NOVARTIS EXHIBIT 2165
`Par v Novartis, IPR 2016-00084
`Page 1 of 6
`
`

`
`NOVARTIS EXHIBIT 2165
`Par v Novartis, IPR 2016-00084
`Page 2 of 6
`
`

`
`572
`
`Adria Laboratories
`Division of Erbamont Inc.
`7001 POST ROAD
`DUBLIN, OH 43017
`
`PRODUCT IDENTIFICATION CODES
`
`To provide quick and positive identification of Adria Labora-
`tories products, we have imprinted the product identification
`number on one side of all tablets and capsules. The other side
`of the tablet displays the name "ADRIA”.
`In order that you may quickly identify a product by its code
`number, we have compiled below a numerical list of code
`numbers of prescription products with their corresponding
`product names:
`[See table below]
`
`ADRIAMYCIN PFS™ R
`[adree ’ah-mi-ctn ]
`(Doxorubicin Hydrochloride, USP)
`Injection
`FOR INTRAVENOUS USE ONLY
`
`WARNINGS
`1 Severe local tissue necrosis will occur if there is extra-
`vasation during administration (See Dosage and Ad-
`ministration). ADRIAMYCIN PFS must not be given
`by the intramuscular or subcutaneous route.
`2. Serious irreversible myocardial toxicity with delayed
`congestive failure often unresponsive to any cardiac
`supportive therapy may be encountered as total dos-
`age approaches 550 mg/m2. This toxicity may occur
`at lower cumulative doses in patients with prior medi-
`astinal irradiation or on concurrent cyclophospha-
`mide therapy.
`3 Dosage should be reduced in patients with impaired
`hepatic function.
`4. Severe myelosuppression may occur
`5. ADRIAMYCIN PFS should be administered only
`under the supervision of a physician who is experi-
`enced in the use of cancer chemotherapeutic agents.
`
`DESCRIPTION
`Doxorubicin is a cytotoxic anthracycline antibiotic isolated
`from cultures of Streptomyces peucetius var. caesius. Dox-
`orubicin consists of a naphthacenequinone nucleus linked
`through a glycosidic bond at ring atom 7 to an amino sugar,
`daunosamine.
`Doxorubicin binds to nucleic acids, presumably by specific
`intercalation of the planar anthracycline nucleus with the
`DNA double helix. The anthracycline ring is lipophilic but
`the saturated end of the ring system contains abundant hy-
`droxyl groups adjacent to the amino sugar, producing a hy-
`drophilic center. The molecule is amphoteric, containing
`acidic functions in the ring phenolic groups and a basic func-
`tion in the sugar amino group. It binds to cell membranes as
`well as plasma proteins.
`ADRIAMYCIN PFS™ (doxorubicin hydrochloride, USP)
`Injection is a parenteral, isotonic, preservative-free, single
`use only solution and is available in 5 mL (10 mg), 10 mL (20
`mg), and 25 mL (50 mg) single dose vials and 100 mL (200 mg)
`multidose vial.
`Each mL contains doxorubicin hydrochloride and the follow-
`ing inactive ingredients: sodium chloride 0.9% and water for
`injection q.s. Hydrochloric acid is used to adjust pH to a tar-
`get pH of 3.0.
`CLINICAL PHARMACOLOGY
`Though not completely elucidated, the mechanism of action
`of doxorubicin is related to its ability to bind DNA and in-
`hibit nucleic acid synthesis. Cell culture studies have demon-
`strated rapid cell penetration and perinucleolar chromatin
`binding, rapid inhibition of mitotic activity and nucleic acid
`synthesis, mutagenesis and chromosomal aberrations. Ani-
`mal studies have shown activity in a spectrum of experimen-
`tal tumors, immunosuppression, carcinogenic properties in
`
`Product Information
`rodents, induction of a variety of toxic effects, including
`delayed and progressive cardiac toxicity, myelosuppression
`in all species and atrophy to testes in rats and dogs.
`Pharmacokinetic studies show the intravenous administra-
`tion of normal or radiolabeled doxorubicin is followed by
`rapid plasma clearance and significant tissue binding.
