Piascay®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Piasky® (Piasky®)

Composition:

active substance: crovalimab;

1 vial (volume 2 ml) contains 340 mg of crovalimab, corresponding to a concentration of 170 mg/ml;

excipients: L-histidine, L-aspartic acid, L-arginine hydrochloride, poloxamer 188, water for injections.

Pharmaceutical form. Solution for injection or infusion.

Main physicochemical properties: transparent or strongly opalescent, practically colorless or yellowish-brown solution.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Complement inhibitors. Crovalimab.

ATC code L04A J07.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Crovallimab is a recombinant monoclonal antibody based on a humanized immunoglobulin G1 (IgG1) that specifically binds to complement component 5 (C5), thereby inhibiting its cleavage into C5a and C5b, and consequently preventing the formation of the membrane attack complex (MAC). Crovallimab inhibits the activity of terminal complement components. In patients with paroxysmal nocturnal hemoglobinuria (PNH), crovallimab suppresses terminal complement-mediated intravascular hemolysis.

Pharmacodynamic effect

In clinical studies involving patients with PNH, inhibition of terminal complement activity was observed in a concentration-dependent manner following crovallimab treatment. Suppression of terminal complement activity (CH50, measured by liposome immunoassay [LIA]) was achieved immediately after completion of the initial crovallimab infusion and generally persisted throughout the treatment period with crovallimab. Similarly, mean concentrations of free C5 decreased to low levels (< 0.0001 g/L) compared to baseline and remained low throughout the treatment period.

Levels of free C5 and CH50 were similar in pediatric and adult patients receiving crovallimab.

Clinical efficacy and safety

The safety and efficacy of crovallimab in patients with PNH were evaluated in a phase III non-inferiority study (COMMODORE 2, BO42162) and confirmed by clinical data from two additional phase III studies (COMMODORE 3, YO42311 and COMMODORE 1, BO42161).

In all phase III studies, patients were required to be vaccinated against Neisseria meningitidis within 3 years prior to initiation of treatment or within 7 days after starting crovallimab treatment. Patients vaccinated within 2 weeks before starting crovallimab treatment or after study initiation received appropriate antibiotic prophylaxis from the start of Piascay® administration and for at least 2 weeks after vaccination (see section "Special precautions" regarding precautions related to serious meningococcal infection). Patients with a history of Neisseria meningitidis infection within 6 months prior to screening and before the first dose of investigational drug were excluded from the studies.

Patients with a history of allogeneic bone marrow transplantation were also excluded from the studies.

In phase III studies, crovallimab was administered according to the recommended doses described in the section "Dosage and administration". Rescue doses of 340 mg crovallimab were permitted at the investigator's discretion if patients exhibited signs and symptoms of PNH; however, these studies were not designed to evaluate the impact of rescue dosing on the efficacy of crovallimab. Eculizumab was administered according to local prescribing guidelines or, in countries where eculizumab is not available on the market (COMMODORE 2), eculizumab was given intravenously at 600 mg once weekly for the first 4 weeks, followed by 900 mg every 2 weeks. Eculizumab was not used in this study.

The phase III studies consisted of a 24-week primary treatment period, after which patients had the opportunity to continue or switch to crovallimab in an extension period.

Immunogenicity

As with all medicinal products of protein origin, there is a potential for immune response to crovallimab.

Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparisons of the frequency of anti-crovallimab antibody detection with that of other products may be misleading.

In the phase III study COMMODORE 2, treatment-emergent anti-drug antibodies (ADAs) were observed in 35.0% (49/140) of treatment-naïve patients receiving crovallimab and in 38.2% (26/68) of patients switched from another C5 inhibitor to crovallimab. The median time to first ADA development from baseline was 16.1 weeks (range: 1.1–72.3 weeks) and 16.6 weeks (range: 2.1–36.3 weeks) in treatment-naïve patients and patients previously treated with another C5 inhibitor, respectively. In phase III studies, the incidence of treatment-emergent ADA formation was 35.1% (67 out of 191 patients) and 25.4% (51 out of 201 patients) in treatment-naïve patients and patients switched from another C5 inhibitor to crovallimab, respectively.

In phase III studies, the median area under the concentration–time curve (AUC) in patients with positive ADA status was slightly lower compared to those with negative ADA status. Despite this effect, concentrations remained above 100 µg/mL (the threshold for complete inhibition of terminal complement activity) in over 80% of patients with positive ADA status. The presence of ADAs was not associated with clinically meaningful impact on pharmacokinetics, pharmacodynamics, or efficacy in most patients. However, among 392 patients evaluated for ADA status, partial or complete loss of exposure associated with ADA development was observed in 23 patients (5.9%); among them, 17 patients (4.3%) with positive ADA status experienced loss of pharmacological activity (as assessed by CH50 or free C5), coinciding with loss of exposure and loss of efficacy, manifested as persistent loss of hemolysis control in 7 patients (1.8%). No evidence of clinical impact of ADA status on the safety profile of Piascay® was observed (see sections "Special precautions" and "Adverse reactions").

Children

Ten children (body weight ≥ 40 kg) receiving crovallimab in the COMMODORE 2 (n = 7; 13–17 years) and COMMODORE 3 (n = 3; 15–17 years) studies were evaluated for efficacy.

Nine patients were treatment-naïve, and one patient was switched from eculizumab to crovallimab during the extension period. All children received the same doses as adult patients, based on body weight. All 9 treatment-naïve patients achieved hemolysis control (defined as LDH ≤ 1.5 × ULN) by week 4, and this control was maintained in 7 patients at each visit from baseline to week 25. The patient switched from eculizumab to crovallimab maintained hemolysis control throughout 24 weeks of treatment in the extension period. Seven out of 10 children avoided blood transfusions and achieved hemoglobin stabilization, and no breakthrough hemolysis events occurred during the 24-week treatment period.

Overall, the treatment effect of crovallimab in children with PNH was similar to that observed in adult patients with PNH.

Pharmacokinetics

The pharmacokinetics of crovallimab were characterized in both healthy volunteers and patients with PNH using nonlinear mixed-effects pharmacokinetic modeling based on a pooled data set including 9 healthy volunteers, 210 treatment-naïve patients, and 211 patients switched from prior C5 inhibitor therapy to crovallimab.

The concentration–time profile of crovallimab was best described by a two-compartment open model with first-order elimination and a first-order constant for subcutaneous absorption. An additional time-varying clearance parameter, exponentially decreasing over time, was added to account for the transient increase in clearance due to type III immune complex formation observed in patients switched from another C5 inhibitor to crovallimab. At steady state, exposure is expected to be similar in treatment-naïve patients and those switched from prior therapy.

Absorption

The absorption rate constant was estimated as 0.126 day⁻¹ [CV%: 38.3]. After subcutaneous administration, bioavailability was estimated at 83.0% [CV%: 116].

Distribution

The central volume of distribution was estimated at 3.23 L [CV%: 22.4], and the peripheral volume of distribution at 2.32 L [CV%: 70.6].

