Patient Information Leaflet
`Detach and give to Patient
`
`Rev.May 2004
`
`Patient Information Leaflet
`Questions and Answers About Taxotere® Injection Concentrate
`(generic name = docetaxel)
`(pronounced as TAX-O-TEER)
`
`What is Taxotere?
`Taxotere is a medication to treat breast cancer, non-small cell lung cancer and prostate cancer. It
`has severe side effects in some patients. This leaflet is designed to help you understand how to
`use Taxotere and avoid its side effects to the fullest extent possible. The more you understand
`your treatment, the better you will be able to participate in your care. If you have questions or
`concerns, be sure to ask your doctor or nurse. They are always your best source of information
`about your condition and treatment.
`
`What is the most important information about Taxotere?
`• Since this drug, like many other cancer drugs, affects your blood cells, your doctor will ask for
`routine blood tests. These will include regular checks of your white blood cell counts. People
`with low blood counts can develop life-threatening infections. The earliest sign of infection may
`be fever, so if you experience a fever, tell your doctor right away.
`• Occasionally, serious allergic reactions have occurred with this medicine. If you have any
`allergies, tell your doctor before receiving this medicine.
`• A small number of people who take Taxotere have severe fluid retention, which can be life-
`threatening. To help avoid this problem, you must take another medication
`such as
`dexamethasone (DECKS-A-METH-A-SONE) prior to each Taxotere treatment. You must follow
`the schedule and take the exact dose of dexamethasone prescribed (see schedule at end of
`brochure). If you forget to take a dose or do not take it on schedule you must tell the doctor or
`nurse prior to your Taxotere treatment.
`• If you are using any other medicines, tell your doctor before receiving your infusions of
`Taxotere.
`
`How does Taxotere work?
`Taxotere works by attacking cancer cells in your body. Different cancer medications attack
`cancer cells in different ways.
`Here’s how Taxotere works: Every cell in your body contains a supporting structure (like a
`skeleton). Damage to this “skeleton” can stop cell growth or reproduction. Taxotere makes the
`“skeleton” in some cancer cells very stiff, so that the cells can no longer grow.
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`How will I receive Taxotere?
`Taxotere is given by an infusion directly into your vein. Your treatment will take about 1 hour.
`Generally, people receive Taxotere every 3 weeks. The amount of Taxotere and the frequency of
`your infusions will be determined by your doctor.
`As part of your treatment, to reduce side effects your doctor will prescribe another medicine
`called dexamethasone. Your doctor will tell you how and when to take this medicine. It is
`important that you take the dexamethasone on the schedule set by your doctor. If you forget to
`take your medication, or do not take it on schedule, make sure to tell your doctor or nurse
`BEFORE you receive your Taxotere treatment. Included with this information leaflet is a
`chart to help you remember when to take your dexamethasone.
`
`What should be avoided while receiving Taxotere?
`Taxotere can interact with other medicines. Use only medicines that are prescribed for you by
`your doctor and be sure to tell your doctor all the medicines that you use, including
`nonprescription drugs.
`
`What are the possible side effects of Taxotere?
`Low Blood Cell Count – Many cancer medications, including Taxotere, cause a temporary drop
`in the number of white blood cells. These cells help protect your body from infection. Your
`doctor will routinely check your blood count and tell you if it is too low. Although most people
`receiving Taxotere do not have an infection even if they have a low white blood cell count, the
`risk of infection is increased.
`Fever is often one of the most common and earliest signs of infection. Your doctor will
`recommend that you take your temperature frequently, especially during the days after
`treatment with Taxotere. If you have a fever, tell your doctor or nurse immediately.
`Allergic Reactions – This type of reaction, which occurs during the infusion of Taxotere, is
`infrequent. If you feel a warm sensation, a tightness in your chest, or itching during or shortly
`after your treatment, tell your doctor or nurse immediately.
`Fluid Retention – This means that your body is holding extra water. If this fluid retention is in
`the chest or around the heart it can be life-threatening. If you notice swelling in the feet and legs
`or a slight weight gain, this may be the first warning sign. Fluid retention usually does not start
`immediately; but, if it occurs, it may start around your 5th treatment. Generally, fluid retention
`will go away within weeks or months after your treatments are completed.
