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Taxol

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Taxol uses



OAS-OAS/PLV/60/US/PIL-001

237103

Paccal Vet®-CA1

(paclitaxel for injection)

60 mg Taxol per vial

Antineoplastic

For intravenous use in dogs only

Conditionally approved by FDA pending a full demonstration of effectiveness under application number 141-422.

CAUTION:

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. Use only as directed. It is a violation of Federal Law to use this product other than as directed in the labeling.

DESCRIPTION:

Paccal Vet®-CA1 is an antimicrotubule agent. The empirical formula of Taxol is C47H51NO14 and the molecular weight is 854. It is highly lipophilic and practically insoluble in water. The chemical name for Taxol is 5β,20-epoxy-1,7β-dihydroxy-9-oxotax-11-ene-2α,4,10β,13α-tetrayl 4,10-diacetate 2 benzoate 13-[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoate]. Taxol has the following structural formula:

Taxol is supplied as a greenish-yellow to yellow sterile lyophilized powder in the form of a cake. Reconstitute the powder prior to intravenous infusion. Each single use vial contains 60 mg of Taxol, 40 mg of N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt and 40 mg of N-(13- cis-retinoyl)-L-cysteic acid methyl ester sodium salt. The reconstituted concentration is 1 mg/mL. In the aqueous solution for infusion these constituents are soluble and form micellar nanoparticles with a size of approximately 20-40 nm.

Taxol Structural Formula

INDICATIONS:

Taxol is indicated for the treatment of:

- Nonresectable stage III, IV or V mammary carcinoma in dogs that have not received previous chemotherapy or radiotherapy.

- Resectable and nonresectable squamous cell carcinoma in dogs that have not received previous chemotherapy or radiotherapy.

DOSAGE AND ADMINISTRATION:

Always provide the Client Information Sheet to the dog owner with each dose administration.

Administer Taxol at 150 mg/m2 body surface area (BSA) intravenously over 15-30 minutes, once every three weeks for up to four doses. Dose reductions of 10 mg/m2 or dose delays may be used to manage adverse reactions.

Reconstitution and administration of Taxol

Taxol is supplied as a sterile powder for reconstitution before use. After reconstitution the solution contains 1 mg of paclitaxel/mL. Taxol should be protected from light throughout the preparation process. Taxol preparation should be done with aseptic technique and the reconstituted product should be used immediately.


Compatibility of administration sets containing DEHP (di(2-ethylhexyl) phthalate) has not been demonstrated.

CONTRAINDICATIONS:

Do not use in dogs that have a neutropenia (< 2000 cells/µL) or that have a concurrent serious infection.

Do not use in dogs that are pregnant, lactating, or intended for breeding. Taxol is a teratogen and can affect female and male fertility. Laboratory studies in the rat have shown reduced fertility, embryotoxicity, teratogenicity, and maternal toxicity.

WARNINGS:

Taxol can cause severe, transient bone marrow suppression within four to seven days of administration (see ADVERSE REACTIONS ).

Taxol can cause gastrointestinal adverse reactions due to transient gastrointestinal mucosal cell toxicity. Monitor patients carefully for vomiting, diarrhea and dehydration. Provide supportive care as clinically indicated.

HUMAN WARNINGS:

NOT FOR USE IN HUMANS. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Persons sensitive to retinoids should avoid contact with Taxol.

Taxol is cytotoxic and can cause birth defects and affect female and male fertility. Pregnant and breast feeding women should not prepare or administer the product. Wear protective gloves to prevent contact with feces, urine, vomit and saliva for three days after the dog has received treatment. Place all waste material in a plastic bag and seal before disposal.

S pecial instructions f o r preparing and administering the product:

- Taxol should be administered under the supervision of a veterinarian experienced in the use of cancer chemotherapeutic agents.

- Use standard measures for the safe handling of cytotoxic drugs.

- Wear gloves, goggles and protective clothing.

- Do not eat, drink or smoke while handling the product.

- Do not store food in or near the preparation area.

A c cidental skin contact

- In case of accidental contact with the skin, wash the affected area immediately and thoroughly with soap and water.

A c cidental eye exposure

- Remove contact lenses.

- Rinse the eyes with large amounts of tap water (use eyewash station if present) for at least 10 minutes while holding back the eyelid.