The relatively small volume of distribution suggests that crovallimab is likely distributed predominantly in blood plasma and/or vascular-rich tissues.

Biotransformation

The metabolism of crovallimab has not been directly studied. IgG antibodies are primarily catabolized via lysosomal proteolysis and are then either excreted or recycled by the body.

Elimination

Clearance was estimated at 0.0791 L/day [CV%: 20.6]. The terminal half-life of crovallimab was 53.1 days [CV%: 39.9], which is longer compared to other humanized IgG antibodies. This prolonged half-life is consistent with crovallimab's ability to undergo recycling.

Special patient populations

Pharmacokinetic studies of crovallimab in special patient populations have not been conducted. Body weight was shown to be a significant covariate, with clearance and volume of distribution increasing and crovallimab exposure decreasing as body weight increases. Therefore, crovallimab dosing is based on patient body weight (see section "Dosage and administration").

After incorporating body weight into the model, population pharmacokinetic analysis in patients with PNH showed that age (13–85 years) and sex have no significant effect on crovallimab pharmacokinetics. No further dose adjustment is required.

Race/ethnicity also did not influence crovallimab pharmacokinetics; however, data in non-Caucasian patients are limited and therefore not considered conclusive for this patient group.

Elderly patients

No specific pharmacokinetic studies of crovallimab were conducted in patients aged ≥ 65 years. However, 46 (10.9%) elderly patients with PNH were included in clinical studies, including 35 patients aged 65–74 years, 10 patients aged 75–84 years, and 1 patient aged ≥ 85 years. Data from PNH clinical studies indicate that exposure in patients aged ≥ 65 years is comparable to that in younger patients. However, due to limited data in patients aged ≥ 85 years, the pharmacokinetics of crovallimab in this age group are unknown.

Renal impairment

No specific pharmacokinetic studies of crovallimab were conducted in patients with renal impairment. However, data from PNH clinical studies (62 [14.7%] patients with mild renal impairment, 38 [9%] with moderate renal impairment, and 4 [1%] with severe renal impairment) indicate that exposure in patients with mild, moderate, or severe renal impairment is comparable to that in patients with normal renal function. However, limited data were available for patients with severe renal impairment in PNH clinical studies.

Hepatic impairment

No specific studies were conducted in patients with hepatic impairment. However, data from PNH clinical studies indicate that exposure in patients with mild hepatic impairment (46 [11%], classified based on alanine aminotransferase levels) is comparable to that in patients without hepatic impairment. Limited pharmacokinetic data were available for patients with PNH and moderate (0 [0%]) to severe (1 [0.23%]) hepatic impairment; therefore, the impact of moderate or severe hepatic impairment on crovallimab pharmacokinetics is unknown, and no dosage recommendations can be provided (see section "Dosage and administration").

Children

Data from 12 children (13–17 years) in PNH clinical studies indicate that exposure in children aged 12 years and older with body weight ≥ 40 kg is comparable to that in adult patients.

Clinical characteristics.

Indications.

Pexvay® as monotherapy is indicated for the treatment of adults and children aged 12 years and older with a body weight of 40 kg or more with paroxysmal nocturnal hemoglobinuria (PNH):

• in patients with hemolysis and clinical symptom(s) indicating high disease activity;
• in patients who are clinically stable following treatment with a complement component 5 (C5) inhibitor for at least the previous 6 months.

Contraindications.

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

• Patients with untreated Neisseria meningitidis infection.
• Patients who are not currently vaccinated against Neisseria meningitidis, except for those receiving prophylactic treatment with appropriate antibiotics for 2 weeks following vaccination. (See section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Crovalimab and other C5 inhibitors bind different epitopes on C5. When both C5-inhibiting drugs are present in the circulation, immune complexes may form consisting of one or more antibodies bound to C5. These immune complexes, also known as "drug–target–drug complexes" (DTDC), may include one or more C5 units bound simultaneously to crovalimab and another C5 inhibitor. Such complexes are expected to be cleared within approximately 8 weeks (in the case of eculizumab). Immune complexes may take longer to clear when switching from C5 inhibitors with prolonged half-lives, such as ravulizumab. In some patients, formation of these complexes may lead to type III immune complex reactions (see sections "Special precautions for use" and "Adverse reactions"). In patients switching from therapy with another C5 inhibitor, a transient increase in clearance due to immune complex formation may occur, leading to faster elimination of crovalimab. However, this transient increase in clearance is not clinically significant and does not require dose adjustment in patients switching from another C5 inhibitor.

No specific interaction studies have been conducted.

Crovalimab is not expected to exhibit pharmacokinetic interactions with other medicinal products that interfere with cytochrome P450 (CYP) enzyme metabolism, since the clearance pathways of immunoglobulins G (IgG) differ from those of small molecules.

Special precautions for use.

Traceability

To improve traceability of biological medicinal products, it is essential to clearly record the name and batch number of the product administered.

Serious meningococcal infection

Due to the mechanism of action of crovalimab, its use may increase patient susceptibility to meningococcal infection (septicaemia and/or meningitis). Cases of serious or fatal meningococcal infection/sepsis have been reported in patients receiving treatment with inhibitors of terminal complement components, which is a known specific effect of drugs in this class.

Meningococcal infection can rapidly become life-threatening or fatal if not diagnosed and treated early. To reduce the risk of infection, all patients must be vaccinated with quadrivalent meningococcal vaccine at least 2 weeks prior to receiving the first dose of crovalimab. If immediate treatment with crovalimab is indicated in an unvaccinated patient, vaccination should be administered as soon as possible, and the patient should receive antibiotic prophylaxis from the start of crovalimab treatment and for at least 2 weeks after vaccination.

To prevent meningococcal infection caused by the most common pathogenic serogroups, vaccination against serogroups A, C, Y, W, and B is recommended, if available. Patients should have up-to-date vaccinations according to current national immunization recommendations. When switching a patient from treatment with another terminal complement inhibitor, physicians must ensure meningococcal vaccination is performed in accordance with current national vaccination guidelines. Vaccination may additionally activate the complement system, potentially leading to transient worsening of signs and symptoms of underlying complement-mediated diseases, including PNH, such as hemolysis. Therefore, disease symptoms should be closely monitored in patients following recommended vaccination.

Vaccination alone may not be sufficient to prevent meningococcal infection. Prophylactic use of antibacterial agents should be considered in accordance with national recommendations. All patients should be monitored for early signs of meningococcal infection, and if infection is suspected, immediate clinical evaluation and treatment with appropriate antibiotics should be initiated. Patients should be informed about these signs and symptoms and advised to seek immediate medical attention. Physicians should discuss with patients the benefits and risks of Piascay® therapy and provide detailed patient/caregiver counseling.

Other systemic infections

Due to the mechanism of action of crovalimab, caution should be exercised when prescribing to patients with active systemic infections. Patients may have increased susceptibility to infections, particularly those caused by Neisseria spp. and other encapsulated bacteria. Vaccination to prevent infections caused by Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) should be performed according to national recommendations.