`Dexamethasone tablets may protect patients from significant fluid retention. It is important that
`you take this medicine on schedule. If you have not taken dexamethasone on schedule, you must
`tell your doctor or nurse before receiving your next Taxotere treatment.
`Gastrointestinal – Diarrhea has been associated with TAXOTERE use and can be severe in
`some patients. Nausea and/or vomiting are common in patients receiving TAXOTERE. Severe
`inflammation of the bowel can also occur in some patients and may be life threatening.
`Hair Loss – Loss of hair occurs in most patients taking Taxotere (including the hair on your
`head, underarm hair, pubic hair, eyebrows, and eyelashes). Hair loss will begin after the first few
`treatments and varies from patient to patient. Once you have completed all your treatments, hair
`generally grows back.
`Your doctor or nurse can refer you to a store that carries wigs, hairpieces, and turbans for
`patients with cancer.
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`Fatigue – A number of patients (about 10%) receiving Taxotere feel very tired following their
`treatments. If you feel tired or weak, allow yourself extra rest before your next treatment. If it is
`bothersome or lasts for longer than 1 week, inform your doctor or nurse.
`Muscle Pain – This happens about 20% of the time, but is rarely severe. You may feel pain in
`your muscles or joints. Tell your doctor or nurse if this happens. They may suggest ways to make
`you more comfortable.
`Rash – This side effect occurs commonly but is severe in about 5%. You may develop a rash
`that looks like a blotchy, hive-like reaction. This usually occurs on the hands and feet but may
`also appear on the arms, face, or body. Generally, it will appear between treatments and will go
`away before the next treatment. Inform your doctor or nurse if you experience a rash. They can
`help you avoid discomfort.
`Odd Sensations – About half of patients getting Taxotere will feel numbness, tingling, or
`burning sensations in their hands and feet. If you do experience this, tell your doctor or nurse.
`Generally, these go away within a few weeks or months after your treatments are completed.
`About 14% of patients may also develop weakness in their hands and feet.
`Nail Changes – Color changes to your fingernails or toenails may occur while taking Taxotere.
`In extreme, but rare, cases nails may fall off. After you have finished Taxotere treatments, your
`nails will generally grow back.
`Eye Changes – Excessive tearing, which can be related to conjunctivitis or blockage of the tear
`ducts, may occur.
`If you are interested in learning more about this drug, ask your doctor for a copy of the package
`insert.
`
`Aventis Pharmaceuticals Inc.
`Bridgewater, NJ 08807 USA
`www.aventis-us.com
`
`Rev. May 2004
`
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`injection of TAXOTERE for
`Every three-week
`breast and non-small cell lung cancers
`Take dexamethasone tablets, 8 mg twice daily.
`
`Dexamethasone dosing:
`
`Day 1 Date:_________ Time:______AM _______PM
`
`Day 2 Date:_________ Time:______AM _______PM
`(Taxotere Treatment Day)
`
`Day 3 Date:_________ Time:______AM _______PM
`
`injection of TAXOTERE for
`
`Every three-week
`prostate cancer
`Take dexamethasone 8 mg, at 12 hours, 3 hours and
`1 hour before TAXOTERE infusion.
`
`Dexamethasone dosing:
`
`Date:_________
`
`Time:___________
`
`Time:___________
`Date:_________
`(Taxotere Treatment Day)
`Time:___________
`
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`Prescribing Information as of May 2004
`
`Injection Concentrate
`
`WARNING
`TAXOTERE® (docetaxel) Injection Concentrate should be administered under the supervision
`of a qualified physician experienced in the use of antineoplastic agents. Appropriate management
`of complications is possible only when adequate diagnostic and treatment facilities are readily
`available.
`The incidence of treatment-related mortality associated with TAXOTERE therapy is increased in
`patients with abnormal liver function, in patients receiving higher doses, and in patients with
`non-small cell lung carcinoma and a history of prior treatment with platinum-based
`chemotherapy who receive TAXOTERE as a single agent at a dose of 100 mg/m2 (see
`WARNINGS).