`Urinary excretion, as determined by fluorimetric methods,
`accounts for approximately 4-5% of the administered dose
`in five days. Biliary excretion represents the major excretion
`route, 40-50% of the administered dose being recovered in
`the bile or the feces in seven days. Impairment of liver func-
`tion results in slower excretion, and consequently, increased
`retention and accumulation in plasma and tissues. Doxorubi-
`cin does not cross the blood brain barrier.
`INDICATIONS AND USAGE
`ADRIAMYCIN® (Doxorubicin HC1, USP) for injection has
`been used successfully to produce regression in disseminated
`neoplastic conditions such as acute lymphoblastic leukemia,
`acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma,
`soft tissue and bone sarcomas, breast carcinoma, ovarian
`carcinoma, transitional cell bladder carcinoma, thyroid car-
`cinoma, lymphomas of both Hodgkin and non-Hodgkin
`types, bronchogenic carcinoma in which the small cell histo-
`logic type is the most responsive compared to other cell types
`and gastric carcinoma.
`A number of other solid tumors have also shown some re-
`sponsiveness but in numbers too limited to justify specific
`recommendation Studies to date have shown malignant
`melanoma, kidney carcinoma, large bowel carcinoma, brain
`tumors and metastases to the central nervous system not to
`be significantly responsive to ADRIAMYCIN therapy.
`CONTRAINDICATIONS
`ADRIAMYCIN therapy should not be started in patients
`who have marked myelosuppression induced by previous
`treatment with other antitumor agents or by radiotherapy.
`Conclusive data are not available on pre-existing heart dis-
`ease as a co-factor of increased risk of ADRIAMYCIN in-
`duced cardiac toxicity. Preliminary data suggest that in such
`cases cardiac toxicity may occur at doses lower than the
`recommended cumulative limit. It is therefore not recom-
`mended to start ADRIAMYCIN in such cases. ADRIAMY-
`CIN treatment is contraindicated in patients who received
`previous treatment with complete cumulative doses of
`ADRIAMYCIN and/or daunorubicin.
`WARNINGS
`Special attention must be given to the cardiac toxicity exhib-
`ited by ADRIAMYCIN. Although uncommon, acute left ven-
`tricular failure has occurred, particularly in patients who
`have received total dosage of the drug exceeding the cur-
`rently recommended limit of 550 mg/m2. This limit appears
`to be lower (400 mg/m2) in patients who received radiother-
`apy to the mediastinal area or concomitant therapy with
`other potentially cardiotoxic agents such as cyclophospha-
`mide. The total dose of ADRIAMYCIN administered to the
`individual patient should also take into account a previous or
`concomitant therapy with related compounds such as
`daunorubicin. Congestive heart failure and/or cardiomyopa-
`thy may be encountered several weeks after discontinuation
`of ADRIAMYCIN therapy.
`Cardiac failure is often not favorably affected by presently
`known medical or physical therapy for cardiac support.
`Early clinical diagnosis of drug induced heart failure ap-
`pears to be essential for successful treatment with digitalis,
`diuretics, low salt diet and bed rest. Severe cardiac toxicity
`may occur precipitously without antecedent EKG changes. A
`baseline EKG and EKGs performed prior to each dose or
`course after 300 mg/m2 cumulative dose has been given is
`suggested. Transient EKG changes consisting of T-wave flat-
`tening, S-T depression and arrhythmias lasting for up to two
`weeks after a dose or course of ADRIAMYCIN are presently
`not considered indications for suspension of ADRIAMYCIN
`therapy. ADRIAMYCIN cardiomyopathy has been reported
`to be associated with a persistent reduction in the voltage of
`the QRS wave, a prolongation of the systolic time interval
`and a reduction of the ejection fraction as determined by
`echocardiography or radionuclide angiography None of
`these tests have yet been confirmed to consistently identify
`those individual patients that are approaching their maxi-
`mally tolerated cumulative dose of ADRIAMYCIN. If test
`
`PRODUCT IDENTIFICATION CODE
`
`PRODUCT INDEX
`
`130
`
`200
`230
`231
`
`304
`
`307
`
`312
`412
`
`Axotal® (butalbital, USP, 50 mg and aspirin, USP, 650 mg.
