Taxotere – Emerging Litigation

TAXOTERE (Docetaxel) is a cancer fighting drug belonging to the taxoid family. It is extracted from the renewable needle biomass of yew plants. One of the most serious and devastating potential side effects of Taxotere is permanent hair loss –a risk not disclosed by Sanofi-Aventis and other manufacturers. Other equally effective agents were available without the alopecia.

taxotere

Manufacturer: Docetaxel is marketed worldwide under the name Taxotere by Sanofi-Aventis as well as Docefrez by Sun Pharma Global and Zytax by Zydus.

Mechanism Of Action:

Molecular Target: Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules. This binding stabilizes microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule. Docetaxel has been found to accumulate to higher concentration in ovarian adenocarcinoma cells than kidney carcinoma cells, which may contribute to the more effective treatment of ovarian cancer by docetaxel. It has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis-blocking in its oncoprotein form.

Modes of Action: The cytotoxic activity of docetaxel is exerted by promoting and stabilizing microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny.

Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein. Both in vitro and in vivo analysis show the anti-neoplastic activity of docetaxel to be effective against a wide range of known cancer cells, cooperate with other anti-neoplastic agents activity, and have greater cytotoxicity than paclitaxel, possibly due to its more rapid intracellular uptake.

The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly, rather than microtubule bundling leading to apoptosis, or the blocking of bcl-2.

Cellular Responses: Docetaxel exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells. Docetaxel does not block disassembly of interphase microtubules and so does not prevent entry into the mitotic cycle, but does block mitosis by inhibiting mitotic spindle assembly. Resistance to paclitaxel or anthracycline doxorubicin does not necessarily indicate resistance to docetaxel. Microtubules formed in the presence of docetaxel are of a larger size than those formed in the presence of paclitaxel, which may result in improved cytotoxic efficacy. Abundant formation of microtubules and the prevention to replicate caused by the presence of docetaxel leads to apoptosis of tumor cells and is the basis of docetaxel use as a cancer treatment. It is unknown if pathophysiological interactions with docetaxel exist at this stage, however tumor type has been shown to have efficacy on cellular activity. Docetaxel activity is significantly greater in ovarian and breast tumors than for lung tumors.

Approval: By U.S. Food & Drug Administration (FDA) for treatment of locally advanced or metastatic breast cancer, head and neck cancer, gastric cancer, hormone-refractory prostate cancer and non small-cell lung cancer. Initial U.S. Approval: 1996.

Serious Side Effects:

One of the most serious and devastating potential side effects, problems and risks caused through the use Taxotere is permanent alopecia (loss of hair).

Other potential side effects include:

·         Bone, muscle or joint pain

·         Constipation

·         Diarrhea

·         Fatigue and weakness

·         Fluid retention with weight gain, swelling of the ankles or abdominal area

·         Infection

·         Low red blood cell count (anemia)

·         Low white blood cell count

·         Mouth or throat sores

·         Nail changes (color changes to your fingernails or toenails)

·         Nausea

·         Peripheral neuropathy (numbness in your fingers and toes)

·         Taste changes

Warning By The Manufacturer: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid Retention (NEED TO VALIDATE WHEN THE WARNING WAS UPDATED IN THE PACKING)

  • Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving TAXOTERE at 100 mg/m2
  • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle
  • Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia
  • Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of TAXOTERE and administration of appropriate therapy
  • Contraindicated if history of severe hypersensitivity reactions to TAXOTERE or to drugs formulated with polysorbate 80
  • Severe fluid retention may occur despite dexamethasone

CONTRAINDICATIONS

  • Hypersensitivity to docetaxel or polysorbate 80
  • Neutrophil counts of <1500 cells/mm3

FDA Drug Safety Communication: FDA warns that cancer drug Docetaxel may cause symptoms of alcohol intoxication after treatment

06/20/2014: The U.S. Food and Drug Administration (FDA) is warning that the intravenous chemotherapy drug docetaxel contains ethanol, also known as alcohol, which may cause patients to experience intoxication or feel drunk during and after treatment. We are revising the labels of all docetaxel drug products to warn about this risk. Health care professionals should consider the alcohol content of docetaxel when prescribing or administering the drug to patients, particularly in those whom alcohol intake should be avoided or minimized and when using it in conjunction with other medications.

FDA Data Summary:

A search of the FDA Adverse Event Reporting System (FAERS) database and the medical literature identified three cases of alcohol intoxication associated with Docetaxel. There was a strong temporal association between the docetaxel infusion and symptoms of alcohol intoxication in the cases. Two patients experienced alcohol intoxication during the infusion and one patient experienced it within 24 hours of drug administration. In one case, the symptoms of alcohol intoxication were transient. In another case, the symptoms resolved in time for the patient to finish his treatment using a slower infusion rate. In two of the three cases, the reporters planned to use a different docetaxel formulation with lower alcohol content for future treatments.

Case review focus areas:

  •  Whether the patient received administration of Taxotere
  • Frequency and treatment details

Critical Review of chemotherapy records

Oncologists Recommendation

  • Did the patient have any pre-existing conditions like alopecia (Family History) or contraindications?
  • Whether the patient received warning about permanent hair loss or baldness?
  • When the patient started developing hair loss?
  • Treatment/management
  • Follow-up visits for treatment/management of complications

Specific Focus:

Identify and report cases with the following scenarios:

  1. No Injuries: Patient had treatment but did not develop any injuries
  2. Any medical/surgical/Family history, social history that could have had an effect

Missing record communication:

Identify and report on missing medical records

Apart from identifying critical missing records that are important for the case, provide a detailed outline on what records are needed, why we need them, how did we get a clue that these records are missing and whether the records missing are confirmatory/probable. This will also help in following up and retrieving the records.

Missing Records are presented in the following format

missing-records