Onxol

Serious side effects have been reported with Onxol including the following:

• Large decreases in the number of white blood cells in your blood. This increases the risk that you will develop a serious infection. You should not receive Onxol if you already have a low number of white blood cells. Your doctor will order laboratory tests before and during your treatment to check the number of white blood cells in your blood. Your doctor will delay or interrupt your treatment if the number of white blood cells is too low. Call your doctor immediately if you have all or some of the following symptoms:
  • temperature greater than 100.4 °F (38 °C)
  • sore throat
  • cough
  • chills
  • difficult, frequent, and/or painful urination
• Severe allergic reactions. Onxol is manufactured with polyoxyethylated castor oil, you may experience a serious or life-threatening allergic reaction. You will receive medications to help prevent an allergic reaction before you receive each dose of Onxol. Tell your doctor if you experience any of the following symptoms of an allergic reaction:
  • itching
  • sudden difficulty breathing
  • sudden and abnormal swelling of the lips, tongue, and/or throat
  • sudden onset red blister-like skin rash
  • flushing
  • fast heartbeat
  • sudden drop in blood pressure
  • dizziness
  • fainting
• Low blood pressure, high blood pressure, and/or abnormally slow heart rate during infusion. Occasionally, low blood pressure, high blood pressure, and/or abnormally slow heart rates are reported during infusions of Onxol. Be sure to inform your physician if you have any blood pressure or heart rhythm disorders before beginning treatment with Onxol.
• Injection site reactions. Injection site reactions ranging in severity from mild to severe have been known to occur with infusions of Onxol. Reported symptoms have included skin redness, tenderness, discoloration, and/or swelling at the injection site. Severe reactions may occur if Onxol is accidentally injected under the skin instead of into a vein. Your physician will monitor you during your infusion to ensure that these reactions are treated if they occur.

​Keep all appointments with your doctor and the laboratory. Your doctor will order certain tests to check your body's response to Onxol.

Do not receive Onxol if:

• you are allergic to any of the ingredients in Onxol
• are allergic to medicines containing polyoxyl 35 castor oil
• you have low white blood cell counts

You should not receive this medication if you are allergic to paclitaxel, or to other medications that contain an ingredient called Cremophor EL (polyoxyethylated castor oil). This includes cyclosporine and teniposide.

To make sure paclitaxel is safe for you, tell your doctor if you have:

• HIV, AIDS, or Kaposi's sarcoma;

• heart disease;

• high blood pressure; or

• liver disease.

Do not receive paclitaxel if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether paclitaxel passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using paclitaxel.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• fever, chills, body aches, flu symptoms, sores in your mouth and throat;

• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• flushing (warmth, redness, or tingly feeling);

• slow heart rate, feeling like you might pass out;

• seizure (convulsions);

• chest pain, dry cough, wheezing, feeling short of breath;

• numbness, tingling, or burning pain in your hands or feet;

• jaundice (yellowing of the skin or eyes); or

• severe redness or swelling, severe irritation, a hard lump, or skin changes where the injection was given.

Common side effects may include:

• mild nausea, vomiting, diarrhea, constipation;

• weakness;

• joint or muscle pain;

• darkening of your skin or nails; or

• temporary hair loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Black or tarry stools
• blurred vision
• burning, numbness, tingling, or painful sensations
• confusion
• cough or hoarseness with fever or chills
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• feeling of warmth
• fever or chills
• lower back or side pain
• painful or difficult urination
• pale skin
• redness of the face, neck, arms, and occasionally, upper chest
• shortness of breath
• skin rash or itching
• sore throat
• sweating
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• weakness in the arms, hands, legs, or feet

• Blood in the urine or stools
• difficult or labored breathing
• pinpoint red spots on the skin
• shortness of breath (severe)
• slow heartbeat
• tightness in the chest
• wheezing

• Anxiety
• blue lips, fingernails, or skin
• difficult or troubled breathing
• fainting
• fast heartbeat
• irregular, fast or slow, or shallow breathing
• sudden shortness of breath

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
• cracked lips
• diarrhea
• difficulty with swallowing
• hair loss
• nausea or vomiting
• numbness, burning, or tingling in the hands or feet
• pain in the joints or muscles, especially in the arms or legs
• thinning of the hair

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.

Following intravenous administration of paclitaxel, paclitaxel plasma concentrations declined in a biphasic manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.

