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Aliqopa

Generic Name: Copanlisib Hydrochloride
Class: Antineoplastic Agents
Chemical Name: 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride
Molecular Formula: C23H28N8O4
CAS Number: 1032568-63-0

Introduction

Copanlisib hydrochloride is an antineoplastic agent.

Uses for Aliqopa

Copanlisib hydrochloride has the following uses:

Copanlisib hydrochloride is a kinase inhibitor indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.1

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1

Aliqopa Dosage and Administration

General

Copanlisib is available in the following dosage form(s) and strength(s):

For injection: 60 mg as a lyophilized solid in single-dose vial for reconstitution.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Recommended dosage: 60 mg administered as a 1-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Modify dosage for toxicity.1

  • Continue treatment until disease progression or unacceptable toxicity.1

  • See full prescribing information for important information on preparation, administration, and dosage modification for toxicities.1

Cautions for Aliqopa

Contraindications

None.1

Warnings/Precautions

Infections

Serious, including fatal, infections occurred in 19% of 317 patients treated with copanlisib hydrochloride monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold copanlisib hydrochloride for Grade 3 and higher infection.1

Serious Pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with copanlisib hydrochloride monotherapy. Before initiating treatment with copanlisib hydrochloride, consider PJP prophylaxis for populations at risk. Withhold copanlisib hydrochloride in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume copanlisib hydrochloride at previous dose with concomitant PJP prophylaxis.1

Hyperglycemia

Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with copanlisib hydrochloride monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with copanlisib hydrochloride may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after copanlisib hydrochloride infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.1

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with copanlisib hydrochloride following adequate glucose control and should be monitored closely.1

Achieve optimal blood glucose control before starting each copanlisib hydrochloride infusion. Withhold, reduce dose, or discontinue copanlisib hydrochloride depending on the severity and persistence of hyperglycemia.1

Hypertension

Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with copanlisib hydrochloride monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with copanlisib hydrochloride may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on cycle 1 day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the copanlisib hydrochloride infusion. Optimal BP control should be achieved before starting each copanlisib hydrochloride infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue copanlisib hydrochloride depending on the severity and persistence of hypertension.1

Non-infectious Pneumonitis

Non-infectious pneumonitis occurred in 5% of 317 patients treated with copanlisib hydrochloride monotherapy. Withhold copanlisib hydrochloride and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by copanlisib hydrochloride have been managed by withholding copanlisib hydrochloride and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue copanlisib hydrochloride depending on the severity and persistence of non-infectious pneumonitis.1

Neutropenia

Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with copanlisib hydrochloride monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with copanlisib hydrochloride. Withhold, reduce dose, or discontinue copanlisib hydrochloride depending on the severity and persistence of neutropenia.1

Severe Cutaneous Reactions

Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with copanlisib hydrochloride monotherapy, respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue copanlisib hydrochloride depending on the severity and persistence of severe cutaneous reactions.1

Embryo-fetal Toxicity

Based on findings in animals and its mechanism of action, copanlisib hydrochloride can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg per day (4.5 mg/m2 per day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and the mechanism of action, copanlisib hydrochloride can cause fetal harm when administered to a pregnant woman.1

There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis resulted in embryo-fetal death and fetal abnormalities at maternal doses approximately 12% of the recommended dose for patients. Advise pregnant women of the potential risk to a fetus.1

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal Data: In an embryo-fetal development study in rats, pregnant animals received intravenous doses of copanlisib of 0, 0.75, or 3 mg/kg per day during the period of organogenesis. Administration of copanlisib at the dose of 3 mg/kg per day resulted in maternal toxicity and no live fetuses. Copanlisib administration at the dose of 0.75 mg/kg per day was maternally toxic and resulted in embryo-fetal death (increased resorptions, increased post-implantation loss, and decreased numbers of fetuses/dam). The dose of 0.75 mg/kg per day also resulted in increased incidence of fetal gross external (domed head, malformed eyeballs or eyeholes), soft tissue (hydrocephalus internus, ventricular septal defects, major vessel malformations), and skeletal (dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) abnormalities. The dose of 0.75 mg/kg per day (4.5 mg/m2 body surface area) in rats is approximately 12% of the recommended dose for patients.1