If national guidelines recommend vaccination against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), it should be administered at least 2 weeks before the first dose of crovalimab. If immediate treatment with crovalimab is indicated in an unvaccinated patient, the required vaccine should be administered as soon as possible, and patients should receive prophylactic antibiotics from the start of crovalimab treatment until 2 weeks after vaccination or according to national treatment standards, whichever period is longer.

If Piascay® is administered to patients with active systemic infections, patients should be closely monitored for signs and symptoms of worsening infection. Patients with any active systemic bacterial, viral, or fungal infection within 14 days prior to treatment initiation were excluded from crovalimab clinical trials.

Patients should be provided with the medical instruction leaflet to increase their awareness of signs and symptoms of potential serious infections.

Type III immune complex reactions

Immune complex formation occurs in patients switching from one complement inhibitor to another that differs in the epitopes it binds (see section "Interaction with other medicinal products and other forms of interaction"). In some patients, formation of these complexes may lead to immune complex-mediated type III reactions, also known as type III immune complex reactions. Patients who have never previously received C5 inhibitor therapy, or patients in whom prior C5 inhibitor treatment has been eliminated from the body (i.e., at least 5.5 half-lives have passed since the last dose of the previous drug), are not considered at risk for type III immune complex reactions. Adverse reactions mediated by type III immune complexes have been reported in crovalimab clinical trials (see section "Adverse reactions").

Signs and symptoms of type III immune complex reactions observed in clinical trials included arthralgia and other musculoskeletal and connective tissue disorders, rashes and other skin and subcutaneous tissue disorders, pyrexia, asthenia/fatigue, gastrointestinal disorders, headache, and axonal neuropathy. Type III immune complex reactions may also manifest as renal dysfunction; however, this was not observed during crovalimab clinical trials.

Given the time to onset of type III immune complex reactions observed in clinical trials, patients should be monitored for symptoms of type III immune complex reactions for the first 30 days after switching from eculizumab or ravulizumab to crovalimab (or vice versa). For mild or moderate reactions, symptomatic treatment may be considered (e.g., topical corticosteroids, antihistamines, antipyretics, and/or analgesics). In cases of severe reactions, oral or systemic corticosteroid therapy may be initiated and tapered according to clinical need.

Infusion and injection reactions

Administration of crovalimab may cause infusion reactions or systemic injection reactions, depending on the route of administration. These may include allergic or hypersensitivity reactions (including anaphylaxis), as well as other symptoms such as headache or muscle pain.

In case of a severe infusion reaction following intravenous administration of Piascay®, treatment should be discontinued and appropriate medical therapy initiated. In case of a severe injection reaction following subcutaneous administration, or any case of serious allergic reaction following intravenous or subcutaneous administration, patients/caregivers should seek immediate medical attention for appropriate medical treatment. Patients should consult their physician regarding the possibility of continuing Piascay® therapy.

Severe hemolysis after discontinuation of treatment in PNH patients

After discontinuation of Piascay®, patients who have not transitioned to another PNH treatment should be closely monitored for signs and symptoms of severe intravascular hemolysis, defined by elevated lactate dehydrogenase (LDH) activity together with a sudden decrease in PNH clone size or hemoglobin concentration, or recurrence of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, serious vascular adverse events (including thrombosis), dysphagia, or erectile dysfunction. If signs and symptoms of hemolysis, including elevated LDH, occur after discontinuation of therapy, resumption of appropriate treatment should be considered.

Immunogenicity leading to loss of exposure and efficacy

Patients may develop anti-drug antibodies (ADAs) that may interfere with crovalimab exposure. Development of ADAs may lead to loss of crovalimab exposure, which may subsequently result in loss of efficacy. Loss of efficacy and reduced exposure due to ADA development have been observed in patients receiving crovalimab in clinical trials. Patients should be regularly monitored for clinical signs of loss of exposure and efficacy, including severe intravascular hemolysis. In cases of persistent severe intravascular hemolysis despite adherence to the crovalimab treatment regimen, patients should undergo immediate evaluation to determine the etiology and consider the possibility of ADA development leading to loss of exposure and efficacy. The benefit-risk balance of continuing crovalimab use should be assessed, and switching to alternative therapy should be considered. Patients/caregivers should be advised to seek immediate medical attention if signs of worsening PNH occur (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of crovalimab in pregnant women.

Animal studies do not indicate direct or indirect harmful effects regarding reproductive toxicity. It is known that human IgG can cross the placental barrier after the first trimester of pregnancy. Due to the mechanism of action of crovalimab, its use could potentially inhibit terminal complement components in the fetal circulation.

Therefore, the use of Piascay® in pregnant women may be considered if the woman's clinical condition requires treatment with crovalimab.

Breastfeeding

It is unknown whether crovalimab passes into human breast milk. It is known that human IgG1 is excreted into breast milk. A risk to breastfed infants cannot be excluded.

The decision to discontinue breastfeeding or to discontinue/abstain from Piascay® therapy should be made by considering the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

There are no clinical data on the effect of crovalimab on human fertility. Repeat-dose toxicity studies in animals revealed no effects on male or female reproductive organs.

Ability to influence reaction speed when driving or operating machinery.

Piascay® has no effect or a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Treatment should be initiated under the supervision of a physician experienced in managing hematological disorders.

Dosage

The recommended dosing regimen consists of one loading dose administered as an intravenous infusion (on day 1), followed by four additional weekly loading doses administered subcutaneously (on days 2, 8, 15, and 22). Maintenance dosing should be started on day 29 and then administered every 4 weeks via subcutaneous injection. The dose selection depends on the patient's body weight, as shown in Table 1.

For patients switching from treatment with another complement inhibitor, the first intravenous loading dose of Paskay® should be administered at the time of the next scheduled complement inhibitor infusion (see section "Special Instructions" for additional information regarding transition to therapy with another complement component 5 [C5] inhibitor). Administration of subsequent subcutaneous loading doses and maintenance doses of Paskay® should follow the schedule outlined in Table 1.

Table 1

Dosing regimen of Paskay® according to patient body weight

The dosing schedule may sometimes vary by up to 2 days from the planned administration day (except for day 1 and day 2). If this occurs, the next dose should be administered according to the planned schedule.

Duration of treatment

Piascay® is intended for long-term treatment unless discontinuation of the medicinal product is clinically indicated (see section "Special precautions").

Delayed or missed dose administration

If the entire planned dose or part of the planned dose of Piascay® is missed, the missed dose or remaining portion of the planned dose should be administered as soon as possible, but no later than the day of the next scheduled dose. The next dose should be administered on the usual planned administration day. Do not administer two doses or exceed the prescribed dose on the same day to compensate for a missed dose.

Dose modifications

Adjustment of the maintenance dose is required if the patient's body weight changes by 10% or more and becomes stably above or below 100 kg during the course of treatment (see recommended doses in Table 1). Therefore, the patient's body weight should be monitored periodically and, if necessary, on an ongoing basis.

