Aliqopa
(copanlisib)Dosage & Administration
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Aliqopa Prescribing Information
ALIQOPA is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.
Accelerated approval was granted for this indication based on overall response rate [see Clinical Studies ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Recommended Dosage
The recommended dose of ALIQOPA is 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). Continue treatment until disease progression or unacceptable toxicity [see Warnings and Precautions ].
Dose Modification for Moderate or Severe Hepatic Impairment
Reduce ALIQOPA dose to 45 mg in patients with moderate hepatic impairment (Child-Pugh B). Reduce ALIQOPA dose to 30 mg in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations ].
Dose Modification for Use with Strong CYP3A Inhibitors
Reduce ALIQOPA dose to 45 mg if a strong CYP3A inhibitor must be used. Concomitant use of ALIQOPA with strong CYP3A inhibitors increases copanlisib exposure (AUC) and may increase the risk for toxicity [see Drug Interactions ].
Dosage Modifications for Toxicities
Manage toxicities per Table 1 with dose reduction, treatment delay, or discontinuation of ALIQOPA. Discontinue ALIQOPA if life-threatening ALIQOPA-related toxicity occurs.
| Toxicities | Adverse Reaction Gradeb | Recommended Management |
|---|---|---|
Infections [see Warnings and Precautions ( 5.1)]
| Grade 3 or higher | Withhold ALIQOPA until resolution. |
Suspected pneumocystis jiroveci pneumonia (PJP) infection of any grade | Withhold ALIQOPA. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis. | |
Cytomegalovirus (CMV) infection or viremia of any grade | Withhold ALIQOPA until infection or viremia resolves, then resume at previous dose. | |
Hyperglycemia [see Warnings and Precautions ( 5.2)]
| Pre-dose fasting blood glucose | Withhold ALIQOPA until fasting glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. |
Pre-dose or post-dose blood glucose 500 mg/dL or more | On first occurrence, withhold ALIQOPA until fasting blood glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Then reduce ALIQOPA from 60 mg to 45 mg and maintain. | |
|
| On subsequent occurrences, withhold ALIQOPA until fasting blood glucose is 160 mg/dL or less, or a random/non-fasting blood glucose of 200 mg/dL or less. Then reduce ALIQOPA from 45 mg to 30 mg and maintain. If persistent at 30 mg, discontinue ALIQOPA. |
Hypertension [see Warnings and Precautions ( 5.3)]
| Pre-dose blood pressure (BP) 150/90 or greaterc | Withhold ALIQOPA until BP is less than 150/90 based on two consecutive BP measurements at least 15 minutes apart. |
Post-dose BP 150/90 or greaterc (non-life-threatening) | If anti-hypertensive treatment is not required, continue ALIQOPA at previous dose. If anti-hypertensive treatment is required, consider reduction of ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. Discontinue ALIQOPA if BP remains uncontrolled (BP greater than 150/90) despite anti-hypertensive treatment | |
Post-dose elevated BP with life-threatening consequences | Discontinue ALIQOPA. | |
Non-infectious pneumonitis (NIP) [see Warnings and Precautions ( 5.4)]
| Grade 2 | Withhold ALIQOPA and treat NIP. If NIP recovers to Grade 0 or 1, resume ALIQOPA at 45 mg. If Grade 2 NIP recurs, discontinue ALIQOPA. |
Grade 3 or higher | Discontinue ALIQOPA. | |
Neutropenia [see Warnings and Precautions ( 5.5)] | Absolute neutrophil count (ANC) 0.5 to 1.0 x 103 cells/mm3 | Maintain ALIQOPA dose. Monitor ANC at least weekly. |
ANC less than 0.5 x 103 cells/mm3 | Withhold ALIQOPA. Monitor ANC at least weekly until ANC 0.5 x 103 cells/mm3 or greater, then resume ALIQOPA at previous dose. If ANC 0.5 x 103 cells/mm3 or less recurs, then reduce ALIQOPA to 45 mg. | |
Severe cutaneous reactions [see Warnings and Precautions ( 5.6)] | Grade 3 | Withhold ALIQOPA until toxicity is resolved and reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. |
Life-threatening | Discontinue ALIQOPA. | |
Thrombocytopenia [see Adverse Reactions ( 6.1)] | Less than 25 x 109/L | Withhold ALIQOPA; resume when platelet levels return to 75.0 x 109/L or greater. If recovery occurs within 21 days, reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. If recovery does not occur within 21 days, discontinue ALIQOPA. |
Other severe and non-life-threatening toxicities [see Adverse Reactions ( 6.1)]
| Grade 3 | Withhold ALIQOPA until toxicity is resolved and reduce ALIQOPA from 60 mg to 45 mg or from 45 mg to 30 mg. |
aEnsure a minimum of 7 days between any two consecutive infusions.
