DRUGS & SUPPLEMENTS

Colhidrol

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Colhidrol uses


1. INDICATIONS AND USAGE

Colhidrol hydrochloride, USP is an anthracycline topoisomerase II inhibitor indicated:

  • as a component of multiagent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.
  • for the treatment of: acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, Non-Hodgkin lymphoma, metastatic breast cancer, metastatic Wilms' tumor, metastatic neuroblastoma,metastatic soft tissue sarcoma, metastatic bone sarcomas, metastatic ovarian carcinoma, metastatic transitional cell bladder carcinoma, metastatic thyroid carcinoma, metastatic gastric carcinoma, metastatic bronchogenic carcinoma (1.2).

1.1 Adjuvant Breast Cancer

Colhidrol hydrochloride, USP is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer .

1.2 Other Cancers

Colhidrol hydrochloride, USP is indicated for the treatment of

  • acute lymphoblastic leukemia
  • acute myeloblastic leukemia
  • Hodgkin lymphoma
  • non-Hodgkin lymphoma (NHL)
  • metastatic breast cancer
  • metastatic Wilms' tumor
  • metastatic neuroblastoma
  • metastatic soft tissue sarcoma
  • metastatic bone sarcoma
  • metastatic ovarian carcinoma
  • metastatic transitional cell bladder carcinoma
  • metastatic thyroid carcinoma
  • metastatic gastric carcinoma
  • metastatic bronchogenic carcinoma
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2. DOSAGE AND ADMINISTRATION

  • Single agent: 60 to 75 mg/m2 given intravenously every 21 days.
  • In combination therapy: 40 to 75 mg/m2 given intravenously every 21 to 28 days (2.1).
  • Discontinue Colhidrol hydrochloride in patients who develop signs or symptoms of cardiomyopathy (2.2).
  • Reduce dose in patients with hepatic impairment (2.2).

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of Colhidrol hydrochloride, USP is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles .

Metastatic Disease, Leukemia, or Lymphoma

  • The recommended dose of Colhidrol hydrochloride, USP when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days.
  • The recommended dose of Colhidrol hydrochloride, USP, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days.
  • Consider use of the lower Colhidrol dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients.
  • Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy .

2.2 Dose Modifications

Cardiac Impairment

Discontinue Colhidrol in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Colhidrol hydrochloride, USP is contraindicated in patients with severe hepatic impairment .

Decrease the dose of Colhidrol hydrochloride, USP in patients with elevated serum total bilirubin concentrations as follows:


Serum bilirubin concentration


Doxorubicin hydrochloride, USP Dose reduction


1.2 to 3 mg/dL


50 %


3.1 to 5 mg/dL


75 %


greater than 5 mg/dL


Do not initiate doxorubicin hydrochloride, USP

Discontinue doxorubicin hydrochloride, USP



2.3 Preparation and Administration

Preparation of Colhidrol Hydrochloride for injection, USP

Reconstitute Colhidrol hydrochloride for injection, USP with 0.9% Sodium Chloride Injection, USP to obtain a final concentration of 2 mg per mL as follows:

  • 5 mL 0.9% Sodium Chloride Injection, USP to reconstitute 10 mg Colhidrol hydrochloride, USP vial.
  • 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg Colhidrol hydrochloride, USP vial.

Gently shake vial until the contents have dissolved.

Protect reconstituted solution from light.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

Storage of vials of Colhidrol hydrochloride for injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [150 to 300 C ] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Administration by Intravenous Injection:

  • Administer Colhidrol hydrochloride, USP as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
  • Administer Colhidrol hydrochloride, USP intravenously over 3 to 10 minutes. Decrease the rate of Colhidrol hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.

Administration by Continuous Intravenous Infusion:

Infuse only through a central catheter. Decrease the rate of Colhidrol hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.

Protect from light from preparation for infusion until completion of infusion.