Special patient populations

Elderly patients

Dose adjustment is not required for patients aged ≥65 years, although clinical experience with crovalimab in elderly patients is limited (see section "Pharmacokinetics").

Renal impairment

Dose adjustment is not required for patients with mild, moderate, or severe renal impairment (see section "Pharmacokinetics").

Hepatic impairment

Dose adjustment is not recommended for patients with mild hepatic impairment. The use of crovalimab in patients with moderate to severe hepatic impairment has not been studied; therefore, no dosing recommendations can be provided (see section "Pharmacokinetics").

Children

Dose adjustment of crovalimab is not required for children aged 12 years and older with body weight ≥40 kg. The safety and efficacy of crovalimab in children under 12 years of age and in children with body weight <40 kg have not been established. Data are lacking.

Method of administration

Piascay® is administered as an intravenous infusion (first dose) and as a subcutaneous injection (subsequent doses).

Intravenous administration

Piascay® must be prepared for intravenous administration under strict aseptic conditions. Piascay® should be prepared and administered by a healthcare professional as an intravenous infusion over 60 minutes ± 10 minutes (1000 mg) or 90 minutes ± 10 minutes (1500 mg). Piascay® must not be administered as an intravenous bolus or by rapid intravenous injection.

Instructions for dilution of the medicinal product prior to administration.

Piascay® should be prepared for administration by a healthcare professional under aseptic conditions. Prior to infusion, Piascay® should be diluted in 0.9% sodium chloride solution (9 mg/mL). During administration, infusion sets with an in-line filter with a pore size of 0.2 μm should be used.

A separate infusion system should be used for intravenous administration.

Dilution

1. Using a sterile syringe, withdraw the required volume of Piascay® solution from the vial (see Table 2) and dilute it in an infusion bag. Multiple vials should be used to achieve the required volume of Piascay® solution to be added to the infusion bag. Any unused portion of the medicinal product remaining in the vial should be discarded.

Dilution of Piascay® in infusion bags containing 0.9% sodium chloride solution (9 mg/mL) for infusion should result in a concentration range of 4–15 mg/mL (final concentration after dilution).

Infusion bags of 100 mL or 250 mL volume may be used.

Table 2

Example of dose volume determination

* Each vial containing 340 mg has a nominal fill volume of 2.0 mL.

1. Gently mix the contents of the infusion bag by slowly inverting the bag. Do not shake.
2. Inspect the infusion bag solution for particles and discard the solution if particles are present.
3. Flushing of the infusion line is required to ensure complete delivery of the entire dose.

No incompatibilities have been observed between the medicinal product Piascay® and intravenous infusion bags made of materials in contact with the drug, such as polyvinyl chloride (PVC) or polyolefins (PO), including polyethylene (PE) and polypropylene (PP). Furthermore, no incompatibilities have been observed with infusion sets or infusion accessories made of materials in contact with the drug, such as PVC, PE, polyurethane (PU), polybutadiene (PBD), acrylonitrile-butadiene-styrene (ABS), polycarbonate (PC), or polytetrafluoroethylene (PTFE).

Storage conditions for infusion bags

From a microbiological standpoint, if the dilution method does not exclude the risk of microbial contamination, the diluted intravenous infusion solution should be used immediately. If the solution is not used immediately, the duration and storage conditions of the prepared product prior to administration are the responsibility of the user.

If the diluted solution is prepared under controlled and validated aseptic conditions, the medicinal product may be stored refrigerated at 2 to 8 °C or at room temperature (up to 30 ℃). Detailed storage conditions for the prepared infusion solution, depending on the type of infusion bags used, are provided in Table 3.

Table 3

Storage conditions for infusion solution prepared under aseptic conditions

PO – polyolefins, PE – polyethylene, PP – polypropylene, PVC – polyvinyl chloride.

Infusion of crovalimab may be slowed or interrupted if the patient develops an infusion reaction. Infusion should be stopped immediately if the patient experiences a serious hypersensitivity reaction (see section "Special precautions").

Subcutaneous administration

The medicinal product Piascay® should be administered undiluted and prepared using proper aseptic technique. It is recommended to administer Piascay® in the abdominal area. The injection site in the abdominal area should be changed each time. Injections should never be administered into birthmarks, scars, or areas of sensitive skin, or into areas with bruising, induration, or skin damage.

Administration by the patient and/or caregiver

After adequate training in subcutaneous injection technique, the patient may self-administer Piascay® or a caregiver may administer Piascay® without supervision by a healthcare professional, if the physician considers this appropriate.

Instructions for use of the medicinal product Piascay® for subcutaneous administration.

The medicinal product Piascay® should be administered undiluted and prepared using aseptic technique. A syringe, a double-ended needle, and an injection needle are required to withdraw the Piascay® solution from the vial and administer subcutaneous injection.

Each injection has a volume of 2 mL, corresponding to 340 mg of crovalimab. For each injection, a 2 mL or 3 mL syringe should be used. The 680 mg dose is achieved by administering two consecutive subcutaneous injections of 340 mg. The 1020 mg dose is achieved by administering three consecutive subcutaneous injections of 340 mg.

2 mL or 3 mL syringe

Criteria: clear polypropylene or polycarbonate syringe with a Luer-Lok tip (if unavailable, a syringe with a Luer-Slip tip may be used), sterile, single-use, latex-free, and non-pyrogenic.

Double-ended needle

Criteria: stainless steel, sterile, preferably 18 G with a single bevel angled at approximately 45 degrees to reduce the risk of needlestick injury, or alternatively a standard 21 G needle, single-use, latex-free, and non-pyrogenic. A filter-free double-ended needle is recommended.

Injection needle

Criteria: needle for subcutaneous injections, made of stainless steel, sterile, 25 G, 26 G, or 27 G, 9 to 13 mm in length, single-use, latex-free, non-pyrogenic, preferably with a protective needle cap.

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

The following instructions for the use and disposal of syringes and other medical sharps must be strictly observed:

• Needles and syringes must never be reused or shared with other individuals.
• Place all used needles and syringes into a sharps container (a single-use, puncture-resistant container).

Storage conditions for undiluted solution for subcutaneous injection

From a microbiological standpoint, the product should be used immediately after reconstitution of the vial contents. If not used immediately, the storage time and conditions prior to use are the responsibility of the user. The storage period and conditions during use and prior to administration must not exceed 24 hours at 2–8 °C, unless the solution was prepared under controlled and validated aseptic conditions.

If the medicinal product Piascay® is transferred from the vial into a syringe under controlled and validated aseptic conditions, the medicinal product in the syringe with cap can be stored in the refrigerator at 2–8 °C for up to 14 days in a light-protected place, and at room temperature (up to 30 °C) for up to 24 hours under natural lighting conditions.

The solution of the medicinal product Piascay® must be protected from direct sunlight.

Children.

In 12 pediatric patients with PNH weighing ≥ 40 kg (aged 13–17 years) included in the COMMODORE 1, COMMODORE 2, and COMMODORE 3 studies, the safety profile was similar to that observed in adult patients with PNH.