`Warning: May be habit forming)
`Ilozyme® (pancrelipase, USP) Tablets
`Octamide™ (metociopramide hydrochloride) Tablets, 10 mg
`Dopan-Choline® Tablets (dexpanthenol 50 mg./choline bitar-
`trate 25 me)
`Kaon CL-10™ (potassium chloride) Controlled Release Tab-
`lets, 750 mg. (10 mEq)
`Kaon-CL® (potassium chloride) Controlled Release Tablets,
`500 mg (6 7 mEq)
`Kaon® (potassium gluconate) Tablets, 1.7 g (5 mEq)
`Magan® (magnesium salicylate) Tablets, 545 mg.
`
`Always consult Supplement
`
`results indicate change in cardiac function associated with
`ADRIAMYCIN the benefit of continued therapy must be
`carefully evaluated against the risk of producing irreversible
`cardiac damage.
`Acute life-threatening arrhythmias have been reported to
`occur during or within a few hours after ADRIAMYCIN ad-
`ministration.
`There is a high incidence of bone marrow depression, primar-
`ily of leukocytes, requiring careful hematologic monitoring.
`With the recommended dosage schedule, leukopenia is usu-
`ally transient, reaching its nadir at 10-14 days after treat-
`ment with recovery usually occurring by the 21st day. White
`blood cell counts as low as 1000 mm3 are to be expected dur-
`ing treatment with appropriate doses of ADRIAMYCIN. Red
`blood cell and platelet levels should also be monitored since
`they may also be depressed. Hematologic toxicity may re-
`quire dose reduction or suspension or delay of ADRIAMY-
`CIN therapy Persistent severe myelosuppression may result
`in superinfection or hemorrhage.
`ADRIAMYCIN may potentiate the toxicity of other antican-
`cer therapies Exacerbation of cyclophosphamide induced
`hemorrhagic cystitis and enhancement of the hepatotoxicity
`of 6-mercaptopurine have been reported. Radiation induced
`toxicity to the myocardium, mucosae, skin and liver have
`been reported to be increased by the administration of
`ADRIAMYCIN.
`Toxicity to recommended doses of ADRIAMYCIN is en-
`hanced by hepatic impairment, therefore, prior to the indi-
`vidual dosing, evaluation of hepatic function is recom-
`mended using conventional clinical laboratory tests such as
`SGOT, SGPT, alkaline phosphatase and bilirubin. (See Dos-
`age and Administration).
`Necrotizing colitis manifested by typhlitis (cecal inflamma-
`tion), bloody stools and severe and sometimes fatal infections
`have been associated with a combination of ADRIAMYCIN
`given by i.v. push daily for 3 days and cytarabine given by
`continuous infusion daily for 7 or more days
`On intravenous administration of ADRIAMYCIN extravasa-
`tion may occur with or without an accompanying stinging or
`burning sensation and even if blood returns well on aspira-
`tion of the infusion needle (See Dosage and Administration).
`If any signs or symptoms of extravasation have occurred the
`injection or infusion should be immediately terminated and
`restarted in another vein.
`ADRIAMYCIN and related compounds have also been
`shown to have mutagenic and carcinogenic properties when
`tested in experimental models.
`Usage in Pregnancy—Safe use of ADRIAMYCIN in preg-
`nancy has not been established. ADRIAMYCIN is em-
`bryotoxic and teratogenic in rats and embryotoxic and abor-
`tifacient in rabbits. Therefore, the benefits to the pregnant
`patient should be carefully weighed against the potential
`toxicity to fetus and embryo. The possible adverse effects on
`fertility in males and females in humans or experimental
`animals have not been adequately evaluated.
`PRECAUTIONS
`Initial treatment with ADRIAMYCIN requires close obser-
`vation of the patient and extensive laboratory monitoring. It
`is recommended, therefore, that patients be hospitalized at
`least during the first phase of the treatment.
`Like other cytotoxic drugs, ADRIAMYCIN may induce hy-
`peruricemia secondary to rapid lysis of neoplastic cells. The
`clinician should monitor the patient’s blood uric acid level
`and be prepared to use such supportive and pharmacologic
`measures as might be necessary to control this problem.
`ADRIAMYCIN imparts a red coloration to the urine for 1-2
`days after administration and patients should be advised to
`expect this during active therapy.
`ADRIAMYCIN is not an anti-microbial agent.