  • Infuse only through a central catheter. Decrease the rate of Colhidrol hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
  • Protect from light from preparation for infusion until completion of infusion.

Management of Suspected Extravasation

Discontinue Colhidrol hydrochloride, USP for burning or stinging sensation or other evidence indicating peri venous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:

  • Do not remove the needle until attempts are made to aspirate extravasated fluid.
  • Do not flush the line.
  • Avoid applying pressure to the site.
  • Apply ice to the site intermittently for 15 min 4 times a day for 3 days.
  • If the extravasation is in an extremity, elevate the extremity.
  • In adults, consider administration of dexrazoxane .

Incompatibility with Other Drugs

Do not admix Colhidrol hydrochloride, USP with other drugs. If Colhidrol hydrochloride, USP is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of Colhidrol hydrochloride, USP.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of Colhidrol hydrochloride, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.

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3. DOSAGE FORMS AND STRENGTHS

  • Colhidrol hydrochloride for injection: Vials contain 10 mg and 50 mg as a lyophilized powder (3)

Colhidrol hydrochloride for injection, USP: Vials contain 10 mg and 50 mg Colhidrol hydrochloride as a red-orange lyophilized powder.

4. CONTRAINDICATIONS

  • Severe myocardial insufficiency (4)
  • Recent myocardial infarction (4)
  • Severe persistent drug-induced myelosuppression (4)
  • Severe hepatic impairment (4)
  • Hypersensitivity to Colhidrol hydrochloride (4)

Colhidrol hydrochloride is contraindicated in patients with:

  • Severe myocardial insufficiency
  • Recent (occurring within the past 4-6 weeks) myocardial infarction
  • Severe persistent drug-induced myelosuppression
  • Severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL)
  • Severe hypersensitivity reaction to Colhidrol hydrochloride including anaphylaxis
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5. WARNINGS AND PRECAUTIONS

  • Radiation-induced toxicity can be increased by the administration of Colhidrol hydrochloride. Radiation recall can occur in patients who receive Colhidrol hydrochloride after prior radiation therapy.
  • Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus (5.8).

5.1 Cardiomyopathy and Arrhythmias

Cardiomyopathy

Colhidrol hydrochloride can result in myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy is generally proportional to the cumulative exposure. Include prior doses of other anthracyclines or anthracenediones in calculations of total cumulative dosage for Colhidrol hydrochloride. Cardiomyopathy may develop during treatment or up to several years after completion of treatment and can include decrease in LVEF and signs and symptoms of congestive heart failure. The probability of developing cardiomyopathy is estimated to be 1 to 2% at a total cumulative dose of 300 mg/m2 of Colhidrol hydrochloride, 3 to 5% at a dose of 400 mg/m2, 5 to 8% at a dose of 450 mg/m2, and 6 to 20% at a dose of 500 mg/m2, when Colhidrol hydrochloride is administered every 3 weeks. There is an additive or potentially synergistic increase in the risk of cardiomyopathy in patients who have received radiotherapy to the mediastinum or concomitant therapy with other known cardiotoxic agents such as cyclophosphamide and trastuzumab.

Pericarditis and myocarditis have also been reported during or following Colhidrol hydrochloride treatment.

Assess left ventricular cardiac function (e.g., MUGA or echocardiogram) prior to initiation of Colhidrol hydrochloride, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Increase the frequency of assessments as the cumulative dose exceeds 300 mg/m2. Use the same method of assessment of LVEF at all time points .

Consider the use of dexrazoxane to reduce the incidence and severity of cardiomyopathy due to Colhidrol hydrochloride administration in patients who have received a cumulative Colhidrol hydrochloride dose of 300 mg/m2 and who will continue to receive Colhidrol hydrochloride.

