ASH News Daily 2017 - Issue 3 - A-17

T:10"
S:9"

7
DRUG INTERACTIONS
7.1
Effect of Other Drugs on Copanlisib
Strong CYP3A Inducers
Avoid concomitant use of ALIQOPA with strong CYP3A inducers. Concomitant use of ALIQOPA
with strong CYP3A inducers may decrease copanlisib AUC and Cmax [see Clinical Pharmacology
(12.3)].
Examplesa of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane,
phenytoin, rifampin, St. John's wortb.
Strong CYP3A Inhibitors
Concomitant use of ALIQOPA with strong CYP3A inhibitors increases the copanlisib AUC. If
concomitant use with strong CYP3A inhibitors cannot be avoided, reduce the ALIQOPA dose to
45 mg. An increase in the copanlisib AUC may increase the risk of adverse reactions [see Clinical
Pharmacology (12.3)].
Examplesa of strong CYP3A inhibitors include: boceprevir, clarithromycin, cobicistat, conivaptan,
danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juicec, idelalisib,
indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir,
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir
and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole.
a These examples are a guide and not considered a comprehensive list of all possible drugs
that may fit this category. The healthcare provider should consult appropriate references for
comprehensive information.
b The induction potency of St. John's wort may vary widely based on preparation.
c The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and
preparation-dependent. Studies have shown that it can be classified as a "strong CYP3A
inhibitor" when a certain preparation was used (e.g., high dose, double strength) or as a
"moderate CYP3A inhibitor" when another preparation was used (e.g., low dose, single
strength).

8.5
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.
13
NONCLINICAL TOXICOLOGY
13.1
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 doserelated reduction in the numbers of female rats in estrus.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981 USA
© 2017 Bayer HealthCare Pharmaceuticals Inc.
6908601BS2

S:13"

17
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 (5.1)].
* 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 [see Warnings and Precautions (5.2)].
* 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 (5.3)].
* 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 (5.4)].
* 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 (5.5)].
* 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 (5.6)].
* 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 (5.7)].
* 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 (8.2)].

T:14"

8
USE IN SPECIFIC POPULATIONS
8.1
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 (12.1)].
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 (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.
8.2
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.
8.3
Females and Males of Reproductive Potential
Pregnancy Testing
ALIQOPA can cause fetal harm when administered to a pregnant woman [see Use in Specific
Populations (8.1)]. 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 (13.1)].

8.4
Pediatric Use
Safety and effectiveness have not been established in pediatric patients.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 3