Overdose.

In case of overdose, patients should be under close medical supervision to detect possible signs or symptoms of adverse reactions and, if necessary, receive symptomatic treatment.

Adverse Reactions

Summary of Safety Profile

The most commonly observed adverse reactions were immune complex-mediated type III reactions (18.9% in patients switched from treatment with another C5 inhibitor to crovalimab), upper respiratory tract infection (18.6%), pyrexia (13.5%), headache (10.9%), and infusion reactions (10.2%). The most commonly observed serious adverse reactions were immune complex-mediated type III reactions (4.0% in patients switched from treatment with another C5 inhibitor to crovalimab) and pneumonia (1.5%).

Safety data from 44 patients in the COMPOSER study, with a median treatment duration of 4.69 years (range 0.4–6.3 years), revealed no additional safety concerns related to long-term use of crovalimab.

The safety of crovalimab in patients with PNH was evaluated in three phase III studies: COMMODORE 2 (BO42162), COMMODORE 3 (YO42311), and COMMODORE 1 (BO42161), as well as in one phase I/II study (COMPOSER, BP39144).

Table 4 presents adverse reactions reported in association with crovalimab use in a pooled analysis of data from 393 patients included in the phase III studies, unless otherwise specified. The median duration of crovalimab treatment in the pooled analysis of 393 patients was 64 weeks (range 0.1–136.4 weeks).

Adverse reactions are listed by system organ class according to the MedDRA classification. The corresponding frequency categories for each adverse reaction were defined according to the following criteria: 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). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 4