Pharmacokinetic parameters of paclitaxel following 3 and 24 hour infusions of paclitaxel at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table:

It appeared that with the 24 hour infusion of paclitaxel, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the CMAX by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3 hour infusion, for a 30% increase in dose, the CMAX and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24 hour infusion of paclitaxel, ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single doses of 15 to 135 mg/m2 given by 1 hour infusions (n=15), 30 to 275 mg/m2 given by 6 hour infusions (n=36), and 200 to 275 mg/m2 given by a 24 hour infusions (n=54) in Phase 1 & 2 studies. Values for CL T and volume of distribution were consistent with the findings in the Phase 3 study.

In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicate that between 89-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

After intravenous administration of 15 to 275 mg/m2 doses of paclitaxel as 1, 6, or 24 hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In 5 patients administered a 225 or 250 mg/m2 dose of radio-labeled paclitaxel as a 3 hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6-α, 3’-p-dihydroxypaclitaxel by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See “PRECAUTIONS: Drug Interactions” section.) The effect of ranal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

Ovarian Carcinoma

Second-Line Data: Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of paclitaxel in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients), utilized an initial dose of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in these two studies were 22% (95% Cl = 11% to 37%) and 30% (95% Cl = 18% to 46%) with a total of six complete and 18 partial responses in 92 patients. The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5 to 15.8 months) and 7.5 months (range: 5.3 to 17.4 months), respectively. The median survival was 8.1 months (range: 0.2 to 36.7 months) and 15.9 months (range: 1.8 to 34.5+ months).

The Phase 3 study had a bifactorial design and compared the efficacy and safety of paclitaxel, administered at two different doses (135 or 175 mg/m2) and schedules (3 or 24 hour infusion). The overall response rate for the 407 patients was 16.2% (95% Cl = 12.8% to 20.2%), with 6 complete and 60 partial responses. Duration of responses, measured from the first day of treatment was 8.3 months (range: 3.2 to 21.6 months). Median time to progression was 3.7 months (range: 0.1+ to 25.1+ months). Median survival was 11.5 months (range: 0.2 to 26.3 + months).

Response rates, median survival and median time to progression for the 4 arms are given in the following table:

Analyses were performed as planned by the bifactorial study design described in the protocol, by comparing the two doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the two schedules irrespective of dose. Patients receiving the 175 mg/m2 dose had a response rate similar to that of those receiving the 135 mg/m2 dose: 18% vs. 14% (p=0.28). No difference in response rate was detected when comparing the 3 hour with the 24 hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2 dose of paclitaxel had a longer time to progression than those receiving the 135 mg/m2 dose: median 4.2 vs. 3.1 months (p=0.03). The median time to progression for patients receiving the 3 hours vs. the 24 hour infusion was 4.0 months vs. 3.7 months respectively. Median survival was 11.6 months in patients receiving the 175 mg/m2 dose of paclitaxel and 11.0 months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months for patients receiving the 3-hour infusion of paclitaxel and 11.2 months for patients receiving the 24-hour infusion (p=0.91). These statistical analyses should be viewed with caution because of the multiple comparisons made.

Paclitaxel remained active in patients who had developed resistance to platinum containing therapy (defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical studies.

The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in ten clinical studies. These adverse events and adverse events from the Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 4 & 5) and narrative form.

The results of the randomized study support the use of paclitaxel injection at doses of 135 to 175 mg/m2, administered by a 3 hour intravenous infusion. The same doses administered by 24 hour infusion were more toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced superior efficacy.

Breast Carcinoma

After Failure of Initial Chemotherapy: Data from 83 patients accrued in three Phase 2 open label studies and from 471 patients enrolled in a Phase 3 randomized study were available to support the use of paclitaxel in patients with metastatic breast carcinoma.

Phase 2 Open Label Studies: Two studies were conducted in 53 patients previously treated with a maximum of one prior chemotherapeutic regimen. Paclitaxel was administered in these 2 trials as a 24 hour infusion at initial doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The response rates were 57% (95% Cl: 37% - 75%) and 52% (95% Cl: 32% - 72%), respectively. The third Phase 2 study was conducted in extensively pretreated patients who had failed anthracycline therapy and who had received a minimum of 2 chemotherapy regimens for the treatment of metastatic disease. The dose of paclitaxel was 200 mg/m2 as a 24 hour infusion with G-CSF support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% Cl: 15% - 50%).