`TAXOTERE should generally not be given to patients with bilirubin > upper limit of normal
`(ULN), or to patients with SGOT and/or SGPT >1.5 x ULN concomitant with alkaline
`phosphatase > 2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase
`concurrent with alkaline phosphatase are at increased risk for the development of grade 4
`neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe
`skin toxicity, and toxic death. Patients with isolated elevations of transaminase > 1.5 x ULN also
`had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic
`death. Bilirubin, SGOT or SGPT, and alkaline phosphatase values should be obtained prior to
`each cycle of TAXOTERE therapy and reviewed by the treating physician.
`TAXOTERE therapy should not be given to patients with neutrophil counts of < 1500 cells/mm3.
`In order to monitor the occurrence of neutropenia, which may be severe and result in infection,
`frequent blood cell counts should be performed on all patients receiving TAXOTERE.
`Severe hypersensitivity reactions characterized by hypotension and/or bronchospasm, or
`generalized rash/erythema occurred in 2.2% (2/92) of patients who received the recommended 3-
`day dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of the
`TAXOTERE infusion were reported in five patients who did not receive premedication. These
`reactions resolved after discontinuation of the infusion and the administration of appropriate
`therapy. TAXOTERE must not be given to patients who have a history of severe hypersensitivity
`reactions to TAXOTERE or to other drugs formulated with polysorbate 80 (see WARNINGS).
`Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone
`premedication regimen. It was characterized by one or more of the following events: poorly
`tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage,
`dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) (see
`PRECAUTIONS).
`DESCRIPTION
`Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by
`semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew
`plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl
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`ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-
`benzoate, trihydrate. Docetaxel has the following structural formula:
`
`Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14• 3H2O,
`and a molecular weight of 861.9. It is highly lipophilic and practically insoluble in water.
`TAXOTERE (docetaxel) Injection Concentrate is a clear yellow to brownish-yellow viscous
`solution. TAXOTERE is sterile, non-pyrogenic, and is available in single-dose vials containing
`20 mg (0.5 mL) or 80 mg (2 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel
`(anhydrous) and 1040 mg polysorbate 80.
`TAXOTERE Injection Concentrate requires dilution prior to use. A sterile, non-pyrogenic,
`single-dose diluent is supplied for that purpose. The diluent for TAXOTERE contains 13%
`ethanol in water for injection, and is supplied in vials.
`CLINICAL PHARMACOLOGY
`Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that
`is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and
`promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their
`disassembly. This leads to the production of microtubule bundles without normal function and to
`the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s
`binding to microtubules does not alter the number of protofilaments in the bound microtubules, a
`feature which differs from most spindle poisons currently in clinical use.
`HUMAN PHARMACOKINETICS
`The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of
`20-115 mg/m2 in phase I studies. The area under the curve (AUC) was dose proportional
`following doses of 70-115 mg/m2 with infusion times of 1 to 2 hours. Docetaxel’s
`pharmacokinetic profile is consistent with a three-compartment pharmacokinetic model, with
`half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. The initial rapid
`decline represents distribution to the peripheral compartments and the late (terminal) phase is
`due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean
`values for total body clearance and steady state volume of distribution were 21 L/h/m2 and 113
`L, respectively. Mean total body clearance for Japanese patients dosed at the range of 10-90
`mg/m2 was similar to that of European/American populations dosed at 100 mg/m2, suggesting no
`significant difference in the elimination of docetaxel in the two populations.
`A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in
`both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal
`excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted
`for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the
`radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor
`metabolites with very small amounts (less than 8%) of unchanged drug.
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`A population pharmacokinetic analysis was carried out after TAXOTERE treatment of 535
`patients dosed at 100 mg/m2. Pharmacokinetic parameters estimated by this analysis were very
`close to those estimated from phase I studies. The pharmacokinetics of docetaxel were not
`influenced by age or gender and docetaxel total body clearance was not modified by pretreatment
`with dexamethasone. In patients with clinical chemistry data suggestive of mild to moderate liver
`function impairment (SGOT and/or SGPT >1.5 times the upper limit of normal [ULN]
`concomitant with alkaline phosphatase >2.5 times ULN), total body clearance was lowered by an
`average of 27%, resulting in a 38% increase in systemic exposure (AUC). This average,
`however, includes a substantial range and there is, at present, no measurement that would allow
`recommendation for dose adjustment in such patients. Patients with combined abnormalities of
`transaminase and alkaline phosphatase should, in general, not be treated with TAXOTERE.
