotic events

Based on animal studies, a potential thrombogenic threshold exists at doses exceeding 200 units*/kg. Patients with known risk factors for thrombotic events (including indwelling catheters) should be closely monitored.

*Historically established activity values were defined relative to an internal reference standard, according to which 1 unit (U) corresponds to the average amount of C1 inhibitor present in 1 mL of normal human plasma. Currently, an international reference standard (IU) has been introduced, in which 1 IU is also defined as the amount of C1 inhibitor present in 1 mL of normal human plasma.

Transmissible agents

Standard precautions to prevent infection from medicinal products derived from human blood or plasma include donor selection, screening of individual donations and plasma pools for specific infection markers, and effective manufacturing steps for virus inactivation/removal. Nevertheless, when using medicinal products derived from human blood or plasma, the possibility of transmitting infectious agents cannot be completely excluded.

This also applies to unknown or emerging viruses and other pathogens.

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

Patients receiving repeated or regular treatment with human plasma-derived C1 inhibitor should be considered for appropriate vaccination (hepatitis A and B).

It is strongly recommended that the name and batch number of the product administered be recorded each time the patient receives Sinreprez, to establish a link between the patient's condition and the administered batch.

Hypersensitivity reactions

As with any biological product, hypersensitivity reactions may occur. Hypersensitivity reactions may present with symptoms similar to attacks of angioedema. Patients should be informed about early signs of hypersensitivity reactions, including urticaria, generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis. If these symptoms occur after administration, patients should immediately inform their physician. Immediate medical intervention is required in case of anaphylactic reactions or shock.

Home use and self-administration

There are limited data on the use of this medicinal product at home and on self-administration. Potential risks are associated with home use, self-administration of the product, and management of adverse reactions, including hypersensitivity. The decision on home use for an individual patient should be made by a physician, who must ensure appropriate training and periodic monitoring of such use.

Use in children

Thrombotic events have been reported in neonates and children undergoing cardiac bypass procedures who received high doses of another C1 inhibitor (up to 500 units*/kg) to prevent capillary leak syndrome.

Sodium content

Each vial of Sinreprez contains approximately 11.5 mg of sodium. This should be taken into account when prescribing the product to patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

Pregnancy

Data from a limited number of identified pregnancies during treatment with Sinreprez indicate no adverse effect of C1 inhibitor on pregnancy or on fetal/neonatal health. Currently, no other relevant epidemiological data are available. In reproductive studies in rats, at doses exceeding the recommended human dose by 28 times (1000 IU) based on an average adult human body weight of 70 kg, no effects on maternal or embryonal health were observed. The potential risk for humans is unknown.

Therefore, Sinreprez should be administered to pregnant women only if clearly necessary.

Breastfeeding

It is unknown whether C1 inhibitor is excreted in human breast milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/defer treatment with Sinreprez, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

No specific studies on fertility, early embryonic development, or postnatal development, or on carcinogenicity have been conducted.

Ability to affect reaction speed when driving or operating machinery.

Available clinical data indicate that Sinreprez has negligible influence on the ability to drive or operate machinery.

Administration and Dosage

Treatment with Cinryze should be initiated under the supervision of a physician experienced in the management of patients with hereditary angioedema (HAE).

For intravenous administration.

Dosage

Adults

Treatment of angioedema attacks

• 1000 IU of Cinryze at the first sign of an angioedema attack.
• A second dose of 1000 IU may be administered if the patient has not adequately responded after 60 minutes.
• In patients with laryngeal attacks or in cases of delayed initiation of treatment, the second dose may be given earlier than 60 minutes.

Routine prophylaxis of angioedema attacks

• The recommended initial dose for routine prophylaxis of angioedema attacks is 1000 IU of Cinryze every 3 or 4 days; the dosing interval may be adjusted according to individual response. The need for ongoing regular prophylaxis with Cinryze should be reviewed systematically.

Prophylaxis of angioedema attacks prior to a procedure

• 1000 IU of Cinryze within 24 hours prior to a medical, dental, or surgical procedure.

Children

Children aged 12 years and older

For treatment, routine prophylaxis, and pre-procedural prophylaxis in adolescents aged 12 to 17 years, the dose is the same as that for adults.

Children aged 2 to 11 years

The safety and efficacy of Cinryze in children under 2 years of age have not been established. Data supporting dosage recommendations for children under 6 years of age are very limited. Available data are presented in the sections “Adverse Reactions,” “Pharmacodynamics,” and “Pharmacokinetics.”