Phase 3 Randomized Study: This multicenter trial was conducted in patients previously treated with one or two regimens of chemotherapy. Patients were randomized to receive paclitaxel at a dose of either 175 mg/m2 or 135 mg/m2 given as a 3 hour infusion. In the 471 patients enrolled, 60% had symptomatic disease with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease considered resistant to this class of agents.

The overall response rate for the 454 evaluable patients was 26% (95% Cl: 22% - 30%), with 17 complete and 99 partial responses. The median duration of response, measured from the first day of treatment, was 8.1 months (range: 3.4 – 18.1+ months). Overall for the 471 patients, the median time to progression was 3.5 months (range: 0.03 – 17.1 months). Median survival was 11.7 months (range: 0-18.9 months).

Response rates, median survival and median time to progression for the 2 arms are given in the following table:

The adverse event profile of the patients who received single-agent paclitaxel in the phase 3 study was consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE REACTIONS section in tabular (Tables 4 & 6) and narrative form.

There is no known antidote for Onxol overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Overdoses in pediatric patients may be associated with acute ethanol toxicity (See PRECAUTIONS: Pediatric Use section).

NDC 0172-3754-73 Onxol (paclitaxel) Injection is available as a 30 mg/5 mL multi-dose vial individually packaged in a carton.

NDC 0172-3756-75 Onxol (paclitaxel) Injection is available as a 150 mg/25 mL multi-dose vial individually packaged in a carton.

NDC 0172-3753-77 Onxol (paclitaxel) Injection is available as a 300 mg/50 mL multi-dose vial individually packaged in a carton.

Storage: Store the vials in original cartons between 20˚-25˚C (68˚-77˚F). Retain in the original package to protect from light.

Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published 1-7. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Onxol® (paclitaxel) Injection
(generic name = paclitaxel)

What is Onxol® Injection?

Paclitaxel is a prescription cancer medicine, it is injected into a vein and it is used to treat different types of tumors. The tumors include advanced ovary and breast cancer.

What is cancer?

Under normal conditions, the cells in your body divide and grow in an orderly, controlled way. Cell division and growth are necessary for the human body to perform its functions and to repair itself, when necessary. Cancer cells are different from normal cells because they are not able to control their own growth. The reasons for this abnormal growth are not yet fully understood.

A tumor is a mass of unhealthy cells that are dividing and growing fast and in an uncontrolled way. When a tumor invades surrounding health body tissue it is known as a malignant tumor. A malignant tumor can spread (metastasize) from its original site to other parts of the body if not found and treated early.

How does Onxol Injection work?

Onxol Injection is a type of medical treatment called chemotherapy. The purpose of chemotherapy is to kill cancer cells or prevent their growth.

All cells, whether they are healthy cells or cancer cells, go through several stages of growth. During one of the stages, the cell starts to divide. Onxol may stop the cells from dividing and growing, so they eventually die. In addition, normal cells may also be affected by Onxol causing some of the side effects. (See What are the possible side effects of paclitaxel? below.)

Who should not take Onxol?

Patients who have a history of hypersensitivity (allergic reactions) to Onxol or other drugs containing polyoxyl 35 castor oil, like cyclosporine or teniposide, should not be given Onxol. In addition, Onxol should not be given to patients with dangerously low white blood cell counts.

How is Onxol Injection given?

Onxol is injected into a vein (intravenous (IV) infusion). Before you are given Onxol, you will have to take certain medicines (premedications) to prevent or reduce the chance you will have a serious allergic reaction. Such reactions have occurred in a small number of patients while receiving paclitaxel and have been rarely fatal. (See What are the possible side effects of paclitaxel? below.)

What are the possible side effects of paclitaxel?

Most patients taking paclitaxel will experience side effects, although it is not always possible to tell whether such effects are caused by paclitaxel, another medicine they may be taking, or the cancer itself. Important side effects are described below; however some patients may experience other side effects that are less common. Report any unusual symptoms to your doctor.