- Seek medical advice immediately and show the package insert or label to the physician.

A c cidental self-injection

- Remove glove.

- Let the wound bleed a few drops of blood.

- Rinse the wound thoroughly with plenty of tap water.

- Seek medical advice immediately and show the package insert or label to the physician.

PRECAUTIONS:

Avoid extravasation during intravenous administration of Taxol as focal tissue necrosis can occur (see ADVERSE REACTIONS ).

Drug interaction studies have not been performed. Taxol is metabolized by cytochrome P450 isoenzymes and is a P-glycoprotein (P-gp) substrate. Exercise caution when administering Taxol with medications that inhibit or induce cytochrome P450 isoenzymes or with medications that are P-gp substrates.

ADVERSE REACTIONS:

Field Study:

In a field study, 168 dogs with cancer were treated with Taxol at 150 mg/m2 IV administered over 30 minutes, for up to four cycles, three weeks apart.

All dogs experienced at least one adverse reaction. Eighty-five percent of dogs experienced a severe adverse reaction (VCOG1 Grade 3, 4 or 5), and 11 dogs discontinued treatment due to adverse reactions. Five dogs died and three dogs were euthanized due to adverse reactions during the study. Taxol has a low margin of safety, but adverse reactions were manageable with appropriate patient monitoring or supportive care. The most common adverse reactions are summarized in Table 1.

Table 1: Common Adverse Reactions in Taxol Treated Dogs (n=168)

Adverse Reaction Number affected Percent affected
Neutropenia 137 82%
Vomiting 133 79%
Anorexia 127 76%
Diarrhea 118a 70%
Lethargy 116 69%
Alopecia 66 39%
Dehydration 43 26%
Dermatitis 40b 24%
Hepatopathy 32c 19%
Edema 24 14%
Pyrexia 22 13%
Lameness 20 12%
Urine abnormality 16 10%
Pruritis 16 10%
Erythema 14 8%
Anemia 13 8%
Loss of body condition 12 7%
Ulceration, cutaneous 12 7%
Thrombocytopenia 11 7%
Neoplasia 11 7%
Polydyplasia 10 6%
Conjunctivitis 10 6%
Death 5d 3%
Euthanasia 3d 2%

a Nine dogs had hemorrhagic diarrhea

b Eight dogs had pyoderma and eleven had undefined skin lesions

c One dog had hepatomegaly

d Not related to disease progression

Adverse reactions that occurred in less than 6% of dogs during the study included leukopenia, lymphopenia, hypoproteinemia, hypoalbuminemia, hypotension, colitis, melena, hematochezia, septicemia, injection site reactions, focal necrosis associated with extravasation, transient aggression, behavioral changes, shivering, heart murmur, weakness, benign tumors, abdominal pain, dyspnea, decreased appetite, gastrointestinal ulceration, panting, tachycardia, mast cell tumor degranulation, acute tumor lysis syndromes, and possible cerebrovascular event.

In pilot studies conducted in dogs with mammary carcinoma and squamous cell carcinoma treated with Paccal Vet ® -CA1, adverse reactions were generally consistent with those reported in Table 1 and the paragraph above.

To report suspected adverse events, for technical assistance, or to obtain a copy of the Material Safety Data Sheet (MSDS) contact Oasmia Pharmaceutical Inc. at 1-866-466-1226.

For additional information about adverse drug experience reporting for animal drugs contact FDA by telephone at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth.

INFORMATION FOR DOG OWNERS:

Always provide the Client Information Sheet and review it with the dog owner or person responsible for care of the dog. Advise dog owners about possible adverse reactions, when to contact a veterinarian, and how to clean up any saliva, urine, feces or vomit from dogs treated with Taxol.

CLINICAL

Pharmacology:

Mechanism of action

Taxol is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. Stabilization results in inhibition of the normal dynamic reorganization of the microtubular network that is essential for vital interphase and mitotic cellular functions. In addition, Taxol induces microtubule bundle formation throughout the cell cycle and induces microtubule aster formation during mitosis.