`ADVERSE REACTIONS
`Dose limiting toxicities of therapy are myelosuppression and
`cardiotoxicity (See Warnings). Other reactions reported are:
`Cutaneous—Reversible complete alopecia occurs in most
`cases. Hyperpigmentation of nailbeds and dermal creases,
`primarily in children, and onycholysis have been reported in
`a few cases. Recall of skin reaction due to prior radiotherapy
`has occurred with ADRIAMYCIN administration.
`Gastrointestinal—Acute nausea and vomiting occurs fre-
`quently and may be severe. This may be alleviated by antie-
`metic therapy. Mucositis (stomatitis and esophagitis) may
`occur 5-10 days after administration. The effect may be se-
`vere leading to ulceration and represents a site of origin for
`severe infections. The dose regimen consisting of administra-
`tion of ADRIAMYCIN on three successive days results in the
`greater incidence and severity of mucositis Ulceration and
`necrosis of the colon, especially the cecum, may occur lead-
`ing to bleeding or severe infections which can be fatal. This
`reaction has been reported in patients with acute non-lym-
`phocytic leukemia treated with a 3-day course of ADRIAMY-
`CIN combined with cytarabine. Anorexia and diarrhea have
`been occasionally reported.
`Vascular—£hlebosclerosis has been reported especially
`when small veins are used or a single vein is used for re-
`
`NPC02237166
`
`NOVARTIS EXHIBIT 2165
`Par v Novartis, IPR 2016-00084
`Page 3 of 6
`
`

`
`for possible revisions
`
`peated administration Facial flushing may occur if the in-
`jection is given too rapidly.
`Local—Severe cellulitis, vesication and tissue necrosis will
`occur if ADRIAMYC1N is extravasated during administra-
`tion. Erythematous streaking along the vein proximal to the
`site of the injection has been reported (See Dosage and Ad-
`ministration)
`Hypersensitivity—Fever, chills and urticaria have been re-
`ported occasionally. Anaphylaxis may occur. A case of appar-
`ent cross sensitivity to lincomycin has been reported.
`Other—Conjunctivitis and lacrimation occur rarely.
`OVERDOSAGE
`Acute overdosage with ADRIAMYCIN enhances the toxic
`effects of mucositis, leukopenia and thrombopenia. Treat-
`ment of acute overdosage consists of treatment of the se-
`verely myelosuppressed patient with hospitalization, antibi-
`otics, platelet and granulocyte transfusions and symptom-
`atic treatment of mucositis. The 200 mg vial is packaged as a
`multiple dose vial and caution should be exercised to prevent
`inadvertent overdosage.
`Chronic overdosage with cumulative doses exceeding 550
`mg/m2 increases the risk of cardiomyopathy and resultant
`congestive heart failure. Treatment consists of vigorous
`management of congestive heart failure with digitalis prepa-
`rations and diuretics. The use of peripheral vasodilators has
`been recommended.
`DOSAGE AND ADMINISTRATION
`Care in the administration of ADRIAMYCIN will reduce the
`chance of perivenous infiltration It may also decrease the
`chance of local reactions such as urticaria and erythematous
`streaking. On intravenous administration of ADRIAMY-
`CIN, extravasation may occur with or without an accompa-
`nying stinging or burning sensation and even if blood re-
`turns well on aspiration of the infusion needle. If any signs or
`symptoms of extravasation have occurred, the injection or
`infusion should be immediately terminated and restarted in
`another vein. If it is known or suspected that subcutaneous
`extravasation has occurred, local infiltration with an inject-
`able corticosteroid and flooding the site with normal saline
`has been reported to lessen the local reaction Because of the
`progressive nature of extravasation reactions, the area of
`injection should be frequently examined and plastic surgery
`consultation obtained. If ulceration begins, early wide exci-
`sion of the involved area should be considered.1
`The most commonly used dosage schedule is 60-75 mg/m2 as
`a single intravenous injection administered at 21-day inter-
`vals. The lower dose should be given to patients with inade-
`quate marrow reserves due to old age, or prior therapy, or
`neoplastic marrow infiltration An alternative dose schedule
`is weekly doses of 20 mg/m2 which has been reported to pro-
`duce a lower incidence of congestive heart failure. Thirty
`mg/m2 on each of three successive days repeated every 4
`weeks has also been used. ADRIAMYCIN dosage must be
`reduced if the bilirubin is elevated as follows: serum biliru-
`bin i.2-3.0 mg/dL—give V2 normal dose, > 3 mg/dL—give
`V4 normal dose.