Important side effects observed in studies of patients taking paclitaxel were as follows:

allergic reactions. Allergic reactions can vary in degrees of severity. They may cause death in rare cases. When a severe allergic reaction develops, it usually occurs at the time the medicine is entering the body (during paclitaxel infusion). Allergic reactions may cause trouble breathing, very low blood pressure, sudden swelling, and/or hives or rash. The likelihood of a serious allergic reaction is lowered by the use of several kinds of medicines that are given to you before the paclitaxel infusion.

heart and blood vessel (cardiovascular) effects. Paclitaxel may cause a drop in heart rate (bradycardia) and low blood pressure (hypotension). The patient usually does not notice these changes. These changes usually do not require treatment. Your heart function, including blood pressure and pulse, will be monitored while you are receiving the medicine. You should notify your doctor if you have a history of heart disease.

infections due to low white blood cell count. Among the body’s defenses against bacterial infections are white blood cells. Between your paclitaxel treatment cycles, you will often have blood tests to check your white blood cell counts. Paclitaxel usually causes a brief drop in white blood cells. If you have a fever (temperature above 100.4° F) or other signs of infection, tell your doctor right away. Sometimes serious infections develop that require treatment in the hospital with antibiotics. Serious illness or death could result if such infections are not treated when white blood cells counts are low.

hair loss. Complete hair loss, or alopecia, almost always occurs with paclitaxel. This usually involves the loss of eyebrows, eyelashes, and pubic hair, as well as scalp hair. It can occur suddenly after treatment has begun, but usually happens 14 to 21 days after treatment. Hair generally grows back after you’ve finished your paclitaxel treatment.

joint and muscle pain. You may get joint and muscle pain a few days after your paclitaxel treatment. These symptoms usually disappear in a few days. Although pain medicine may not be necessary, tell your doctor if you are uncomfortable.

irritation at the injection site. Paclitaxel sometimes causes irritation at the site where it enters the vein. Reactions may include discomfort, redness, swelling, inflammation (of the surrounding skin or of the vein itself) and ulceration (open sores). These reactions are usually caused by the IV (intravenous) fluid leaking into the surrounding area. If you notice anything unusual at the site of the injection (needle), either during or after treatment, tell your doctor right away.

low red blood cell count. Red blood cells deliver oxygen to tissues throughout all part of the body and take carbon dioxide from the tissues by using a protein called hemoglobin. A lowering of the volume of red blood cells may occur following paclitaxel treatment causing anemia. Some patients may need a blood transfusion to treat the anemia. Patients can feel tired, tire easily, appear pale, and become short of breath. Contact your doctor if you experience any of these symptoms following paclitaxel treatment.

mouth or lip sores (mucositis). Some patients develop redness and/or sores in the mouth or on the lips. These symptoms might occur a few days after the paclitaxel treatment and usually decrease or disappear within one week. Talk with your doctor about proper mouth care and other ways to prevent or reduce your chances of developing mucositis.

numbness, tingling, or burning in the hands and/or feet (neuropathy). These symptoms occur often with paclitaxel and usually get better or go away without medication within several months of completing treatment. However, if you are uncomfortable, tell your doctor so that he/she can decide the best approach for relief of your symptoms.

stomach upset and diarrhea. Some patients experience nausea, vomiting, and/or diarrhea following paclitaxel use. If you experience nausea or stomach upset, tell your doctor. Diarrhea will usually disappear without treatment; however, if you experience severe abdominal or stomach area pain and/or severe diarrhea, tell your doctor right away.

Talk with your doctor or other healthcare professional to discuss ways to prevent or reduce some of these side effects. Because this leaflet does not include all possible side effects that can occur with paclitaxel, it is important to talk with your doctor about other possible side effects.

Can I take Onxol if I am pregnant or nursing a baby?

Onxol could harm the fetus when given to a pregnant woman. Women should avoid becoming pregnant while they are undergoing treatment with paclitaxel. Tell your doctor if you become pregnant or plan to become pregnant while taking Onxol. Because studies have shown paclitaxel to be present in the breast milk of animals receiving the drug, it may be present in human breast milk as well. Therefore, nursing a baby while taking paclitaxel is NOT recommended.

This medicine was prescribed for your particular condition. This summary does not include everything there is to know about paclitaxel. Medications are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about paclitaxel, your doctor or pharmacist have the complete prescribing information upon which this guide is based. You may want to read it and discuss it with your doctor. Remember, no written summary can replace careful discussion with your doctor.

This Patient Information Leaflet has been approved
by the U.S. Food and Drug Administration
L5099, issue date 08/00
(L5130 06/05)
481407