Pharmacokinetics

Similar to that observed in other animal species and in human patients, Taxol undergoes extensive tissue distribution in dogs. Consequently, Taxol follows a three-compartment model, with a rapid initial disappearance which ranges from 3 to 5 hours. However, a small proportion of the total exposure (e.g., 3 – 7% of the administered dose) may remain in the tissues from which it slowly depletes. The duration of this terminal phase may be as long as 12 hours. However, due to the very small proportion of the total dose associated with this deep compartment, no drug accumulation is observed when the drug is administered once every three weeks at an intravenous (IV) dose of 130 to 150 mg/m2. Systemic drug exposure is directly proportional to dose within the dosing range of 130 to 150 mg/m2.

REASONABLE EXPECTATION OF EFFECTIVENESS:

This drug is conditionally approved pending a full demonstration of effectiveness.

The following studies were used to demonstrate a reasonable expectation of effectiveness for Paccal Vet ® -CA1 (paclitaxel for injection) for specific indications (see INDICATIONS ).

Mammary carcinoma

Clinical data from 10 dogs with advanced-stage mammary carcinoma that were treated with Taxol in two separate pilot studies support a reasonable expectation of effectiveness.

A single group, single-center, open label, dose escalating, clinical study in 32 dogs with solid tumors was conducted to assess the safety and pharmacokinetics of Taxol. Seven dogs had advanced stage mammary carcinoma. Dogs were treated once every 21 days for up to three cycles. Taxol was administered as an intravenous infusion over 15 to 30 minutes at an initial dose of 100 to 150 mg/m2. Response to treatment was evaluated by tumor measurements (sum of the longest perpendicular diameters) prior to each treatment cycle. Complete response (CR) was defined as disappearance of all lesions, and partial response (PR) was defined as a minimum 50% decrease in the tumor measurement without the appearance of new lesions. At the study end (Day 84), one dog had CR, two had PR, and four had progressive disease (PD). Progression free survival (PFS) for the dog with a complete response was 1 year and survival was 498 days. Of the two dogs with PR, one had subsequent surgical excision of the tumor resulting in long term survival of 480 days. The other dog with PR had PFS and survival of 131 days. The dogs with PD had PFS of 20-56 days and survival of 40-56 days.

In a separate study in dogs with cancer, three dogs with metastatic mammary carcinoma were treated with Taxol. Treatment with Taxol resulted in PR in two of three dogs with metastatic mammary tumors and PFS of 84 and 258 days.

Collectively, six of the 10 dogs with mammary carcinoma that were treated with Taxol were assessed as responders (complete or partial response), including three responding cases with PFS greater than four months and one additional dog whose response to Taxol allowed subsequent surgical excision of the tumor resulting in long term control.

Squamous ce l l carcinoma

Clinical data from 17 dogs with resectable or nonresectable squamous cell carcinoma treated with Taxol in two separate pilot studies support a reasonable expectation of effectiveness.

A single group, multi-center, open label clinical study, was conducted in 14 dogs with resectable or nonresectable squamous cell carcinoma. Lesion locations included oral/tonsil, prepuce, nose/nares, and carpus. Four dogs had metastatic disease, one dog had previous chemotherapy, one dog had previous radiation therapy and one dog had previous surgery. Dogs were treated once every three weeks (one cycle) for up to four cycles. Taxol was administered as an intravenous infusion over 15 to 30 minutes at an initial dose of 150 mg/m2. Dose reductions or dose delays were used to manage severe adverse reactions (VCOG-CTCAE grade 3-5). Response to treatment was evaluated by tumor measurements prior to each cycle. One dog died prior to the first tumor response measurement (Day 8), and three dogs were lost to follow up during the study. Two dogs had stable disease (SD) that was maintained through study end (Day 84), and were progression free on 91 and 144 days (time of last contact). Progression free survival (PFS) ranged from 21-63 days for dogs that developed progressive disease (n=8) during the study.

A single group, single-center, open label, dose escalating, clinical study in 32 dogs with solid tumors was conducted to assess the safety and pharmacokinetics of Taxol. Three dogs had nonresectable oral squamous cell carcinoma, and two of these three dogs also had metastatic disease. Dogs were treated once every three weeks (one cycle) for up to four cycles. Taxol was administered as an intravenous infusion over 15 to 30 minutes at an initial dose of 150 mg/m2. Response to treatment was evaluated by tumor measurements (sum of the longest perpendicular diameters) prior to each cycle. Complete response (CR) was defined as disappearance of all lesions, and partial response (PR) was defined as a minimum 50% decrease in the tumor measurements without the appearance of new lesions. At study end (Day 84), one dog had CR, one had PR, and one had progressive disease (PD, progressed at Day 64). The dog with PR was progression free until Day 260, and the dog with a CR was alive at the time of last contact (Day 388).

