Qivigy

Description for Qivigy

QIVIGY (immune globulin intravenous, human-kthm) 10% solution is indicated for the treatment of adults with Primary Humoral Immunodeficiency (PI).

This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

ADVERSE REACTIONS

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data described in this section reflects exposure to QIVIGY in one clinical study. A total of 47 patients with PI received intravenous infusion of QIVIGY at a dose range of 266 to 826 mg/kg every 3 or 4 weeks for up to 12 months [see Clinical Studies (14)]. A total of 643 infusions of QIVIGY were administered, 136 in the every 3-week schedule and 507 in the 4-week schedule. During the study, 4 out of 47 (9%) patients received premedication.

The most common product-related adverse events observed in ≥ 5% of clinical study patients with PI were headache, infusion- related reaction, Coombs direct test positive, fatigue, and nausea. Table 2 lists the most common adverse reactions reported in ≥5% of patients.

Table 2: Adverse Reactions* Occurring in ≥ 5% of Patients

Adverse Reaction	By Patients n (%) [n = 47]	By Infusions n (%) [n = 643]
Headache	14 (30)	26 (4)
Fatigue	7 (15)	10 (2)
Nausea	6 (13)	6 (<1)
Infusion-related Reaction	5 (11)	7 (1)
Coombs Direct Test Positive	5 (11)	8 (1)
Sinusitis	3 (6)	3 (<1)
Dizziness	3 (6)	3 (<1)
Diarrhea	3 (6)	4 (<1)
* Adverse reactions were defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period.

Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified and reported during the post-approval use of IGIV products:

• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), respiratory failure, hypoxemia, pulmonary edema, dyspnea, wheezing, cough, bronchospasm, pulmonary
• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension, phlebitis, pallor, angina, tachycardia, bradycardia, palpitations, myocardial infarction, cyanosis.
• Neurological: Coma, loss of consciousness, seizures, (acute) encephalopathy, tremor, aseptic meningitis syndrome, migraine, speech disorder, paresthesia, hypoesthesia, photophobia.
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis, eczema, erythematous rash, dermatitis, pruritus, alopecia, urticaria.
• Gastrointestinal: Hepatic dysfunction, abdominal pain, diarrhea.
• Renal: Acute renal failure, osmotic nephropathy, renal pain.
• Hematologic: Pancytopenia, leukopenia, hemolysis.
• Musculoskeletal: Musculoskeletal pain, muscle spasm, arthralgia, myalgia, muscle stiffness.
• General disorders and administration site conditions: Pyrexia, rigors, injection-site reactions, chills, flushing, lethargy, malaise, burning sensation.
• Psychiatric disorders: Confusion, anxiety, agitation, nervousness.
• Metabolic and nutritional: Fluid overload, (pseudo) hyponatremia.
• Immune system disorders: Hypersensitivity (e.g. anaphylaxis, allergic reaction), angioedema.
• Investigations: Falsely elevated erythrocyte sedimentation rate, positive direct antiglobulin (Coombs’) test, increased hepatic enzymes.

Drug Interactions for Qivigy

Effect of QIVIGY on Live attenuated virus vaccines

Immune globulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella, s and varicella because the continued presence of high levels of passively acquired antibody may interfere with an active antibody response. Inform the immunizing physician of recent therapy with QIVIGY so that appropriate measures may be taken.

Effect of QIVIGY on Serological Testing

Passive transmission of antibodies through immune globulin administration may interfere with some serological testing [see Warnings and Precautions ( 5.10 )].

Effect of Loop diuretics on QIVIGY

The use of loop diuretics should be avoided. Concomitant use of loop diuretics with IGIV may contribute to an increased blood viscosity and subsequently increase the risk of thromboembolic events.

Warnings for Qivigy

Included as part of the PRECAUTIONS section.

Precautions for Qivigy

Hypersensitivity

Severe hypersensitivity reactions, including anaphylaxis, may occur with QIVIGY [see Adverse Reactions ( 6)] In case of hypersensitivity, discontinue QIVIGY infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

QIVIGY contains IgA (≤ 50 mg/L) [see Description (11)]. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. QIVIGY is contraindicated in IgA deficient patients with antibodies against IgA and patients with a history of hypersensitivity reaction [see Contraindications ( 4)].

Thrombosis

Thrombosis may occur following treatment with immune globulin products, including QIVIGY. Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia, high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombosis, administer QIVIGY at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis [see Boxed Warning, Dosage and Administration ( 2)].