Treatment of angioedema attacks	Prevention of angioedema attacks prior to a procedure	Regular prophylaxis of angioedema attacks
Children aged 2 to 11 years weighing > 25 kg: 1000 IU of Cinryze at the first signs of an acute attack. A second dose of 1000 IU may be administered if the patient does not respond adequately within 60 minutes. Children aged 2 to 11 years weighing 10–25 kg: 500 IU of Cinryze at the first signs of an acute attack. A second dose of 500 IU may be administered if the patient does not respond adequately within 60 minutes.	Children aged 2 to 11 years weighing > 25 kg: 1000 IU of Cinryze within 24 hours prior to a medical, dental, or surgical procedure. Children aged 2 to 11 years weighing 10–25 kg: 500 IU of Cinryze within 24 hours prior to a medical, dental, or surgical procedure.	Children aged 6 to 11 years: The recommended initial dose for regular prophylaxis of angioedema attacks is 500 IU of Cinryze every 3 or 4 days. The dosing interval and dose may be adjusted according to individual response. The need for ongoing prophylaxis with Cinryze should be regularly reviewed.

Geriatric Patients

No specific studies have been conducted. The dosage for treatment, routine prophylaxis, and prophylaxis prior to procedures in elderly patients aged 65 years and older is the same as that for adults.

Patients with Renal or Hepatic Impairment

No specific studies have been conducted. The dosage of the drug for treatment, routine prophylaxis, and prophylaxis prior to procedures in patients with renal or hepatic impairment is the same as that for adults.

Administration

The reconstituted preparation should be administered intravenously at a rate of 1 mL per minute.

The reconstituted preparation should be used immediately after reconstitution.

Each kit contains materials for one dose of 1000 MO or two doses of 500 MO.

Reconstitution and Administration of Cinryze

Reconstitution, administration of the drug, and handling of the administration set and needles must be performed with caution.

Use either the transfer device with filter supplied in the Cinryze medicinal product kit or a commercially available double-ended needle.

Preparation and Handling

Cinryze is intended for intravenous administration after reconstitution with water for injections.

The Cinryze vial is intended for single use only.

Preparation of Reconstituted Solution

To prepare one 500 MO dose, one vial of powder, one vial of diluent, one transfer device with filter, one 10 mL single-use syringe, one venipuncture set, and one protective mat are required.

To prepare one 1000 MO dose, two vials of powder, two vials of diluent, two transfer devices with filter, one 10 mL single-use syringe, one venipuncture set, and one protective mat are required.

Each vial of the drug must be reconstituted with 5 mL of water for injections.

One vial of reconstituted Cinryze corresponds to a dose of 500 MO.

Two vials of reconstituted Cinryze correspond to a dose of 1000 MO. Therefore, two vials are combined to obtain a 1000 MO dose.

1. Preparation should be performed on the mat provided in the kit, and hands should be washed before performing the procedures described below.
2. Aseptic technique must be maintained during the reconstitution procedure.
3. Ensure that the vial of powder and the vial of diluent are at room temperature (15–25 °C).
4. Remove the label from the powder vial by peeling off the purple tape indicated by the arrow.
5. Remove the plastic caps from the vials of powder and diluent.
6. Clean the stoppers with a disinfectant swab and allow them to dry before use.
7. Remove the protective covering from the top part of the transfer device packaging. Do not remove the device from the packaging.
8. Note: To maintain the vacuum in the powder vial, the transfer device must first be attached to the diluent vial, then to the powder vial. Place the diluent vial on a flat surface and insert the blue end of the transfer device into the diluent vial, pressing down until the spike penetrates the center of the diluent vial stopper and the device is securely in place. The transfer device must be positioned vertically before piercing the stopper.
9. Remove the transfer device from its packaging and discard the packaging. Do not touch the open end of the transfer device.
10. Place the powder vial on a flat surface. Invert the transfer device and the diluent vial containing water for injections, and insert the transparent end of the transfer device into the powder vial, pressing down until the spike penetrates the rubber stopper and the transfer device locks into place. The transfer device must be positioned vertically before piercing the powder vial stopper. The vacuum in the powder vial will draw the diluent into the vial. Do not use the drug if there is no vacuum in the vial.
11. Gently swirl the powder vial until all the powder is dissolved. Do not shake the powder vial. Ensure that all the powder is completely dissolved.
12. Detach the diluent vial by turning it counterclockwise. Do not remove the transparent end of the transfer device from the powder vial.

One vial of reconstituted Cinryze contains 500 MO of C1 inhibitor in 5 mL, corresponding to a concentration of 100 MO/mL. If a patient requires administration of 500 MO of the drug, proceed to administration.

To obtain one dose (1000 MO/10 mL), two vials of Cinryze powder must be reconstituted. Repeat steps 1 to 12 above, using an additional package containing a transfer device to reconstitute the second powder vial. Reuse of the transfer device is prohibited. After reconstituting both vials, proceed to administration of the 1000 MO dose.

