Dose modifications and toxicity management1

Adverse events may be managed by dose reduction, treatment delay, or discontinuation of AliqopaTM1

DOSE MODIFICATION AND TOXICITY MANAGEMENT*

TOXICITIES

ADVERSE REACTION GRADE

RECOMMENDED MANAGEMENT

Infections

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

Hyperglycemia

Predose fasting blood glucose 160 mg/dL or more or random/nonfasting blood glucose of 200 mg/dL or more
Withhold Aliqopa until fasting glucose is 160 mg/dL or less, or a random/nonfasting blood glucose of 200 mg/dL or less

Predose or postdose 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/nonfasting 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/nonfasting 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

Predose blood pressure (BP) 150/90 mmHg or greater
Withhold Aliqopa until BP is less than 150/90 mmHg based on 2 consecutive BP measurements at least 15 minutes apart

Postdose BP 150/90 mmHg or greater (non–life-threatening)
If antihypertensive treatment is not required, continue Aliqopa at previous dose If antihypertensive 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 mmHg) despite antihypertensive treatment

Postdose elevated BP with life-threatening consequences
Discontinue Aliqopa

Noninfectious pneumonitis (NIP)

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

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

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

Less than 25 x 109/L
Withhold Aliqopa; resume when platelet levels return to 75.0 x 10/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

Grade 3
Withhold Aliqopa until toxicity is resolved and reduce Aliqopa from 60 mg to 45 mg or from 45 mg to 30 mg
*Ensure a minimum of 7 days between any 2 consecutive infusions. National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03. Both systolic of less than 150 mmHg and diastolic of less than 90 mmHg are required.

  • Discontinue if life-threatening Aliqopa-related toxicity occurs
  • 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

Indication

ALIQOPA (copanlisib) 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Important Safety Information

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

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. 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.

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. 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.

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. 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.

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. 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.

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

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA 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 ALIQOPA depending on the severity and persistence of severe cutaneous reactions.

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.

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.

For important risk and use information about Aliqopa, please see the full Prescribing Information.

You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
For Bayer products you can report these directly to Bayer by clicking here.

Reference:

1. Aliqopa (copanlisib) for injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; September 2017.

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