Renal Injury

Renal injury including acute renal dysfunction, acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and, osmotic nephrosis may occur after treatment with immune globulin products including QIVIGY. Ensure that patients are not volume depleted prior to the initiation of the infusion of QIVIGY. For patients judged to be at risk for developing renal dysfunction because of pre- existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic drugs, or age over 65 years), administer QIVIGY at the minimum infusion rate practicable [see Dosage and Administration ( 2)]. The risk of renal dysfunction and acute renal failure is greater in products that contain sucrose, though may still occur in products without sucrose. QIVIGY does not contain sucrose.

Conduct periodic monitoring of renal function and urine output in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of QIVIGY and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing QIVIGY [see Dosage and Administration (2)].

Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, hyperviscosity, and hyponatremia may occur in patients receiving immune globulin treatment, including QIVIGY. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a possible predisposition to thromboembolic events.

Aseptic Meningitis Syndrome

Aseptic meningitis syndrome (AMS) may occur in patients following immune globulin treatment, including QIVIGY. The risk of AMS may be higher with high doses (2 g/kg) and/or rapid infusion of immune globulin products. AMS usually begins within several hours to two days following immune globulin treatment and is characterized by the following symptoms and signs: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting symptoms and signs of AMS, including CSF studies, to rule out other causes of meningitis. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae.

Hemolysis

Hemolysis may occur after administration of immune globulin products, including QIVIGY due to the presence of blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immune globulin, causing a positive direct antiglobulin test and hemolysis. Delayed hemolytic anemia can develop after immune globulin treatment due to enhanced RBC sequestration, and acute hemolysis consistent with intravascular hemolysis has been reported.

The risk factors for hemolysis include high doses (e.g., ≥ 2 g/kg) given either as a single administration or divided over several days, non-O blood group, and an underlying inflammatory disease condition.

Monitor patients for clinical signs and symptoms of hemolysis. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit are observed after QIVIGY infusion, perform confirmatory laboratory testing.

Transfusion-related Acute Lung Injury

Transfusion-Related Acute Lung Injury (TRALI) may occur in patients following immune globulin treatment, including QIVIGY. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours after treatment.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, immediately stop QIVIGY infusion, and perform appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and patient’s serum. Manage patients using oxygen therapy with adequate ventilatory support as appropriate.

Transmissible Infectious Agents

There is risk of transmission of infectious disease or agents including viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and the Creutzfeldt-Jakob disease agent with QIVIGY administration because it is manufactured using human blood. The risk of infectious agent transmission is minimized by plasma donor screening, donation testing, and manufacturing steps proven to inactivate and remove bloodborne pathogens.

Any infection suspected to have been transmitted by this product should be reported by the physician or other healthcare provider to Kedrion Biopharma Inc. at 1-855-3KDRION (1-855-353-7466).

Monitoring Laboratory Tests

• Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of QIVIGY and at appropriate intervals thereafter [see Warnings and Precautions (3)].
• Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia, markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis [see Warnings and Precautions (2)].
• If signs and/or symptoms of hemolysis are present after an infusion of QIVIGY, perform appropriate laboratory testing for confirmation [see Warnings and Precautions (6)].
• If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and the patient's serum [see Warnings and Precautions (5.7)].

Interference with Laboratory Tests

After the administration of immune globulin, the transitory rise of the various passively transferred antibodies in the patients’ blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies for example the direct or indirect antiglobulin test (Coombs test).

NONCLINICAL TOXICOLOGY

Carcinogenesis, mutagenesis, impairment of fertility

No animal studies were conducted to evaluate the carcinogenic or mutagenic effect of QIVIGY or its effects on fertility.

Animal toxicology and/or pharmacology

An acute animal toxicology study was conducted to evaluate possible toxicity of QIVIGY before clinical trial. There were no toxicological concerns for the therapeutic use of QIVIGY.

OVERDOSAGE

Overdosage of QIVIGY may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with renal impairment.

Contraindications for Qivigy

QIVIGY is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

QIVIGY is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity [see Warnings and Precautions (5.1)].

Clinical Pharmacology for Qivigy

Mechanism of Action

QIVIGY is an IgG replacement therapy for primary humoral immunodeficiency. QIVIGY supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against bacterial and, viral agents. The mechanism of action of IgG in PI has not been fully elucidated.