bNational Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.
cBoth systolic of less than 150 mmHg and diastolic of less than 90 mmHg are required.
Preparation and Administration
For intravenous infusion only.
Administer ALIQOPA as a single agent, following reconstitution and dilution. Mix only with sterile 0.9% Sodium Chloride Injection, USP solution. Do not mix or inject ALIQOPA with other drugs or other diluents.
Reconstitution Instructions
Reconstitute ALIQOPA with 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution leading to a concentration of 15 mg/mL.
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- Withdraw 4.4 mL of sterile 0.9% Sodium Chloride Injection, USP solution by using a 5 mL sterile syringe with needle.
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- Inject the measured volume through the disinfected stopper surface into the vial of ALIQOPA.
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- Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.
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- Allow to stand for one minute to let bubbles rise to the surface.
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- Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure.
- •
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After reconstitution, the solution should be colorless to slightly yellowish.
- •
- Once the solution is free of visible particles, withdraw the reconstituted solution for further dilution.
Dilution Instructions for Intravenous Use
Further dilute the reconstituted solution in 100 mL sterile 0.9% Sodium Chloride Injection, USP solution for injection. With a sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage:
60 mg: Withdraw 4 mL of the reconstituted solution with a sterile syringe.
45 mg: Withdraw 3 mL of the reconstituted solution with a sterile syringe.
30 mg: Withdraw 2 mL of the reconstituted solution with a sterile syringe.
Inject the contents of the syringe into the patient infusion bag of 100 mL sterile 0.9% Sodium Chloride Injection, USP solution. Mix the dose well by inverting.
Discard any unused reconstituted or diluted solution appropriately.
Use reconstituted and diluted ALIQOPA immediately or store the reconstituted solution in the vial or diluted solution in the infusion bag at 2°C to 8°C (36°F to 46°F) for up to 24 hours before use. Allow the product to adapt to room temperature before use following refrigeration. Avoid exposure of the diluted solution to direct sunlight.
For injection: 60 mg of copanlisib as a lyophilized solid in single-dose vial for reconstitution.
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 1 month after the last dose.
Females and Males of Reproductive Potential
ALIQOPA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ].
Pregnancy Testing
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 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 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 of ALIQOPA have not been established in pediatric patients.
Geriatric Use
No dosage adjustment of ALIQOPA 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.
Hepatic Impairment
Reduce ALIQOPA dose to 45 mg for patients with moderate hepatic impairment (Child-Pugh B). Reduce ALIQOPA dose to 30 mg for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration ]. No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN, or total bilirubin >1 to 1.5 × ULN and any AST) [see Clinical Pharmacology ].
None.
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 ].
Grade 1 or 2 cytomegalovirus (CMV) reactivation or infection has occurred in 0.97% of patients treated with ALIQOPA monotherapy. Monitor for CMV infection during treatment with ALIQOPA in patients with a history of CMV infection. For clinical CMV infection or viremia, withhold ALIQOPA until infection or viremia resolves. If ALIQOPA is resumed, administer at the previous dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly [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 one month after the last dose [see Use in Specific Populations and Clinical Pharmacology ].