Following administration of radiolabeled copanlisib to pregnant rats, approximately 1.5% of the radioactivity (copanlisib and metabolites) reached the fetal compartment.1

Lactation

There are no data on the presence of copanlisib and/or metabolites in human milk, the effects on the breastfed child, or on milk production. Following administration of radiolabeled copanlisib to lactating rats, approximately 2% of the radioactivity was secreted into milk; the milk to plasma ratio of radioactivity was 25-fold. Because of the potential for serious adverse reactions in a breastfed child from copanlisib, advise a lactating woman not to breastfeed during treatment with copanlisib hydrochloride and for at least 1 month after the last dose.1

Females And Males Of Reproductive Potential

Copanlisib hydrochloride can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing prior to initiation of copanlisib hydrochloride treatment.1

Advise female patients of reproductive potential to use highly effective contraception (contraception with a failure rate <1% per year) during treatment with copanlisib hydrochloride and for at least one month after the last dose. 1

Advise male patients with female partners of reproductive potential to use highly effective contraception during treatment with copanlisib hydrochloride and for at least one month after the last dose.1

There are no data on the effect of copanlisib hydrochloride on human fertility. Due to the mechanism of action of copanlisib and findings in animal studies, adverse effects on reproduction, including fertility, are expected. 1

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.1

Geriatric Use

No dose adjustment is necessary in patients ≥65 years of age. Of 168 patients with follicular lymphoma and other hematologic malignancies treated with copanlisib hydrochloride, 48% were age 65 or older while 16% were age 75 or older. No clinically relevant differences in efficacy were observed between elderly and younger patients. In patients ≥65 years of age, 30% experienced serious adverse reactions and 21% experienced adverse reactions leading to discontinuation. In the patients <65 years of age, 23% experienced serious adverse reactions and 11% experienced adverse reactions leading to discontinuation.1

Common Adverse Effects

The most common adverse reactions (≥20%) are hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A Inducers: Avoid concomitant use with strong CYP3A inducers.1

  • CYP3A Inhibitors: Reduce the copanlisib dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.1

Actions

Mechanism Of Action

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

  • Infections: Advise patients that copanlisib hydrochloride can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection.1

  • Hyperglycemia: Advise patients that an infusion-related increase in blood glucose may occur, and to notify their healthcare provider of any symptoms such as pronounced hunger, excessive thirst, headaches, or frequently urinating. Blood glucose levels should be well controlled prior to infusion.1

  • Hypertension: Advise patients that an infusion-related increase in blood pressure may occur, and to notify their healthcare provider of any symptoms such as dizziness, passing out, headache, and/or a pounding heart. Blood pressure should be normal or well controlled prior to infusion.1

  • Non-infectious pneumonitis: Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or difficulty breathing.1

  • Neutropenia: Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop a fever or any signs of infection.1

  • Severe cutaneous reactions: Advise patients that a severe cutaneous reaction may occur, and to notify their healthcare provider if they develop skin reactions (rash, redness, swelling, itching or peeling of the skin).1

  • Pregnancy: Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with copanlisib hydrochloride and for at least one month after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during copanlisib hydrochloride treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with copanlisib hydrochloride and for at least one month after the last dose.1

  • Lactation: Advise women not to breastfeed during treatment with copanlisib hydrochloride and for at least 1 month after the last dose.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Copanlisib Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, Powder, Lyophilized, For Solution

60 mg (of copanlisib)

Aliqopa

Bayer HealthCare Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions October 2, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Bayer HealthCare Pharmaceuticals Inc.. ALIQOPA (copanlisib) INTRAVENOUS prescribing information.2017 Sep.

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