Pharmacodynamics

QIVIGY contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents reflecting the IgG activity found in the donor population. QIVIGY which is prepared from pooled material from not less than 1000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of IGIV can restore abnormally low IgG level to the normal range. Standard pharmacodynamic studies were not performed.

Pharmacokinetics

In the clinical study assessing the efficacy and safety of QIVIGY in 47 patients with PI [see Clinical Studies (14)], serum concentrations of total IgG were measured in 23 patients following the 5^th infusion of QIVIGY for patients on the 4-week dosing schedule, or the 7^th infusion for patients on the 3-week dosing schedule. The dose of QIVIGY used in these patients ranged from 266 mg/kg to 826 mg/kg. After infusion, blood samples for PK analyses were collected until Day 21 or Day 28 for patients treated according to the 3-week and 4-week schedule, respectively. Table 4 summarizes the PK parameters of QIVIGY based on serum concentrations of total IgG.

Table 4: Pharmacokinetic Parameters of QIVIGY

Parameter	3-Week Dosing Interval (n=5)	4-Week Dosing Interval (n=18)
(unit)	Mean† (CV%)	Mean† (CV%)
Cmax (mg/dL)	2680 (10.5)	2300 (20.3)
Cmin (mg/dL)	1140 (13.2)	994 (20.2)
Tmax (h)a	0.53 (0.5 - 2.02)	0.52 (0.5 - 23.8)
AUC(0-t) (day*mg/dL)	31700 (19.0)	37300 (20.7)
AUCtau (day*mg/dL)	34000 (10.7)	38000 (17.1)
Half-life (day)	24.5 (9.92)	37.3 (30.1)
Clearance (dL/day/kg)	0.019 (15.8)	0.014 (25.5)
Volume of distribution (dL/kg)	0.67 (6.0)	0.70 (16.9)
AUC(0-t) = area under the concentration-time curve from time 0 to the time t of the last quantifiable concentration, AUCtau = area under the concentration versus time curve within a dosing interval, tau = dosing interval, Cmax = maximum observed concentration, Tmax = time at which Cmax was apparent, CV% = coefficient of variation. a: Median and range are presented for tmax. † Arithmetic mean

Patient Information for Qivigy

Discuss the following with the patient.

• Hypersensitivity Reactions: Inform patients that hypersensitivity reactions may occur with QIVIGY infusion. Prior to starting QIVIGY ask about a history of allergic reactions to immune globulin or other blood Advise patients to seek immediate medical evaluation if any signs and symptoms of hypersensitivity or acute infusion reactions occur [see Warnings and precautions (5.1)].
• Renal Injury: Inform patients that renal injury may occur with QIVIGY Advise patients to seek immediate medical evaluation if any signs and symptoms of renal injury occur such as decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath [see Warnings and Precautions (5.3)].
• Thrombosis: Inform patients that thrombosis may occur after QIVIGY infusion. Advise patients to seek immediate medical evaluation if any signs and symptoms of thrombosis occur such as pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body [see Warnings and Precautions (5.2)]
• Aseptic meningitis syndrome (AMS): Inform patients that AMS may occur after QIVIGY infusion. Advise patients to seek immediate medical evaluation if any signs and symptoms of AMS occur such as severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting [see Warnings and Precautions (5.5)]
• Hemolysis: Inform patients that hemolysis may occur after QIVIGY infusion. Advise patients to seek immediate medical evaluation if any signs and symptoms of hemolysis occur such as fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine [see Warnings and Precautions (5.6)]
• Transfusion-Related Acute Lung Injury (TRALI): Inform patients that TRALI may occur after QIVIGY infusion. Advise patients to seek immediate medical evaluation if any signs and symptoms of TRALI occur such as breathing difficulty, chest pain, blue lips or extremities, and fever [see Warnings and Precautions (5.7)].
• Transmission of Infectious Agents: Inform patients that QIVIGY is a derivative of human plasma and may contain infectious agents that cause disease (e.g., viruses, vCJD agent and, theoretically, CJD agent). Inform patients that the risk that QIVIGY may transmit an infectious agent has been reduced by screening plasma donors for prior exposure for certain viruses, by testing the donated plasma for certain virus infections, and by inactivating and/or removing certain viruses during manufacturing [see Warnings and Precautions (5.8)].
• Drug Interactions: Inform patients that QIVIGY can interfere with their immune response to live virus vaccines such as measles, mumps, varicella and rubella. Inform patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations [see Drug Interactions (5.7)].