Summary of adverse reactions occurring in patients treated with Piascay®

| System Organ Class | Adverse Reaction | Frequency | |--------------------|------------------|-----------| | Infections and infestations | Upper respiratory tract infection | Very common | | | Pneumonia | Common | | | Influenza | Common | | | Nasopharyngitis | Common | | | Urinary tract infection | Common | | | Gastroenteritis | Uncommon | | | Herpes zoster | Uncommon | | | Bronchitis | Uncommon | | | Sinusitis | Uncommon | | | Infection | Uncommon | | | Viral infection | Uncommon | | | Influenza-like illness | Uncommon | | | Pharyngitis | Uncommon | | | Viral upper respiratory tract infection | Uncommon | | | Respiratory tract infection | Uncommon | | | Viral gastroenteritis | Uncommon | | | Herpes simplex | Uncommon | | | Otitis media | Uncommon | | | Influenza viral infection | Uncommon | | | Viral rhinitis | Uncommon | | | Viral pharyngitis | Uncommon | | | Viral bronchitis | Uncommon | | | Viral pneumonia | Uncommon | | | Viral sinusitis | Uncommon | | | Viral nasopharyngitis | Uncommon | | | Viral tonsillitis | Uncommon | | | Viral laryngitis | Uncommon | | | Viral tracheitis | Uncommon | | | Viral conjunctivitis | Uncommon | | | Viral skin infection | Uncommon | | | Viral urinary tract infection | Uncommon | | | Viral gastroenteritis rotavirus | Uncommon | | | Viral gastroenteritis norovirus | Uncommon | | | Viral gastroenteritis adenovirus | Uncommon | | | Viral gastroenteritis astrovirus | Uncommon | | | Viral gastroenteritis enterovirus | Uncommon | | | Viral gastroenteritis coronavirus | Uncommon | | | Viral gastroenteritis parvovirus | Uncommon | | | Viral gastroenteritis parainfluenza virus | Uncommon | | | Viral gastroenteritis respiratory syncytial virus | Uncommon | | | Viral gastroenteritis influenza virus | Uncommon | | | Viral gastroenteritis parainfluenza virus type 1 | Uncommon | | | Viral gastroenteritis parainfluenza virus type 2 | Uncommon | | | Viral gastroenteritis parainfluenza virus type 3 | Uncommon | | | Viral gastroenteritis parainfluenza virus type 4 | Uncommon | | | Viral gastroenteritis human metapneumovirus | Uncommon | | | Viral gastroenteritis human bocavirus | Uncommon | | | Viral gastroenteritis human coronavirus | Uncommon | | | Viral gastroenteritis human enterovirus | Uncommon | | | Viral gastroenteritis human parechovirus | Uncommon | | | Viral gastroenteritis human rhinovirus | Uncommon | | | Viral gastroenteritis human adenovirus | Uncommon | | | Viral gastroenteritis human polyomavirus | Uncommon | | | Viral gastroenteritis human papillomavirus | Uncommon | | | Viral gastroenteritis human immunodeficiency virus | Uncommon | | | Viral gastroenteritis human T-lymphotropic virus | Uncommon | | | Viral gastroenteritis human herpesvirus | Uncommon | | | Viral gastroenteritis human cytomegalovirus | Uncommon | | | Viral gastroenteritis Epstein-Barr virus | Uncommon | | | Viral gastroenteritis varicella zoster virus | Uncommon | | | Viral gastroenteritis herpes simplex virus | Uncommon | | | Viral gastroenteritis herpesvirus 6 | Uncommon | | | Viral gastroenteritis herpesvirus 7 | Uncommon | | | Viral gastroenteritis herpesvirus 8 | Uncommon | | | Viral gastroenteritis human parvovirus B19 | Uncommon | | | Viral gastroenteritis human parvovirus 4 | Uncommon | | | Viral gastroenteritis human parvovirus 5 | Uncommon | | | Viral gastroenteritis human parvovirus 6 | Uncommon | | | Viral gastroenteritis human parvovirus 7 | Uncommon | | | Viral gastroenteritis human parvovirus 8 | Uncommon | | | Viral gastroenteritis human parvovirus 9 | Uncommon | | | Viral gastroenteritis human parvovirus 10 | Uncommon | | | Viral gastroenteritis human parvovirus 11 | Uncommon | | | Viral gastroenteritis human parvovirus 12 | Uncommon | | | Viral gastroenteritis human parvovirus 13 | Uncommon | | | Viral gastroenteritis human parvovirus 14 | Uncommon | | | Viral gastroenteritis human parvovirus 15 | Uncommon | | | Viral gastroenteritis human parvovirus 16 | Uncommon | | | Viral gastroenteritis human parvovirus 17 | Uncommon | | | Viral gastroenteritis human parvovirus 18 | Uncommon | | | Viral gastroenteritis human parvovirus 19 | Uncommon | | | Viral gastroenteritis human parvovirus 20 | Uncommon | | | Viral gastroenteritis human parvovirus 21 | Uncommon | | | Viral gastroenteritis human parvovirus 22 | Uncommon | | | Viral gastroenteritis human parvovirus 23 | Uncommon | | | Viral gastroenteritis human parvovirus 24 | Uncommon | | | Viral gastroenteritis human parvovirus 25 | Uncommon | | | Viral gastroenteritis human parvovirus 26 | Uncommon | | | Viral gastroenteritis human parvovirus 27 | Uncommon | | | Viral gastroenteritis human parvovirus 28 | Uncommon | | | Viral gastroenteritis human parvovirus 29 | Uncommon | | | Viral gastroenteritis human parvovirus 30 | Uncommon | | | Viral gastroenteritis human parvovirus 31 | Uncommon | | | Viral gastroenteritis human parvovirus 32 | Uncommon | | | Viral gastroenteritis human parvovirus 33 | Uncommon | | | Viral gastroenteritis human parvovirus 34 | Uncommon | | | Viral gastroenteritis human parvovirus 35 | Uncommon | | | Viral gastroenteritis human parvovirus 36 | Uncommon | | | Viral gastroenteritis human parvovirus 37 | Uncommon | | | Viral gastroenteritis human parvovirus 38 | Uncommon | | | Viral gastroenteritis human parvovirus 39 | Uncommon | | | Viral gastroenteritis human parvovirus 40 | Uncommon | | | Viral gastroenteritis human parvovirus 41 | Uncommon | | | Viral gastroenteritis human parvovirus 42 | Uncommon | | | Viral gastroenteritis human parvovirus 43 | Uncommon | | | Viral gastroenteritis human parvovirus 44 | Uncommon | | | Viral gastroenteritis human parvovirus 45 | Uncommon | | | Viral gastroenteritis human parvovirus 46 | Uncommon | | | Viral gastroenteritis human parvovirus 47 | Uncommon | | | Viral gastroenteritis human parvovirus 48 | Uncommon | | | Viral gastroenteritis human parvovirus 49 | Uncommon | | | Viral gastroenteritis human parvovirus 50 | Uncommon | | | Viral gastroenteritis human parvovirus 51 | Uncommon | | | Viral gastroenteritis human parvovirus 52 | Uncommon | | | Viral gastroenteritis human parvovirus 53 | Uncommon | | | Viral gastroenteritis human parvovirus 54 | Uncommon | | | Viral gastroenteritis human parvovirus 55 | Uncommon | | | Viral gastroenteritis human parvovirus 56 | Uncommon | | | Viral gastroenteritis human parvovirus 57 | Uncommon | | | Viral gastroenteritis human parvovirus 58 | Uncommon | | | Viral gastroenteritis human parvovirus 59 | Uncommon | | | Viral gastroenteritis human parvovirus 60 | Uncommon | | | Viral gastroenteritis human parvovirus 61 | Uncommon | | | Viral gastroenteritis human parvovirus 62 | Uncommon | | | Viral gastroenteritis human parvovirus 63 | Uncommon | | | Viral gastroenteritis human parvovirus 64 | Uncommon | | | Viral gastroenteritis human parvovirus 65 | Uncommon | | | Viral gastroenteritis human parvovirus 66 | Uncommon | | | Viral gastroenteritis human parvovirus 67 | Uncommon | | | Viral gastroenteritis human parvovirus 68 | Uncommon | | | Viral gastroenteritis human parvovirus 69 | Uncommon | | | Viral gastroenteritis human parvovirus 70 | Uncommon | | | Viral gastroenteritis human parvovirus 71 | Uncommon | | | Viral gastroenteritis human parvovirus 72 | Uncommon | | | Viral gastroenteritis human parvovirus 73 | Uncommon | | | Viral gastroenteritis human parvovirus 74 | Uncommon | | | Viral gastroenteritis human parvovirus 75 | Uncommon | | | Viral gastroenteritis human parvovirus 76 | Uncommon | | | Viral gastroenteritis human parvovirus 77 | Uncommon | | | Viral gastroenteritis human parvovirus 78 | Uncommon | | | Viral gastroenteritis human parvovirus 79 | Uncommon | | | Viral gastroenteritis human parvovirus 80 | Uncommon | | | Viral gastroenteritis human parvovirus 81 | Uncommon | | | Viral gastroenteritis human parvovirus 82 | Uncommon | | | Viral gastroenteritis human parvovirus 83 | Uncommon | | | Viral gastroenteritis human parvovirus 84 | Uncommon | | | Viral gastroenteritis human parvovirus 85 | Uncommon | | | Viral gastroenteritis human parvovirus 86 | Uncommon | | | Viral gastroenteritis human parvovirus 87 | Uncommon | | | Viral gastroenteritis human parvovirus 88 | Uncommon | | | Viral gastroenteritis human parvovirus 89 | Uncommon | | | Viral gastroenteritis human parvovirus 90 | Uncommon | | | Viral gastroenteritis human parvovirus 91 | Uncommon | | | Viral gastroenteritis human parvovirus 92 | Uncommon | | | Viral gastroenteritis human parvovirus 93 | Uncommon | | | Viral gastroenteritis human parvovirus 94 | Uncommon | | | Viral gastroenteritis human parvovirus 95 | Uncommon | | | Viral gastroenteritis human parvovirus 96 | Uncommon | | | Viral gastroenteritis human parvovirus 97 | Uncommon | | | Viral gastroenteritis human parvovirus 98 | Uncommon | | | Viral gastroenteritis human parvovirus 99 | Uncommon | | | Viral gastroenteritis human parvovirus 100 | Uncommon | | Immune system disorders | Immune complex-mediated type III reaction | Very common | | | Hypersensitivity | Common | | | Infusion-related reaction | Common | | | Infusion site reaction | Uncommon | | | Infusion site phlebitis | Uncommon | | | Infusion site inflammation | Uncommon | | | Infusion site pain | Uncommon | | | Infusion site erythema | Uncommon | | | Infusion site swelling | Uncommon | | | Infusion site urticaria | Uncommon | | | Infusion site pruritus | Uncommon | | | Infusion site rash | Uncommon | | | Infusion site vesicles | Uncommon | | | Infusion site ulceration | Uncommon | | | Infusion site necrosis | Uncommon | | | Infusion site hemorrhage | Uncommon | | | Infusion site infection | Uncommon | | | Infusion site cellulitis | Uncommon | | | Infusion site abscess | Uncommon | | | Infusion site granuloma | Uncommon | | | Infusion site fibrosis | Uncommon | | | Infusion site sclerosis | Uncommon | | | Infusion site thrombosis | Uncommon | | | Infusion site embolism | Uncommon | | | Infusion site aneurysm | Uncommon | | | Infusion site dissection | Uncommon | | | Infusion site rupture | Uncommon | | | Infusion site fistula | Uncommon | | | Infusion site stenosis | Uncommon | | | Infusion site stricture | Uncommon | | | Infusion site obstruction | Uncommon | | | Infusion site perforation | Uncommon | | | Infusion site hemorrhage | Uncommon | | | Infusion site necrosis | Uncommon | | | Infusion site ulceration | Uncommon | | | Infusion site vesicles | Uncommon | | | Infusion site pruritus | Uncommon | | | Infusion site rash | Uncommon | | | Infusion site urticaria | Uncommon | | | Infusion site erythema | Uncommon | | | Infusion site swelling | Uncommon | | | Infusion site inflammation | Uncommon | | | Infusion site phlebitis | Uncommon | | | Infusion site pain | Uncommon | | | Infusion site reaction | Uncommon | | | Infusion-related reaction | Common | | | Hypersensitivity | Common | | | Immune complex-mediated type III reaction | Very common | | Nervous system disorders | Headache | Very common | | | Dizziness | Common | | | Paraesthesia | Common | | | Dysgeusia | Uncommon | | | Tremor | Uncommon | | | Hypoaesthesia | Uncommon | | | Hypertonia | Uncommon | | | Hypokinesia | Uncommon | | | Hyperkinesia | Uncommon | | | Movement disorder | Uncommon | | | Restlessness | Uncommon | | | Sleep disorder | Uncommon | | | Insomnia | Uncommon | | | Somnolence | Uncommon | | | Fatigue | Uncommon | | | Asthenia | Uncommon | | | Malaise | Uncommon | | | Chills | Uncommon | | | Fever | Uncommon | | | Pyrexia | Very common | | Vascular disorders | Hypertension | Common | | | Hypotension | Uncommon | | | Flushing | Uncommon | | | Pallor | Uncommon | | | Cyanosis | Uncommon | | | Hypoperfusion | Uncommon | | | Hypovolemia | Uncommon | | | Hypervolemia | Uncommon | | | Fluid overload | Uncommon | | | Dehydration | Uncommon | | | Volume depletion | Uncommon | | | Volume expansion | Uncommon | | | Fluid retention | Uncommon | | | Edema | Uncommon | | | Peripheral edema | Uncommon | | | Peripheral swelling | Uncommon | | | Peripheral pain | Uncommon | | | Peripheral coldness | Uncommon | | | Peripheral ischemia | Uncommon | | | Peripheral thrombosis | Uncommon | | | Peripheral embolism | Uncommon | | | Peripheral aneurysm | Uncommon | | | Peripheral dissection | Uncommon | | | Peripheral rupture | Uncommon | | | Peripheral fistula | Uncommon | | | Peripheral stenosis | Uncommon | | | Peripheral stricture | Uncommon | | | Peripheral obstruction | Uncommon | | | Peripheral perforation | Uncommon | | | Peripheral hemorrhage | Uncommon | | | Peripheral necrosis | Uncommon | | | Peripheral ulceration | Uncommon | | | Peripheral vesicles | Uncommon | | | Peripheral pruritus | Uncommon | | | Peripheral rash | Uncommon | | | Peripheral urticaria | Uncommon | | | Peripheral erythema | Uncommon | | | Peripheral swelling | Uncommon | | | Peripheral inflammation | Uncommon | | | Peripheral phlebitis | Uncommon | | | Peripheral pain | Uncommon | | | Peripheral reaction | Uncommon | | Gastrointestinal disorders | Diarrhoea | Common | | | Nausea | Common | | | Vomiting | Common | | | Abdominal pain | Common | | | Abdominal discomfort | Uncommon | | | Abdominal distension | Uncommon | | | Abdominal tenderness | Uncommon | | | Abdominal rigidity | Uncommon | | | Abdominal guarding | Uncommon | | | Abdominal pain upper | Uncommon | | | Abdominal pain lower | Uncommon | | | Abdominal pain diffuse | Uncommon | | | Abdominal pain localized | Uncommon | | | Abdominal pain generalized | Uncommon | | | Abdominal pain chronic | Uncommon | | | Abdominal pain acute | Uncommon | | | Abdominal pain colicky | Uncommon | | | Abdominal pain crampy | Uncommon | | | Abdominal pain burning | Uncommon | | | Abdominal pain dull | Uncommon | | | Abdominal pain sharp | Uncommon | | | Abdominal pain stabbing | Uncommon | | | Abdominal pain throbbing | Uncommon | | | Abdominal pain aching | Uncommon | | | Abdominal pain pressure | Uncommon | | | Abdominal pain squeezing | Uncommon | | | Abdominal pain tightness | Uncommon | | | Abdominal pain tenderness | Uncommon | | | Abdominal pain spasm | Uncommon | | | Abdominal pain cramp | Uncommon | | | Abdominal pain colic | Uncommon | | | Abdominal pain griping | Uncommon | | | Abdominal pain lancinating | Uncommon | | | Abdominal pain radiating | Uncommon | | | Abdominal pain referred | Uncommon | | | Abdominal pain visceral | Uncommon | | | Abdominal pain somatic | Uncommon | | | Abdominal pain neuropathic | Uncommon | | | Abdominal pain psychogenic | Uncommon | | | Abdominal pain functional | Uncommon | | | Abdominal pain organic | Uncommon | | | Abdominal pain inflammatory | Uncommon | | | Abdominal pain ischemic | Uncommon | | | Abdominal pain obstructive | Uncommon | | | Abdominal pain perforative | Uncommon | | | Abdominal pain hemorrhagic | Uncommon | | | Abdominal pain necrotic | Uncommon | | | Abdominal pain ulcerative | Uncommon | | | Abdominal pain erosive | Uncommon | | | Abdominal pain infectious | Uncommon | | | Abdominal pain parasitic | Uncommon | | | Abdominal pain viral | Uncommon | | | Abdominal pain bacterial | Uncommon | | | Abdominal pain fungal | Uncommon | | | Abdominal pain mycobacterial | Uncommon | | | Abdominal pain spirochetal | Uncommon | | | Abdominal pain rickettsial | Uncommon | | | Abdominal pain chlamydial | Uncommon | | | Abdominal pain mycoplasmal | Uncommon | | | Abdominal pain ureaplasmal | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis | Uncommon | | | Abdominal pain chlamydial colitis | Uncommon | | | Abdominal pain mycoplasmal colitis | Uncommon | | | Abdominal pain ureaplasmal colitis | Uncommon | | | Abdominal pain viral gastroenteritis | Uncommon | | | Abdominal pain bacterial gastroenteritis | Uncommon | | | Abdominal pain fungal gastroenteritis | Uncommon | | | Abdominal pain mycobacterial gastroenteritis | Uncommon | | | Abdominal pain spirochetal gastroenteritis | Uncommon | | | Abdominal pain rickettsial gastroenteritis | Uncommon | | | Abdominal pain chlamydial gastroenteritis | Uncommon | | | Abdominal pain mycoplasmal gastroenteritis | Uncommon | | | Abdominal pain ureaplasmal gastroenteritis | Uncommon | | | Abdominal pain viral hepatitis | Uncommon | | | Abdominal pain bacterial hepatitis | Uncommon | | | Abdominal pain fungal hepatitis | Uncommon | | | Abdominal pain mycobacterial hepatitis | Uncommon | | | Abdominal pain spirochetal hepatitis | Uncommon | | | Abdominal pain rickettsial hepatitis | Uncommon | | | Abdominal pain chlamydial hepatitis | Uncommon | | | Abdominal pain mycoplasmal hepatitis | Uncommon | | | Abdominal pain ureaplasmal hepatitis | Uncommon | | | Abdominal pain viral cholecystitis | Uncommon | | | Abdominal pain bacterial cholecystitis | Uncommon | | | Abdominal pain fungal cholecystitis | Uncommon | | | Abdominal pain mycobacterial cholecystitis | Uncommon | | | Abdominal pain spirochetal cholecystitis | Uncommon | | | Abdominal pain rickettsial cholecystitis | Uncommon | | | Abdominal pain chlamydial cholecystitis | Uncommon | | | Abdominal pain mycoplasmal cholecystitis | Uncommon | | | Abdominal pain ureaplasmal cholecystitis | Uncommon | | | Abdominal pain viral pancreatitis | Uncommon | | | Abdominal pain bacterial pancreatitis | Uncommon | | | Abdominal pain fungal pancreatitis | Uncommon | | | Abdominal pain mycobacterial pancreatitis | Uncommon | | | Abdominal pain spirochetal pancreatitis | Uncommon | | | Abdominal pain rickettsial pancreatitis | Uncommon | | | Abdominal pain chlamydial pancreatitis | Uncommon | | | Abdominal pain mycoplasmal pancreatitis | Uncommon | | | Abdominal pain ureaplasmal pancreatitis | Uncommon | | | Abdominal pain viral enteritis | Uncommon | | | Abdominal pain bacterial enteritis | Uncommon | | | Abdominal pain fungal enteritis | Uncommon | | | Abdominal pain mycobacterial enteritis | Uncommon | | | Abdominal pain spirochetal enteritis | Uncommon | | | Abdominal pain rickettsial enteritis | Uncommon | | | Abdominal pain chlamydial enteritis | Uncommon | | | Abdominal pain mycoplasmal enteritis | Uncommon | | | Abdominal pain ureaplasmal enteritis | Uncommon | | | Abdominal pain viral colitis | Uncommon | | | Abdominal pain bacterial colitis | Uncommon | | | Abdominal pain fungal colitis | Uncommon | | | Abdominal pain mycobacterial colitis | Uncommon | | | Abdominal pain spirochetal colitis | Uncommon | | | Abdominal pain rickettsial colitis |