`Clearance of docetaxel in combination therapy with cisplatin was similar to that previously
`observed following monotherapy with docetaxel. The pharmacokinetic profile of cisplatin in
`combination therapy with docetaxel was similar to that observed with cisplatin alone.
`A population pharmacokinetic analysis of plasma data from 40 patients with hormone-refractory
`metastatic prostate cancer indicated that docetaxel systemic clearance in combination with
`prednisone is similar to that observed following administration of docetaxel alone.
`In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid
`glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma
`proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding
`of docetaxel.
`In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4
`isoenzyme, and its metabolism can be inhibited by CYP3A4 inhibitors, such as ketoconazole,
`erythromycin, troleandomycin, and nifedipine. Based on in vitro findings, it is likely that
`CYP3A4 inhibitors and/or substrates may lead to substantial increases in docetaxel blood
`concentrations. No clinical studies have been performed to evaluate this finding (see
`PRECAUTIONS).
`CLINICAL STUDIES
`Breast Cancer: The efficacy and safety of TAXOTERE have been evaluated in locally
`advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-
`containing regimens or anthracycline-containing regimens), primarily at a dose of 100 mg/m2
`given as a 1-hour infusion every 3 weeks, but with some experience at 60 mg/m2, in two large
`randomized trials and a number of smaller single arm studies.
`Randomized Trials: In one randomized trial, patients with a history of prior treatment with an
`anthracycline-containing regimen were assigned to treatment with TAXOTERE or the
`combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 every 3 weeks).
`203 patients were randomized to TAXOTERE and 189 to the comparator arm. Most patients had
`received prior chemotherapy for metastatic disease; only 27 patients on the TAXOTERE arm
`and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy.
`Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time
`to progression. The following table summarizes the study results:
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`Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients
`Previously Treated with an Anthracycline-Containing Regimen
`(Intent-to-Treat Analysis)
`Docetaxel
`Mitomycin/
`Vinblastine
`(n=189)
`8.7 months
`
`p-value
`
`Efficacy Parameter
`
`Median Survival
`Risk Ratio*, Mortality
`(Docetaxel: Control)
`
`95% CI (Risk Ratio)
`Median Time to
`Progression
`Risk Ratio*, Progression
`(Docetaxel: Control)
`
`(n=203)
`11.4 months
`
`0.73
`
`0.58-0.93
`
`4.3 months
`
`2.5 months
`
`0.75
`
`p=0.01
`Log Rank
`
`p=0.01
`Log Rank
`
`0.61-0.94
`
`95% CI (Risk Ratio)
`28.1%
`Overall Response Rate
`3.4%
`Complete Response Rate
`*For the risk ratio, a value less than 1.00 favors docetaxel.
`In a second randomized trial, patients previously treated with an alkylating-containing regimen
`were assigned to treatment with TAXOTERE or doxorubicin (75 mg/m2 every 3 weeks). 161
`patients were randomized to TAXOTERE and 165 patients to doxorubicin. Approximately one-
`half of patients had received prior chemotherapy for metastatic disease, and one-half entered the
`study following relapse after adjuvant therapy. Three-quarters of patients had measurable,
`visceral metastases. The primary endpoint was time to progression. The study results are
`summarized below:
`
`9.5%
`1.6%
`
`p<0.0001
`Chi Square
`
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`Efficacy of TAXOTERE in the Treatment of Breast Cancer Patients
`Previously Treated with an Alkylating-Containing Regimen
`(Intent-to-Treat Analysis)
`Docetaxel
`Doxorubicin
`(n=161)
`(n=165)
`14.7 months
`14.3 months
`
`p-value
`
`Efficacy Parameter
`
`Median Survival
`Risk Ratio*, Mortality
`(Docetaxel: Control)
`
`95% CI (Risk Ratio)
`Median Time to
`Progression
`Risk Ratio*, Progression
`(Docetaxel: Control)
`
`0.89
`
`0.68-1.16
`
`6.5 months
`
`5.3 months
`
`0.93
`
`p=0.39
`Log Rank
`
`p=0.45
`Log Rank
`
`0.71-1.16
`
`45.3%
`6.8%
`
`29.7%
`4.2%
`
`p=0.004
`Chi Square
`
`95% CI (Risk Ratio)
`Overall Response Rate
`Complete Response
`Rate
`*For the risk ratio, a value less than 1.00 favors docetaxel.