`It is recommended that ADRIAMYCIN PFS be slowly ad-
`ministered into the tubing of a freely running intravenous
`infusion of Sodium Chloride Injection USP or 5% Dextrose
`Injection USP. The tubing should be attached to a Butter-
`fly® needle inserted preferably into a large vein. If possible,
`avoid veins over joints or in extremities with compromised
`venous or lymphatic drainage. The rate of administration is
`dependent on the size of the vein and the dosage. However
`the dose should be administered in not less than 3 to 5 mi-
`nutes. Local erythematous streaking along the vein as well
`as facial flushing may be indicative of too rapid an adminis-
`tration. A burning or stinging sensation may be indicative of
`perivenous infiltration and the infusion should be immedi-
`ately terminated and restarted in another vein. Perivenous
`infiltration may occur painlessly.
`ADRIAMYCIN should not be mixed with heparin or 5-
`fluorouracil since it has been reported that these drugs are
`incompatible to the extent that a precipitate may form. Un-
`til specific compatibility data are available, it is not recom-
`mended that ADRIAMYCIN PFS be mixed with other drugs
`ADRIAMYCIN has been used concurrently with other ap-
`proved chemotherapeutic agents Evidence is available that
`in some types of neoplastic disease combination chemother-
`apy is superior to single agents. The benefits and risks of
`such therapy continue to be elucidated.
`Handling and Disposal: Skin reactions associated with
`ADRIAMYCIN have been reported. Caution in the handling
`of the solution must be exercised and the use of gloves is
`recommended. If ADRIAMYCIN PFS contacts the skin or
`mucosae, immediately wash thoroughly with soap and wa-
`ter.
`Procedures for proper handling and disposal of anti-cancer
`drugs should be considered. Several guidelines on this sub-
`ject have been published.2-7 There is no general agreement
`that all of the procedures recommended in the guidelines are
`necessary or appropriate.
`
`Product Information
`
`HOW SUPPLIED
`ADRIAMYCIN PFS™ (doxorubicin hydrochloride, USP)
`Injection
`Sterile, single use only, contains no preservative
`NDC 0013-1136-9110 mg vial^ 2 mg/mL, 5 mL, 10 vial packs.
`NDC 0013-1146-94 20 mg vial, 2 mg/mL, 10 mL, 5 vial packs.
`NDC 0013-1156-79 50 mg vial, 2 mg/mL, 25 mL, single vial
`packs.
`Store under refrigeration, 2*-8°C (36e-46°F), protect from
`light and retain in carton until time of use. Discard unused
`solution.
`Sterile, multidose vial, contains no preservative.
`NDC 0013-1166-83 200 mg, 2 mg/mL, 100 mL multidose vial,
`single vial packs
`Store under refrigeration 2#-8#C (36“-46T), protect from light
`and retain in carton until time of use
`REFERENCES
`1. Rudolph R et al: Skin Ulcers Due to ADRIAMYCIN. Can-
`cer 38- 1087-1094, Sept. 1976.
`2. Recommendations for the Safe Handling of Parenteral
`Antineoplastic Drugs. NIH Publication No. 83-2621. For
`sale by the Superintendent of Documents, U S. Govern-
`ment Printing Office, Washington, D.C. 20402
`3. AMA Council Report Guidelines for Handling Parenteral
`Antineoplastics. JAMA, March 15, 1985.
`4. National Study Commission on Cytotoxic Exposure—
`Recommendations for Handling Cytotoxic Agents. Avail-
`able from Louis P. Jeffrey, Sc. D., Director of Pharmacy
`Services, Rhode Island Hospital, 593 Eddy Street, Provi-
`dence, Rhode Island 02902.
`5. Clinical Oncological Society of Australia: Guidelines and
`recommendations for safe handling of antineoplastic
`agents Med J. Australia 1.426-428, 1983.
`6. Jones R, et al. Safe handling of chemotherapeutic agents:
`A report from the Mount Sinai Medical Center. Ca—A
`Cancer Journal for Clinicians Sept/Oct, 258-263, 1983.
`7. American Society of Hospital Pharmacists technical assis-
`tance bulletin on handling cytotoxic drugs in hospitals.