Arrhythmias

Colhidrol hydrochloride can result in arrhythmias, including life-threatening arrhythmias, during or within a few hours after Colhidrol hydrochloride administration and at any time point during treatment. Tachyarrhythmias, including sinus tachycardia, premature ventricular contractions, and ventricular tachycardia, as well as bradycardia may occur. Electrocardiographic changes including non-specific ST-T wave changes, atrioventricular and bundle-branch block can also occur. These electrocardiographic changes may be transient and self-limited and may not require dose-modifications of Colhidrol hydrochloride.

5.2 Secondary Malignancies

The risk of developing secondary acute myelogenous leukemia and myelodysplastic syndrome (MDS) is increased following treatment with Colhidrol hydrochloride. Cumulative incidences ranged from 0.2% at five years to 1.5% at 10 years in two separate trials involving the adjuvant treatment of women with breast cancer. These leukemias generally occur within 1 to 3 years of treatment.

5.3 Extravasation and Tissue Necrosis

Extravasation of doxorubicin hydrochloride can result in severe local tissue injury manifesting as blistering, ulceration, and necrosis requiring wide excision of the affected area and skin grafting. When given via a peripheral venous line, infuse Colhidrol over 10 minutes or less to minimize the risk of thrombosis or perivenous extravasation. If signs or symptoms of extravasation occur, immediately terminate the injection or infusion . Extravasation may be present in patients who do not experience a stinging or burning sensation or when blood return is present on aspiration of the infusion needle. If extravasation is suspected, apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days. If appropriate, administer dexrazoxane at the site of extravasation as soon as possible and within the first 6 hours after extravasation.

5.4 Severe Myelosuppression

Colhidrol hydrochloride can cause myelosuppression. In Study 1, the incidence of severe myelosuppression was: grade 4 leukopenia, grade 3 leukopenia (3%), and grade 4 thrombocytopenia (0.1%). A dose-dependent, reversible neutropenia is the predominant manifestation of hematologic toxicity from Colhidrol hydrochloride. When Colhidrol hydrochloride is administered every 21 days, the neutrophil count reaches its nadir 10 to 14 days after administration with recovery usually occurring by the 21st day.

Obtain baseline assessment of blood counts and carefully monitor patients during treatment for possible clinical complications due to myelosuppression.

5.5 Use in Patients with Hepatic Impairment

The clearance of Colhidrol is decreased in patients with elevated serum bilirubin with an increased risk of toxicity . Reduce the dose of Colhidrol hydrochloride in patients with serum bilirubin levels of 1.2 to 5 mg/dL . Colhidrol is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin level greater than 5 mg/dL) . Obtain liver tests including SGOT, SGPT, alkaline phosphatase, and bilirubin prior to and during Colhidrol hydrochloride therapy.

5.6 Tumor Lysis Syndrome

Colhidrol hydrochloride may induce tumor lysis syndrome in patients with rapidly growing tumors. Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.

5.7 Radiation Sensitization and Radiation Recall

Colhidrol hydrochloride can increase radiation-induced toxicity to the myocardium, mucosa, skin, and liver. Radiation recall, including but not limited to cutaneous and pulmonary toxicity, can occur in patients who receive Colhidrol hydrochloride after prior radiation therapy.

5.8 Embryofetal Toxicity

Colhidrol hydrochloride can cause fetal harm when administered to a pregnant woman. Colhidrol hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses lower than the recommended human dose.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus .

Advise female patients of reproductive potential to use highly effective contraception during treatment with Colhidrol hydrochloride and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Colhidrol hydrochloride .

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6. ADVERSE REACTIONS

The most common adverse drug reactions are alopecia, nausea and vomiting (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The following adverse reactions are discussed in more detail in other sections of the labeling.

  • Cardiomyopathy and Arrhythmias
  • Secondary Malignancies
  • Extravasation and Tissue Necrosis
  • Severe Myelosuppression
  • Tumor Lysis Syndrome
  • Radiation Sensitization and Radiation Recall

6.1 Clinical Trial Experience in Breast Cancer

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data below were collected from 1492 women who received Colhidrol hydrochloride at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) every 3 weeks for 4 cycles for the adjuvant treatment of axillary lymph node positive breast cancer. The median number of cycles received was 4. Selected adverse reactions reported in this study are provided in Table 1. No treatment-related deaths were reported in patients on either arm of the study.

*Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF


AC*


Conventional

CMF


N=1492


N=739


Adverse reactions, % of patients


Leukopenia


Grade 3 (1,000 to 1,999 /mm3)


3.4


9.4


Grade 4 (<1000 /mm3)


0.3


0.3


Thrombocytopenia


Grade 3 (25,000 to 49,999 /mm3)


0


0.3


Grade 4 (<25,000 /mm3)


0.1


0


Shock, sepsis


2


1


Systemic infection


2


1


Vomiting


Vomiting ≤12 hours


34


25


Vomiting >12 hours


37


12


Intractable


5


2


Alopecia


92


71


Cardiac dysfunction


Asymptomatic


0.2


0.1


Transient


0.1


0


Symptomatic


0.1


0

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Colhidrol hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac-cardiogenic shock

Cutaneous-Skin and nail hyperpigmentation, oncolysis, rash, itching, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia

Gastrointestinal-Nausea, mucositis, stomatitis, necrotizing colitis, typhlitis, gastric erosions, gastrointestinal tract bleeding, hematochezia, esophagitis, anorexia, abdominal pain, dehydration, diarrhea, hyperpigmentation of the oral mucosa

Hypersensitivity-Anaphylaxis

Laboratory Abnormalities-Increased alanine aminotransferase, increased aspartate aminotransferase

Neurological-Peripheral sensory and motor neuropathy, seizures, coma

Ocular-Conjunctivitis, keratitis, lacrimation

Vascular-Phlebosclerosis, phlebitis/thrombophlebitis, hot flashes, thromboembolism

Other-Malaise/asthenia, fever, chills, weight gain

7. DRUG INTERACTIONS

  • Avoid concurrent use of Colhidrol hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, and/or P-gp.
  • Do not administer Colhidrol hydrochloride in combination with trastuzumab due to increased risk of cardiac dysfunction (5.1, 7.2).

7.1 Effect of CYP3A4 Inhibitors, Inducers and P-gp

Colhidrol is a major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect of Colhidrol. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John's Wort) and P-gp inducers may decrease the concentration of Colhidrol. Avoid concurrent use of Colhidrol hydrochloride with inhibitors and inducers of CYP3A4, CYP2D6, or P-gp.

7.2 Trastuzumab

Concurrent use of trastuzumab and Colhidrol hydrochloride results in an increased risk of cardiac dysfunction. Avoid concurrent administration of Colhidrol and trastuzumab. The appropriate interval for administering Colhidrol following trastuzumab therapy has not been determined .

7.3 Paclitaxel

Paclitaxel, when given prior to Colhidrol hydrochloride, increases the plasma-concentrations of Colhidrol and its metabolites. Administer Colhidrol hydrochloride prior to paclitaxel if used concomitantly.

7.4 Dexrazoxane

Do not administer dexrazoxane as a cardioprotectant at the initiation of Colhidrol hydrochloride containing chemotherapy regimens. In a randomized trial in women with metastatic breast cancer, initiation of dexrazoxane with Colhidrol hydrochloride-based chemotherapy resulted in a significantly lower tumor response rate and shorter time to progression than in women who received Colhidrol hydrochloride-based chemotherapy alone.

7.5 6-Mercaptopurine

Colhidrol hydrochloride may potentiate 6-mercaptopurine-induced hepatotoxicity. In 11 patients with refractory leukemia treated with 6-mercaptopurine (500 mg/m2 intravenously daily for 5 days per cycle every 2-3 weeks) and Colhidrol hydrochloride (50 mg/m2 intravenous once per cycle every 2-3 weeks) alone or with vincristine and prednisone, all developed hepatic dysfunction manifested by elevations of total serum bilirubin, alkaline phosphatase and aspartate aminotransferase.