`Single Arm Studies: TAXOTERE at a dose of 100 mg/m2 was studied in six single arm studies
`involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy
`had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as
`progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or
`relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients,
`the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response
`rate was 2.1%.
`TAXOTERE was also studied in three single arm Japanese studies at a dose of 60 mg/m2, in 174
`patients who had received prior chemotherapy for locally advanced or metastatic breast cancer.
`Among 26 patients whose best response to an anthracycline had been progression, the response
`rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100
`mg/m2.
`Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry
`abnormalities. Hematologic and other toxicity is increased at higher doses and in patients with
`elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are
`compared for three populations: 730 patients with normal LFTs given TAXOTERE at 100
`mg/m2 in the randomized and single arm studies of metastatic breast cancer after failure of
`previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as
`SGOT and/or SGPT > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN);
`and 174 patients in Japanese studies given TAXOTERE at 60 mg/m2 who had normal LFTs.
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`Hematologic Adverse Events in Breast Cancer Patients
`
`Previously Treated with Chemotherapy
`
`Treated at TAXOTERE 100 mg/m2 with Normal
`
`or Elevated Liver Function Tests or
`
`60 mg/m2 with Normal Liver Function Tests
`
`TAXOTERE
`100 mg/m2
`Elevated
`Normal
`LFTs**
`LFTs*
`n=18
`n=730
`%
`%
`
`TAXOTERE
`60 mg/m2
`Normal
`LFTs*
`n=174
`%
`
`Adverse Event
`
`98.4
`84.4
`
`10.8
`0.6
`94.6
`
`22.5
`7.1
`
`100
`93.8
`
`44.4
`16.7
`94.4
`
`38.9
`33.3
`
`95.4
`74.9
`
`14.4
`1.1
`64.9
`
`1.1
`0
`
`Neutropenia
`3
`<2000 cells/mm
`Any
`3
`<500 cells/mm
`Grade 4
`Thrombocytopenia
`<100,000 cells/mm3
`Any
`3
`Grade 4
`<20,000 cells/mm
`Anemia <11 g/dL
`Infection***
`Any
`Grade 3 and 4
`Febrile Neutropenia****
`33.3
`0
`11.8
`By Patient
`8.6
`0
`2.4
`By Course
`5.6
`1.1
`1.5
`Septic Death
`11.1
`0
`1.1
`Non-Septic Death
`*Normal Baseline LFTs: Transaminases ≤ 1.5 times ULN or alkaline phosphatase ≤ 2.5
`times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times
`ULN
`**Elevated Baseline LFTs: SGOT and/or SGPT >1.5 times ULN concurrent with alkaline
`phosphatase >2.5 times ULN
`***Incidence of infection requiring hospitalization and/or intravenous antibiotics was 8.5%
`(n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent
`grade 3 neutropenia, and 46 patients had grade 4 neutropenia.