`Am J Hosp Pharm 42:131-137, 1985.
`Manufactured by:
`FARMITALIA CARLO ERBA S.p.A.,
`MILAN, ITALY
`Distributed by:
`ADRIA LABORATORIES
`Division of Erbamont Inc.
`COLUMBUS, OHIO 43215.
`
`ADRIAMYCIN RDF™ 9
`[a ,dreeah-mi"sin]
`(Doxorubicin Hydrochloride, USP)
`For Injection
`FOR INTRAVENOUS USE ONLY
`
`PRODUCT OVERVIEW
`KEY FACTS
`ADRIAMYCIN RDF is a cytotoxic agent active against a
`variety of hematologic malignancies and solid tumors. The
`active ingredient, doxorubicin hydrochloride, is an anthracy-
`cline antibiotic that selectively kills malignant cells and
`causes tumor regression. ADRIAMYCIN RDF contains a
`small amount of methylparaben (to enhance dissolution).
`MAJOR USES
`ADRIAMYCIN RDF is clinically effective against dissemi-
`nated neoplastic conditions including acute lymphoblastic
`and myeloblastic leukemia, Wilm’s tumor, neuroblastoma,
`soft tissue and bone sarcomas, breast carcinoma, ovarian
`carcinoma, transitional cell bladder carcinoma, thyroid car-
`cinoma, Hodgkin’s and non-Hodgkin’s lymphoma, broncho-
`genic carcinoma and gastric carcinoma.
`SAFETY INFORMATION
`ADRIAMYCIN RDF is intended for intravenous use only.
`Care must be taken to avoid extravasation. Patients must be
`carefully monitored and doses adjusted to avoid too severe
`myelosuppression or mucositis. Too large cumulative doses
`may cause cardiomyopathy leading to congestive heart fail-
`ure.
`PRESCRIBING INFORMATION
`ADRIAMYCIN RDF™ B>
`(a ,dreeah-mi"sm ]
`(Doxorubicin Hydrochloride, USP)
`For Injection
`FOR INTRAVENOUS USE ONLY
`
`WARNINGS
`1. Severe local tissue necrosis will occur if there is extra-
`vasation during administration (See Dosage and Ad-
`ministration). ADRIAMYCIN RDF must not be given
`by the intramuscular or subcutaneous route.
`2. Serious irreversible myocardial toxicity with delayed
`congestive failure often unresponsive to any cardiac
`
`573
`
`supportive therapy may be encountered as total dos-
`age approaches 550 mg/m2. This toxicity may occur
`at lower cumulative doses in patients with prior medi-
`astinal irradiation or on concurrent cyclophospha-
`mide therapy
`3. Dosage should be reduced in patients with impaired
`hepatic function.
`4. Severe myelosuppression may occur.
`5. ADRIAMYCIN RDF should be administered only
`under the supervision of a physician who is experi-
`enced in the use of cancer chemotherapeutic agents.
`
`DESCRIPTION
`Doxorubicin is a cytotoxic anthracycline antibiotic isolated
`from cultures of Streptomyces peucetius var. caesius. Dox-
`orubicin consists of a naphthacenequinone nucleus linked
`through a glycosidic bond at ring atom 7 to an amino sugar,
`daunosamine.
`Doxorubicin binds to nucleic acids, presumably by specific
`intercalation of the planar anthracycline nucleus with the
`DNA double helix. The anthracycline ring is lipophilic but
`the saturated end of the ring system contains abundant hy-
`droxyl groups adjacent to the amino sugar, producing a hy-
`drophilic center. The molecule is amphoteric, containing
`acidic functions in the ring phenolic groups and a basic func-
`tion in the sugar amino group. It binds to cell membranes as
`well as plasma proteins. It is supplied in the hydrochloride
`form as a freezendried powder containing lactose and methyl-
`paraben (added to enhance dissolution).
`CLINICAL PHARMACOLOGY
`Though not completely elucidated, the mechanism of action
`of doxorubicin is related to its ability to bind to DNA and
`inhibit nucleic acid synthesis. Cell culture studies have dem-
`onstrated rapid cell penetration and perinucleolar chroma-
`tin binding, rapid inhibition of mitotic activity and nucleic
`acid synthesis, mutagenesis and chromosomal aberrations.
