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Aliqopa

WARNINGS

Included as part of the “PRECAUTIONS” Section

PRECAUTIONS

Infections

Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia [see ADVERSE REACTIONS]. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection [see DOSAGE AND ADMINISTRATION].

Serious pneumocystis jiroveci pneumonia (PJP) occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy [see ADVERSE REACTIONS]. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis [see DOSAGE AND ADMINISTRATION].

Hyperglycemia

Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy [see ADVERSE REACTIONS]. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA 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 ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

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 ALIQOPA following adequate glucose control and should be monitored closely.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia [see DOSAGE AND ADMINISTRATION].

Hypertension

Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy [see ADVERSE REACTIONS]. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA 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 ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre-and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension [see DOSAGE AND ADMINISTRATION].

Non-Infectious Pneumonitis

Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy [see ADVERSE REACTIONS]. Withhold ALIQOPA 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 ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis [see DOSAGE AND ADMINISTRATION].

Neutropenia

Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3% [see ADVERSE REACTIONS]. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia [see DOSAGE AND ADMINISTRATION].

Severe Cutaneous Reactions

Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy, respectively [see ADVERSE REACTIONS]. 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 ALIQOPA depending on the severity and persistence of severe cutaneous reactions [see DOSAGE AND ADMINISTRATION].

Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, ALIQOPA 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/day (4.5 mg/m2/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 [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Infections

Advise patients that ALIQOPA can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection [see WARNINGS AND PRECAUTIONS].

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 [see WARNINGS AND PRECAUTIONS].

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 [see WARNINGS AND PRECAUTIONS].

Non-Infectious Pneumonitis

Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or difficulty breathing [see WARNINGS AND PRECAUTIONS].

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 [see WARNINGS AND PRECAUTIONS].

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) [see WARNINGS AND PRECAUTIONS].

Pregnancy

Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with ALIQOPA 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 ALIQOPA treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIQOPA and for at least one month after the last dose [see WARNINGS AND PRECAUTIONS].

Lactation

Advise women not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with copanlisib.

Copanlisib did not cause genetic damage in in vitro or in vivo assays.

Fertility studies with copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies and the mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY].

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 (see Data). Advise pregnant women of the potential risk to a fetus.

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.

Data

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/day during the period of organogenesis. Administration of copanlisib at the dose of 3 mg/kg/day resulted in maternal toxicity and no live fetuses. Copanlisib administration at the dose of 0.75 mg/kg/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/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/day
(4.5 mg/m2 body surface area) in rats is approximately 12% of the recommended dose for patients.

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

Lactation

Risk Summary

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 ALIQOPA and for at least 1 month after the last dose.

Females And Males Of Reproductive Potential

Pregnancy Testing

ALIQOPA can cause fetal harm when administered to a pregnant woman [see Pregnancy]. Conduct pregnancy testing prior to initiation of ALIQOPA treatment.

Contraception

Females

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

Males

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

Infertility

There are no data on the effect of ALIQOPA on human fertility. Due to the mechanism of action of copanlisib, and findings in animal studies, adverse effects on reproduction, including fertility, are expected [see Nonclinical Toxicology].

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

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 ALIQOPA, 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.

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