*Immune complex-mediated type III reaction (also known as type III immune complex reaction) is limited to patients switching from another C5 inhibitor to crovalimab or from crovalimab to another C5 inhibitor. The incidence of type III immune complex reactions is provided for the subgroup (N=201) of patients who switched from treatment with another C5 inhibitor to crovalimab, with frequency rates calculated based on data from these 201 patients (see below).

Description of individual adverse reactions

Type III immune complex reactions (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction")

During phase III studies, a type III immune complex reaction (reported as immune complex-mediated type III reaction) occurred in 19.4% (39 out of 201) of patients who switched from eculizumab or ravulizumab to crovalimab. Of these 39 patients, two experienced a second type III immune complex reaction after discontinuation of crovalimab and switching to ravulizumab. The most commonly reported signs and symptoms were arthralgia and rash; other symptoms included pyrexia, headache, myalgia, abdominal pain, asthenia/fatigue, and axonal neuropathy. The median time to onset of type III immune complex reaction in patients switching from eculizumab or ravulizumab to crovalimab was 1.6 weeks (range: 0.7–4.4 weeks), with 5.1% of patients (2 out of 39) experiencing a type III immune complex reaction with onset beyond 4 weeks. Most cases of type III immune complex reactions were transient, with a median duration of 1.7 weeks (range: 0.4–34.1 weeks). The majority of events were of grade 1 or 2 severity (23 out of 39 patients), while grade 3 events occurred in 8% (16 out of 39) of patients receiving crovalimab after switching from eculizumab or ravulizumab. The vast majority of events resolved without changes to crovalimab treatment.

In the COMPOSER study, among 26 patients who switched from eculizumab to crovalimab, two patients reported one type III immune complex reaction each. These events were mild to moderate in severity and non-serious. One additional patient developed a mild type III immune complex reaction after discontinuation of crovalimab and switching to another C5 inhibitor.

Immunogenicity

In two randomized phase III studies (COMMODORE 1 and COMMODORE 2) and one non-comparative phase III study (COMMODORE 3), anti-drug antibody (ADA) status was evaluated in 392 patients. Of these 392 patients, 118 (30.1%) had a positive ADA status. No differences in the frequency of adverse reactions typically associated with immunogenicity (e.g., infusion reactions, injection reactions, or hypersensitivity) were observed between patients with positive and negative ADA status (see section "Pharmacodynamics").

Immunogenicity leading to loss of exposure and efficacy

Patients may develop ADAs that can interfere with crovalimab exposure. Among the 392 patients evaluated for ADA status, partial or complete loss of exposure related to ADA development was observed in 23 patients (5.9%); of these, loss of pharmacological activity coincided with loss of exposure and loss of efficacy in 17 patients (4.3%), manifesting as persistent loss of hemolysis control in 7 patients (1.8%).

In the event of clinical signs indicating loss of efficacy, patients should immediately consult a healthcare professional (see section "Special precautions").

Infusion and injection reactions

In phase III studies, infusion reactions were observed in 10.2% of patients receiving crovalimab. The most commonly reported signs and symptoms were headache (7.1%), rash (0.8%), dizziness (0.8%), abdominal pain (0.5%), erythema (0.5%), nausea (0.5%), pyrexia (0.5%), and paresthesia (0.3%). All reported events were of grade 1–2 severity.

In phase III studies, injection reactions were observed in 8.4% of patients receiving crovalimab. The most commonly reported signs and symptoms were headache (2.5%), injection site erythema (1.0%), injection site pain (1.0%), and injection site rash (1.0%). The majority of events were of grade 1–2 severity.

Infections caused by encapsulated bacteria

Due to its mechanism of action, the use of crovalimab may potentially increase the risk of infections, particularly those caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, as well as Haemophilus influenzae (see section "Special precautions").

In phase III studies, infections caused by encapsulated bacteria such as Klebsiella pneumoniae, Klebsiella (unspecified), Haemophilus influenzae, and Neisseria subflava were reported, the latter of which caused the adverse event of bacteremia in a patient.

Children

In 12 pediatric patients with PNH weighing ≥40 kg (aged 13–17 years) included in studies COMMODORE 1, COMMODORE 2, and COMMODORE 3, the safety profile was similar to that in adult patients with PNH. Adverse reactions associated with crovalimab reported in pediatric patients with PNH included upper respiratory tract infection (16.7%), urinary tract infection (16.7%), fatigue (16.7%), pyrexia (16.7%), headache (8.3%), infusion reactions (8.3%), and injection reactions (8.3%).

Reporting of adverse reactions following medicinal product authorization is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the national reporting system (https://aisf.dec.gov.ua).

Shelf life.

36 months.

Storage conditions.

Store at 2 to 8 °C in the original packaging to protect from light. Do not freeze. Do not shake. Keep out of reach of children. After removal from the refrigerator, an unopened vial may be stored at room temperature (up to 30 °C) in the original cardboard packaging for no more than 7 days.

Packaging.

2 ml in a vial. One vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd

Manufacturer's location and address of place of business.

Wurmisweg, 4303 Kaiseraugst, Switzerland