`Animal studies have shown activity in a spectrum of experi-
`mental tumors, immunosuppression, carcinogenic proper-
`ties in rodents, induction of a variety of toxic effects, includ-
`ing delayed and progressive cardiac toxicity, myelosuppres-
`sion in all species and atrophy to testes in rats and dogs.
`Pharmacokinetic studies show the intravenous administra-
`tion of normal or radiolabeled doxorubicin is followed by
`rapid, plasma clearance and significant tissue binding.
`Unnary excretion, as determined by fluorimetric methods,
`accounts for approximately 4-5% of the administered dose
`in five days. Biliary excretion represents the major excretion
`route, 40-50% of the administered dose being recovered in
`the bile or the feces in seven days. Impairment of liver func-
`tion results in slower excretion, and, consequently, increased
`retention and accumulation in plasma and tissues. Doxorubi-
`cin does not cross the blood brain barrier.
`INDICATIONS AND USAGE
`ADRIAMYCIN® (Doxorubicin HC1, USP) for Injection has
`been used successfully to produce regression in disseminated
`neoplastic conditions such as acute lymphoblastic leukemia,
`acute myeloblastic leukemia, Wilms’ tumor, neuroblastoma,
`soft tissue and bone sarcomas, breast carcinoma, ovarian
`carcinoma, transitional cell bladder carcinoma, thyroid car-
`cinoma, lymphomas of both Hodgkin and non-Hodgkin
`types, bronchogenic carcinoma in which the small cell histo-
`logic type is the most responsive compared to other cell types
`and gastric carcinoma.
`A number of other solid tumors have also shown some re-
`sponsiveness but in numbers too limited to justify specific
`recommendation. Studies to date have shown malignant
`melanoma, kidney carcinoma, large bowel carcinoma, brain
`tumors and metastases to the central nervous system not to
`be significantly responsive to ADRIAMYCIN therapy.
`CONTRAINDICATIONS
`ADRIAMYCIN therapy should not be started in patients
`who have marked myelosuppression induced by previous
`treatment with other antitumor agents or by radiotherapy.
`Conclusive data are not available on pre-existing heart dis-
`ease as a co-factor of increased risk of ADRIAMYCIN in-
`duced cardiac toxicity. Preliminary data suggest that in such
`cases cardiac toxicity may occur at doses lower than the
`recommended cumulative limit It is therefore not recom-
`mended to start ADRIAMYCIN in such cases. ADRIAMY-
`CIN treatment is contraindicated in patients who received
`previous treatment with complete cumulative doses of
`ADRIAMYCIN and/or daunorubicin.
`WARNINGS
`Special attention must be given to the cardiac toxicity exhib-
`ited by ADRIAMYCIN. Although uncommon, acute left ven-
`tricular failure has occurred, particularly in patients who
`have received total dosage of the drug exceeding the cur-
`rently recommended limit of 550 mg/m2. This limit appears
`to be lower (400 mg/m2) in patients who received radiother-
`apy to the mediastinal area or concomitant therapy with
`
`Continued on next page
`
`NPC02237167
`
`NOVARTIS EXHIBIT 2165
`Par v Novartis, IPR 2016-00084
`Page 4 of 6
`
`

`
`574
`
`Adria—Cont.
`
`other potentially cardiotoxic agents such as cyclophospha-
`mide. The total dose of ADRIAMYCIN administered to the
`individual patient should also take into account a previous or
`concomitant therapy with related compounds such as
`daunorubicin. Congestive heart failure and/or cardiomyopa-
`thy may be encountered several weeks after discontinuation
`of ADRIAMYCIN therapy.
`Cardiac failure is often not favorably affected by presently
`known medical or physical therapy for cardiac support.
`Early clinical diagnosis of drug induced heart failure ap-
`pears to be essential for successful treatment with digitalis,
`diuretics, low salt diet and bed rest. Severe cardiac toxicity
`may occur precipitously without antecedent EKG changes. A
`baseline EKG and EKGs performed prior to each dose or
`course after 300 mg/m2 cumulative dose has been given is
`suggested. Transient EKG changes consisting of T-wave flat-
`tening. S-T depression and arrhythmias lasting for up to two
`weeks after a dose or course of ADRIAMYCIN are presently
`not considered indications foT suspension of ADRIAMYCIN
`therapy. ADRIAMYCIN cardiomyopathy has been reported
`to be associated with a persistent reduction in the voltage of
`the QRS wave, a prolongation of the systolic time interval
`and a reduction of the ejection fraction as determined by
`echocardiography or radionuclide angiography. None of
`these tests have yet been confirmed to consistently identify
`those individual patients that are approaching their maxi-
`mally tolerated cumulative dose of ADRIAMYCIN. If test
`results indicate change in cardiac function associated with
`ADRIAMYCIN the benefit of continued therapy must be
`carefully evaluated against the risk of producing irreversible
`cardiac damage.