8. USE IN SPECIFIC POPULATIONS

  • Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
  • Pediatric Use: Recommend long-term follow-up cardiac evaluations due to risk of delayed cardiotoxicity (8.4).
  • Females and Males of Reproductive Potential: May impair fertility. Counsel female and male patients on pregnancy planning and prevention (8.6).

8.1 Pregnancy

Pregnancy Category D

Risk Summary

Colhidrol hydrochloride can cause fetal harm when administered to a pregnant woman. Colhidrol hydrochloride was teratogenic and embryotoxic in rats and rabbits at doses approximately 0.07 times the recommended human dose of 60 mg/m2. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data

Colhidrol hydrochloride was teratogenic and embryotoxic at doses of 0.8 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) when administered during the period of organogenesis in rats. Teratogenicity and embryotoxicity were also seen using discrete periods of treatment. The most susceptible was the 6- to 9-day gestation period at doses of 1.25 mg/kg/day and greater. Characteristic malformations included esophageal and intestinal atresia, tracheo-esophageal fistula, hypoplasia of the urinary bladder, and cardiovascular anomalies. Colhidrol hydrochloride was embryotoxic (increase in embryofetal deaths) and abortifacient at 0.4 mg/kg/day (about 0.07 times the recommended human dose based on body surface area) in rabbits when administered during the period of organogenesis.

8.3 Nursing Mothers

Colhidrol has been detected in the milk of at least one lactating patient . Because of the potential for serious adverse reactions in nursing infants from Colhidrol hydrochloride, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Based on postmarketing reports, pediatric patients treated with Colhidrol hydrochloride are at risk for developing late cardiovascular dysfunction. Risk factors include young age at treatment (especially < 5 years), high cumulative doses and receipt of combined modality therapy. Long-term periodic cardiovascular monitoring is recommended for all pediatric patients who have received Colhidrol hydrochloride. Colhidrol hydrochloride, as a component of intensive chemotherapy regimens administered to pediatric patients, may contribute to prepubertal growth failure and may also contribute to gonadal impairment, which is usually temporary.

There are no recommended dose adjustments based on age. Colhidrol clearance was increased in patients aged 2 years to 20 years as compared to adults, while Colhidrol clearance was similar in children less than 2 years as compared to adults .

8.5 Geriatric Use

Clinical experience in patients who were 65 years of age and older who received Colhidrol hydrochloride-based chemotherapy regimens for metastatic breast cancer showed no overall differences in safety and effectiveness compared with younger patients.

8.6 Females and Males of Reproductive Potential

Contraception

Females

Colhidrol hydrochloride can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment with Colhidrol hydrochloride and for 6 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Colhidrol hydrochloride .

Males

Colhidrol hydrochloride may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and for 6 months after treatment .

Infertility

Females

In females of reproductive potential, Colhidrol hydrochloride may cause infertility and result in amenorrhea. Premature menopause can occur. Recovery of menses and ovulation is related to age at treatment .

Males

Colhidrol hydrochloride may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy.

8.7 Hepatic Impairment

The clearance of Colhidrol was reduced in patients with elevated serum bilirubin levels. Reduce the dose of Colhidrol hydrochloride in patients with serum bilirubin levels greater than 1.2 mg/dL . Colhidrol hydrochloride is contraindicated in patients with severe hepatic impairment (defined as Child Pugh Class C or serum bilirubin levels greater than 5 mg/dL) .