Administration of 500 MO Dose

1. Aseptic technique must be maintained during the administration procedure.
2. After reconstitution, Cinryze is a clear, colorless or slightly blue solution. Do not use the drug if the solution is cloudy or discolored.
3. Take a sterile 10 mL single-use syringe and pull back the plunger to draw approximately 5 mL of air into the syringe.
4. Attach the syringe to the upper part of the transparent end of the transfer device by turning it clockwise.
5. Carefully invert the vial, inject air into the solution, and then slowly draw the reconstituted Cinryze solution into the syringe.
6. Detach the syringe from the vial by turning it counterclockwise and removing it from the transparent end of the transfer device.
7. Before administration, inspect the reconstituted Cinryze solution for the presence of particulate matter; do not use if particles are present.
8. Attach the venipuncture set to the syringe containing the drug solution and administer intravenously to the patient. Cinryze 500 MO (reconstituted in 5 mL of water for injections) is administered intravenously at a rate of 1 mL per minute over 5 minutes.

Administration of 1000 MO Dose

1. Aseptic technique must be maintained during the administration procedure.
2. After reconstitution, the Cinryze solutions are colorless or slightly blue and clear. Do not use the drug if the solutions are cloudy or discolored.
3. Take a sterile 10 mL single-use syringe and pull back the plunger to draw approximately 5 mL of air into the syringe.
4. Attach the syringe to the upper part of the transparent end of the transfer device by turning it clockwise.
5. Carefully invert the vial, inject air into the solution, and then slowly draw the reconstituted Cinryze solution into the syringe.
6. Detach the syringe from the vial by turning it counterclockwise and removing it from the transparent end of the transfer device.
7. Using the same syringe, repeat steps 3–6 for the second vial of reconstituted Cinryze to obtain the full 10 mL dose.
8. Before administration, inspect the reconstituted Cinryze solution for the presence of particulate matter; do not use if particles are present.
9. Attach the venipuncture set to the syringe containing the drug solution and administer intravenously to the patient. Cinryze 1000 MO (reconstituted in 10 mL of water for injections) is administered intravenously at a rate of 1 mL per minute over 10 minutes.

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

Children

The safety and efficacy of Cinryze in children under 2 years of age have not been established. Data supporting dosage recommendations for children under 6 years of age are very limited (see sections "Pharmacodynamics" and "Pharmacokinetics").

Administered to children according to the specified indications (see sections "Indications" and "Dosage and Administration").

Overdose

No cases of overdose have been reported.

Adverse Reactions

Safety profile summary

The most commonly observed adverse reactions following infusion of Sinrise in clinical trials were headache and nausea.

List of adverse reactions in tabular form

The frequency of adverse reactions was assessed based on 2 main placebo-controlled and 2 open-label studies involving 251 individuals, and was determined from clinical trial results.

Adverse reactions observed during administration of Sinrise are classified by MedDRA system organ classes and absolute frequency, and are presented in Table 2. Within each frequency group, adverse reactions are listed in order of decreasing severity. Frequency is defined as 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), and not known (cannot be estimated from available data).

Table 2. Adverse reactions reported in clinical trials and post-marketing reports

System Organ Class	Frequency	Adverse Reaction
Immune system disorders	Common	Hypersensitivity reaction
Metabolism and nutrition disorders	Uncommon	Hyperglycemia
Nervous system disorders	Very common	Headache
	Common	Dizziness
Vascular disorders	Uncommon	Venous thrombosis, phlebitis, venous irritation, flushing
Respiratory, thoracic and mediastinal disorders	Uncommon	Cough
Gastrointestinal disorders	Very common	Nausea
	Common	Vomiting
	Uncommon	Diarrhea, abdominal pain
Skin and subcutaneous tissue disorders	Common	Rash, erythema, pruritus
	Uncommon	Contact dermatitis
Musculoskeletal and connective tissue disorders	Uncommon	Joint swelling, arthralgia, myalgia
General disorders and administration site conditions	Common	Rash/erythema at injection site, infusion site pain, hyperthermia
	Uncommon	Chest discomfort

Description of individual adverse reactions

The most common risk factor for venous thrombosis was the presence of an indwelling catheter.

Injection site reactions were observed rarely. During clinical studies, local reactions (described as pain, bruising or rash at the injection/catheter site, venous irritation or phlebitis) occurred in approximately 0.2% of infusions.

Children

A total of 61 pediatric patients participated in clinical studies. More than 2500 infusions of Cinryze were administered to pediatric patients (2–5 years, n = 3; 6–11 years, n = 32; 12–17 years, n = 26). Adverse reactions to Cinryze in children included headache, nausea, hyperthermia, and erythema at the infusion site. None of these adverse reactions were severe, and none led to discontinuation of the drug administration.

Overall, the safety and tolerability of Cinryze are similar in children, adolescents, and adults. For information on safety regarding transmissible agents, see section "Special precautions for use".

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

For the powder for solution for injection:

2 years.

The product should be used immediately after reconstitution. Chemical and physical stability has been demonstrated for 3 hours at room temperature (15–25°C).

For the solvent:

5 years.

Storage conditions.

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

Packaging.

2 vials of powder, 2 vials of solvent, 2 transfer devices with filter, 2 single-use 10 ml syringes, 2 venipuncture sets, and 2 protective mats in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Takeda Manufacturing Austria AG, Austria

Manufacturer's location and address of the site of operation.

Industriestrasse 67, 1221 Vienna, Austria