`Acute life-threatening arrhythmias have been reported to
`occur during or within a few hours after ADRIAMYCIN ad-
`ministration.
`There is a high incidence of bone marrow depression, primar-
`ily of leukocytes, requiring careful hematologic monitoring.
`With the recommended dosage schedule, leukopenia is usu-
`ally transient, reaching its nadir at 10-14 days after treat-
`ment with recovery usually occurring by the 21st day. White
`blood cell counts as low as 1000 mm*are to be expected dur-
`ing treatment with appropriate doses of ADRIAMYCIN. Red
`blood cell and platelet levels should also be monitored since
`they may also be depressed. Hematologic toxicity may re-
`quire dose reduction or suspension or delay of ADRIAMY-
`CIN therapy. Persistent severe myelosuppression may result
`in superinfection or hemorrhage.
`ADRIAMYCIN may potentiate the toxicity of other antican-
`cer therapies. Exacerbation of cyclophosphamide induced
`hemorrhagic cystitis and enhancement of the hepatotoxicity
`of 6-mercaptopurine have been reported. Radiation induced
`toxicity to the myocardium, mucosae, skin and liver have
`been reported to be increased by the administration of
`ADRIAMYCIN
`Toxicity to recommended doses of ADRIAMYCIN is en-
`hanced by hepatic impairment, therefore, prior to the indi-
`vidual dosing, evaluation of hepatic function is recom-
`mended using conventional clinical laboratory tests, such as
`SGOT, SGPT, alkaline phosphatase and bilirubin. (See Dos-
`age and Administration).
`Necrotizing colitis manifested by typhlitis (cecal inflamma-
`tion), bloody stools and severe and sometimes fatal infections
`has been associated with a combination of ADRIAMYCIN
`given by i.v. push daily for 3 days and cytarabine given by
`continuous infusion daily for 7 or more days.
`On intravenous administration of ADRIAMYCIN extravasa-
`tion may occur with or without an accompanying stinging or
`burning sensation and even if blood returns well on aspira-
`tion of the infusion needle (See Dosage and Administration)
`If any signs or symptoms of extravasation have occurred the
`injection or infusion should be immediately terminated and
`restarted in another vein.
`ADRIAMYCIN and related compounds have also been
`shown to have mutagenic and carcinogenic properties when
`tested in experimental models.
`Usage in Pregnancy—Safe use of ADRIAMYCIN in preg-
`nancy has not been established. ADRIAMYCIN. is em-
`bryotoxic and teratogenic in rats and embryotoxic and abor-
`tifacient in rabbits. Therefore, the benefits to the pregnant
`patient should be carefully weighed against the potential
`toxicity to fetus and embryo The possible adverse effects on
`fertility in males and females in humans or experimental
`animals have not been adequately evaluated.
`PRECAUTIONS
`Initial treatment with ADRIAMYCIN requires close obser-
`vation of the patient and extensive laboratory monitoring. It
`is recommended, therefore, that patients be hospitalized at
`least during the first phase of the treatment.
`Like other cytotoxic drugs, ADRIAMYCIN may induce hy-
`peruricemia secondary to rapid lysis of neoplastic cells. The
`clinician should monitor the patient's blood uric acid level
`and be prepared to use such supportive and pharmacologic
`measures as might be necessary to control this problem.
`
`Product Information
`ADRIAMYCIN imparts a red coloration to the urine for 1-2
`days after administration and patients should be advised to
`expect this during active therapy.
`ADRIAMYCIN is not an anti-microbial, agent
`ADVERSE REACTIONS
`Dose limiting toxicities of therapy are myelosuppression and
`cardiotoxicity (See Warnings). Other reactions reported are:
`Cutaneous—Reversible complete alopecia occur