Collectively, two of the 17 dogs with squamous cell carcinoma that were treated with Taxol were assessed as responders (CR or PR), and two dogs had stable disease (SD) that was maintained through study end (Day 84). The dog with CR at study end had a PFS of 388 days and the dog with PR at study end had PFS of 260 days. The SD may represent a clinically relevant response, and dogs with SD had PFS of 91 and 144 days. PFS ranged from 21-64 days for dogs that developed PD (n=9) during the study.

ANIMAL SAFETY:

In the multidose target animal safety study, Taxol demonstrated a narrow margin of safety.

All dogs that received Taxol experienced Taxol related toxicities. No dogs died, required euthanasia or discontinued treatment prior to the end of the study.

Twenty-four dogs (8 dogs per group, 4 males and 4 females) were administered either intravenous Lactated Ringer’s Solution as a placebo, or Taxol at 130 mg/m2 or 150 mg/m2 once every three weeks (one cycle) for four cycles. Taxol caused lethargy, depression, weight loss, decreased feed intake, anorexia, vomiting, diarrhea, hematochezia, melena, alopecia, whisker loss, focal dermatitis, focal ulcerative dermatitis, skin wounds of undetermined origin, focal inflammation after subcutaneous injection of antibiotics, conjunctivitis, oligospermia, decreases in hematology variables and injection site swelling.

Three dogs in the 130 mg/m2 group and three dogs in the 150 mg/m2 group became systemically ill after the first dose of Taxol. Clinical signs included anorexia, depression, pale mucous membranes, vomiting, diarrhea, hematochezia, and fever. One dog had clinical signs of shock (pale and cyanotic mucous membranes, slow capillary refill time, hypothermia). Hematology changes included leukopenia (n=4), neutropenia (n=4) and lymphopenia (n=5). Two dogs in the 130 mg/m2 group and three dogs in the 150 mg/m2 group required supportive care with intravenous fluids and systemic antibiotics. These dogs recovered within four days after the onset of clinical signs.

Taxol related hematology changes included leukopenia, neutropenia (Grades 1-3)1, lymphopenia, monocytopenia, thrombocytopenia (Grade 1-2), anemia (Grade 1), and decreases in hemoglobin, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular volume (MCV). The nadir for hematology variables occurred one to four days after Taxol administration and recovery was observed within three weeks. Prothrombin time (PT), partial thromboplastin time (PTT) and buccal mucosal bleeding time (BMBT) were not affected by Taxol.

During the study dogs in the Taxol groups had a higher frequency of vomiting, diarrhea, hematochezia and melena compared to the control group dogs. The increase in vomiting and diarrhea usually occurred within four days of Taxol administration. Feed consumption decreased or was absent up to 3 days after Taxol administration, and body weight decreased in the first week, followed by an increase during the second and third weeks.

Dogs in the Taxol groups had lower albumin, increased fibrinogen, and higher creatine kinase compared to the control group.

Injection site swelling occurred more frequently in the Taxol groups, was mild and resolved within one day after treatment. There were no occurrences of extravasation during the study. Whisker loss and facial alopecia were noted in seven 130 mg/m2 Taxol group dogs and all 150 mg/m2 Taxol group dogs. Coat thinning was noted in three 130 mg/m2 Taxol group dogs and seven 150 mg/m2 paclitaxel group dogs. Whisker loss, facial alopecia and coat thinning started three weeks after the second treatment.

Necropsy occurred seven days after the last administration of Taxol. Toxicologically relevant changes noted in the dogs in the Taxol groups included patchy facial alopecia, whisker loss, thinning of hair coat, dermal ulcerations, focal fat necrosis associated with subcutaneous injections, inflammation and thrombosis at catheter placement sites, oligospermia, mild mineralization and smooth muscle hypertrophy in the media of the aorta, hypercellular bone marrow, and extramedullary splenic hematopoiesis indicative of a normal regenerative response. On histopathology regenerative hair follicles were noted in dogs in the Taxol groups, indicating the alopecia may not be permanent. The hypercellular bone marrow may be a response to the daily blood collections for clinical pathology following the last treatment or a recovery response to the bone marrow suppressive effects of Taxol.