`****Febrile Neutropenia: For 100 mg/m2, ANC grade 4 and fever > 38°C with IV
`antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever > 38.1°C
`
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`Non-Hematologic Adverse Events in Breast Cancer Patients
`
`Previously Treated with Chemotherapy
`
`Treated at TAXOTERE 100 mg/m2 with Normal or Elevated Liver Function Tests or
`
`60 mg/m2 with Normal Liver Function Tests
`
`TAXOTERE
`100 mg/m2
`Normal
`LFTs*
`n=730
`%
`
`TAXOTERE
`60 mg/m2
`Normal
`LFTs*
`n=174
`%
`
`Elevated
`LFTs**
`n=18
`%
`
`Adverse Event
`
`5.6
`0
`
`61.1
`16.7
`
`50
`0
`33.3
`
`61.1
`16.7
`
`44.4
`22.2
`
`27.8
`11.1
`
`0.6
`0
`
`12.6
`0
`
`19.5
`0
`3.4
`
`30.5
`0
`
`65.5
`0
`
`NA
`
`Acute Hypersensitivity
`Reaction Regardless of
`Premedication
`Any
`Severe
`Fluid Retention***
`Regardless of Premedication
`Any
`Severe
`Neurosensory
`Any
`Severe
`Myalgia
`Cutaneous
`Any
`Severe
`Asthenia
`Any
`Severe
`Diarrhea
`Any
`Severe
`Stomatitis
`19.0
`66.7
`53.3
`Any
`0.6
`38.9
`7.8
`Severe
`*Normal Baseline LFTs: Transaminases ≤ 1.5 times ULN or alkaline phosphatase ≤ 2.5
`times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times
`ULN
`** Elevated Baseline Liver Function: SGOT and/or SGPT >1.5 times ULN concurrent with
`alkaline phosphatase >2.5 times ULN
`***Fluid Retention includes (by COSTART): edema (peripheral, localized, generalized,
`lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural,
`pericardial, and ascites); no premedication given with the 60 mg/m2 dose
`NA = not available
`
`13.0
`1.2
`
`56.2
`7.9
`
`56.8
`5.8
`22.7
`
`44.8
`4.8
`
`65.2
`16.6
`
`42.2
`6.3
`
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`Non-Small Cell Lung Cancer (NSCLC): The efficacy and safety of TAXOTERE has been
`evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer
`whose disease has failed prior platinum-based chemotherapy or in patients who are
`chemotherapy-naïve.
`Monotherapy with TAXOTERE for NSCLC Previously Treated with Platinum-Based
`Chemotherapy
`Two randomized, controlled trials established that a TAXOTERE dose of 75 mg/m2 was
`tolerable and yielded a favorable outcome in patients previously treated with platinum-based
`chemotherapy (see below). TAXOTERE at a dose of 100 mg/m2, however, was associated with
`unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose
`should not be used (see BOXED WARNING, WARNINGS, and DOSAGE AND
`ADMINISTRATION sections).
`One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung
`cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an
`ECOG performance status ≤2 to TAXOTERE or best supportive care. The primary endpoint of
`the study was survival. Patients were initially randomized to TAXOTERE 100 mg/m2 or best
`supportive care, but early toxic deaths at this dose led to a dose reduction to TAXOTERE 75
`mg/m2. A total of 104 patients were randomized in this amended study to either TAXOTERE 75
`mg/m2 or best supportive care.
`In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-
`small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG
`performance status ≤2 were randomized to TAXOTERE 75 mg/m2, TAXOTERE 100 mg/m2 and
`a treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15
`repeated every 3 weeks or ifosfamide 2 g/m2 days 1-3 repeated every 3 weeks. Forty percent of
`the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was
`survival in both trials. The efficacy data for the TAXOTERE 75 mg/m2 arm and the comparator
`arms are summarized in the table below and in figures 1 and 2 showing the survival curves for
`the two studies.
`
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`Efficacy of TAXOTERE in the Treatment of Non-Small Cell Lung
`Cancer Patients Previously Treated with a Platinum-Based
`Chemotherapy Regimen (Intent-to-Treat Analysis)
`TAX317
`Docetaxel
`75 mg/m2
`n=55
`
`TAX320
`Docetaxel
`Control
`75 mg/m2
`(V/I)
`n=125
`n=123
`
`Best
`Supportive
`Care/75
`n=49
`
`Overall Survival
`Log-rank Test
`Risk Ratio††, Mortality
`(Docetaxel: Control)
`95% CI (Risk Ratio)
`Median Survival
`95% CI
`% 1-year Survival
`95% CI
`Time to Progression
`95% CI
`Response Rate
`
`p=0.01
`
`p=0.13
`
`0.56
`(0.35, 0.88)
`7.5 months*
`4.6 months
`(5.5, 12.8)
`(3.7, 6.1)
`37%*†
`12%
`(24, 50)
`(2, 23)
`12.3 weeks*
`7.0 weeks
`(9.0, 18.3)
`(6.0, 9.3)
`Not
`5.5%
`Applicable
`
`0.82
`(0.63, 1.06)
`5.7 months
`5.6 months
`(5.1, 7.1)
`(4.4, 7.9)
`30%*†
`20%
`(22, 39)
`(13, 27)
`8.3 weeks
`7.6 weeks
`(7.0, 11.7)
`(6.7, 10.1)
`5.7%
`0.8%
`
`(0.0, 4.5)
`(2.3, 11.3)
`(1.1, 15.1)
`95% CI
`* p≤0.05; † uncorrected for multiple comparisons; †† a value less than 1.00 favors docetaxel.
`Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint;
`that trial also showed an increased rate of survival to one year. In the second study (TAX320) the
`rate of survival at one year favored TAXOTERE 75 mg/m2.
`
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`Figure 1: TAX317 Survival K-M Curves - TAXOTERE 75 mg/m2 vs. Best Supportive Care
`
`Figure 2: TAX320 Survival K-M Curves - TAXOTERE 75 mg/m2 vs. Vinorelbine or
`Ifosfamide Control
`
`Patients treated with TAXOTERE at a dose of 75 mg/m2 experienced no deterioration in
`performance status and body weight relative to the comparator arms used in these trials.
`Combination Therapy with TAXOTERE for Chemotherapy-Naïve NSCLC
`In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV
`NSCLC and no prior chemotherapy were randomized to receive one of three treatments:
`TAXOTERE 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over
`30-60 minutes every 3 weeks; vinorelbine 25 mg/m2 administered over 6-10 minutes on days 1,
`
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`8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4
`weeks; or a combination of TAXOTERE and carboplatin.
`The primary efficacy endpoint was overall survival. Treatment with TAXOTERE+cisplatin did
`not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see
`table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and
`multiple comparisons) shows that the addition of TAXOTERE to cisplatin results in an outcome
`ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to
`cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the
`95% confidence interval) 62% of the known survival effect of vinorelbine when added to
`cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was
`maintained. The efficacy data for the TAXOTERE+cisplatin arm and the comparator arm are
`summarized in the table below.
`Survival Analysis of TAXOTERE in Combination Therapy for Chemotherapy-Naïve
`NSCLC
`Comparison
`
`Taxotere+Cisplatin
`n=408
`10.9 months
`
`Vinorelbine+Cisplatin
`n=405
`10.0 months
`
`Kaplan-Meier Estimate of Median Survival
`p-valuea
`0.122
`Estimated Hazard Ratiob
`0.88
`Adjusted 95% CIc
`(0.74, 1.06)
`a From the superiority test (stratified log rank) comparing TAXOTERE+cisplatin to vinorelbine+cisplatin
`bHazard ratio of TAXOTERE+cisplatin vs. vinorelbine+cisplatin. A hazard ratio of less than 1 indicates
`that TAXOTERE+cisplatin is associated with a longer survival.
`cAdjusted for interim analysis and multiple comparisons.
`The second comparison in the study, vinorelbine+cisplatin versus TAXOTERE+carboplatin,
`did not demonstrate superior survival associated with the TAXOTERE arm (Kaplan-Meier
`estimate of median survival was 9.1 months for TAXOTERE+carboplatin compared to 10.0
`months on the vinorelbine+cisplatin arm) and the TAXOTERE+carboplatin arm did not
`demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin.
`Secondary endpoints evaluated in the trial included objective response and time to progression.
`There was no statistically significant difference between TAXOTERE+cisplatin and
`vinorelbine+cisplatin with respect to objective response and time to progression (see table
`below).
`Response and TTP Analysis of TAXOTERE in Combination Therapy for Chemotherapy-
`Naïve NSCLC
`Endpoint
`Objective Response Rate
`(95% CI)a
`Median Time to Progressionb
`(95% CI)a
`aAdjusted for multiple comparisons.
`bKaplan-Meier estimates.
`
`TAXOTERE+Cisplatin Vinorelbine+Cisplatin
`31.6%
`24.4%
`(26.5%, 36.8%)
`(19.8%, 29.2%)
`21.4 weeks
`22.1 weeks
`(19.3, 24.6)
`(18.1, 25.6)
`
`p-value
`Not Significant
`
`Not Significant
`
`Prostate Cancer
`The safety and efficacy of TAXOTERE in combination with prednisone in patients with
`androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a
`
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`randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance
`Statu