STORAGE CONDITIONS:

U n o pened vials: Store the vials refrigerated at 2° to 8°C (36° to 46°F). Retain in the original package to protect from light.

A fter opening and reconstitution: Use the reconstituted product immediately because it does not contain a preservative. Protect from light during preparation and administration.

Disposal: Dispose of any unused product or waste materials in accordance with proper procedures for cytotoxic drugs.

HOW SUPPLIED:

Paccal Vet ® -CA1 is supplied in a 75 mL clear glass vial with rubber stopper, aluminum over-seal and plastic flip-off cap, individually packaged in a carton. Each vial contains 60 mg of Taxol.

P ack size: One vial.

REFERENCES:

1. Veterinary cooperative oncology group – common terminology criteria for adverse events (VCOG-CTCAE) following chemotherapy or biologic antineoplastic therapy in dogs and cats v1.0. Vet Compar Onco 2004; 2(4):194–213.

Conditional Approval Application Number 141-422, conditionally approved by FDA pending a full demonstration of effectiveness.

Manufactured by:

Oasmia Pharmaceutical AB

Uppsala, Sweden

Distributed by:

Oasmia Pharmaceutical Inc.

Matawan, NJ

Product inquiries should be directed to Oasmia Pharmaceutical Inc., 1-866-466-1226

Product of Sweden

Issued JUL 2015

Oasmia Logo

Client Information Sheet

237104

Paccal Vet®-CA1

(paclitaxel for injection)

The client information sheet contains important information about Paccal Vet®-CA1. You should read this information each time your dog receives Taxol. This sheet is provided only as a summary and does not take the place of instructions from your veterinarian. Talk with your veterinarian if you do not understand any of this information or if you want to know more about Taxol.

Taxol is conditionally approved by the FDA. This means the product has a reasonable expectation that it is effective. A clinical trial will be conducted to determine effectiveness (how well the drug works). Conditionally approved animal drugs are limited to a specific use(s), which are listed below. Additional information on conditional approval can be found at http://www.fda.gov, search "conditional approval".

What is Taxol?


What do I need to tell my veterinarian before my dog is treated with Taxol?

Tell your veterinarian:


How is my dog given Taxol?


How will Taxol affect my dog?


What are some possible side effects of Taxol?

The most frequent side effects are:


Your veterinarian will evaluate bloodwork and physical examinations regularly to monitor for side effects.

Contact your veterinarian immediately if you notice any of the following changes in your dog:


There are other side effects that may occur. For more information about side effects ask your veterinarian.

How do I care for my dog after it is treated with Taxol?


This client information sheet gives the most important information about Taxol. For more information about Taxol, talk to your veterinarian.

To report a suspected side effect call Oasmia Pharmaceutical Inc. at 1-866-466-1226.

For additional information about adverse drug experience reporting for animal drugs, contact the FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth.

Paccal Vet® is a registered trademark of Oasmia Pharmaceutical AB.

Manufactured by:

Oasmia Pharmaceutical AB

Uppsala, Sweden

Distributed by:

Oasmia Pharmaceutical Inc.

Matawan, NJ 07747 USA

Product of Sweden

Issued JUL 2015

OAS-OAS/PLV/60/US/CIS-001

Oasmia Logo

Paccal Vet®-CA1

(paclitaxel for injection)

60 mg Taxol per vial

Antineoplastic

Single Use Vial

For IV use in dogs only

Conditionally approved by FDA pending a full demonstration of effectiveness under application number 141-422.

Indication: See package insert for the indications.

Caution: Federal (USA) law restricts this drug for use by or on the order of a licensed veterinarian. Use only as directed. It is a violation of Federal law to use this product other than as directed in the labeling.

Taxol pharmaceutical active ingredients containing related brand and generic drugs:


Taxol available forms, composition, doses:


Taxol destination | category:


Taxol Anatomical Therapeutic Chemical codes:


Taxol pharmaceutical companies:


References

  1. Dailymed."PACCAL VET-CA1 (PACLITAXEL) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION [OASMIA PHARMACEUTICAL AB]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."PACLITAXEL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "paclitaxel". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Taxol?

Depending on the reaction of the Taxol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Taxol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Taxol addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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