10. OVERDOSAGE

Few cases of overdose have been described. A 58-year-old man with acute lymphoblastic leukemia received 10-fold overdose of Colhidrol hydrochloride (300 mg/m2) in one day. He was treated with charcoal filtration, hemopoietic growth factor (G-CSF), proton pump inhibitor and antimicrobial prophylaxis. The patient suffered sinus tachycardia, grade 4 neutropenia and thrombocytopenia for 11 days, severe mucositis and sepsis. The patient recovered completely 26 days after the overdose. A 17-year-old girl with osteogenic sarcoma received 150 mg of Colhidrol hydrochloride daily for 2 days (intended dose was 50 mg per day for 3 days). The patient developed severe mucositis on days 4-7 after the overdose and chills and pyrexia on day 7. The patient was treated with antibiotics and platelets and recovered 18 days after overdose.

11. DESCRIPTION

Colhidrol hydrochloride, USP is a cytotoxic, anthracycline, topoisomerase II inhibitor isolated from cultures of Streptomyces peucetius var. caesius. Chemically, Colhidrol hydrochloride, USP is: 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10 tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. The chemical structure of Colhidrol hydrochloride is:

Colhidrol Hydrochloride for Injection, USP is a sterile red-orange lyophilized powder, provided in single dose vial containing 10 mg, 50 mg Colhidrol HCl, USP.

Colhidrol Hydrochloride for Injection, USP

Each 10 mg lyophilized vial contains 10 mg of Colhidrol Hydrochloride, USP and 50 mg of Lactose Monohydrate, NF.

Each 50 mg lyophilized vial contains 50 mg of Colhidrol Hydrochloride, USP and 250 mg of Lactose Monohydrate, NF.

structure

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The cytotoxic effect of Colhidrol hydrochloride on malignant cells and its toxic effects on various organs are thought to be related to nucleotide base intercalation and cell membrane lipid binding activities of Colhidrol. Intercalation inhibits nucleotide replication and action of DNA and RNA polymerases. The interaction of Colhidrol with topoisomerase II to form DNA-cleavable complexes appears to be an important mechanism of Colhidrol hydrochloride cytocidal activity.

12.3 Pharmacokinetics

Pharmacokinetic studies conducted in patients with various types of tumors have shown that Colhidrol follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours. In four patients, Colhidrol demonstrated dose-independent pharmacokinetics across a dose range of 30 to 70 mg/m2.

Distribution

Steady-state distribution volume ranges from 809 to 1214 L/m2. Binding of Colhidrol and its major metabolite, doxorubicinol, to plasma proteins is about 75% and is independent of plasma concentration of Colhidrol up to 1.1 mcg/mL.

Colhidrol was measured in the milk of one lactating patient after therapy with 70 mg/m2 of Colhidrol hydrochloride given as a 15-minute intravenous infusion. The peak milk concentration at 24 hours after treatment was 4.4-fold greater than the corresponding plasma concentration. Colhidrol was detectable in the milk up to 72 hours.

Colhidrol does not cross the blood brain barrier.

Metabolism

Enzymatic reduction at the 7 position and cleavage of the daunosamine sugar yields aglycones which are accompanied by free radical formation, the local production of which may contribute to the cardiotoxic activity of Colhidrol hydrochloride. Disposition of doxorubicinol in patients is formation rate limited, with the terminal half-life of doxorubicinol being similar to Colhidrol. The relative exposure of doxorubicinol, i.e., the ratio between the AUC of doxorubicinol and the AUC of Colhidrol is approximately 0.5.

Excretion

Plasma clearance is in the range 324 to 809 mL/min/m2 and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days.

Systemic clearance of Colhidrol is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.

Pediatric patients

Following administration of doses ranging from 10 to 75 mg/m2 of Colhidrol hydrochloride to 60 children and adolescents ranging from 2 months to 20 years of age, Colhidrol clearance averaged 1443 ± 114 mL/min/m2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m2) was decreased compared with older children and approached the range of clearance values determined in adults .

Patient Gender

There is no recommended dose adjustment based on gender. A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median Colhidrol clearance in men compared to women (1088 mL/min/m2 versus 433 mL/min/m2). However, the terminal half-life of Colhidrol was longer in men compared to women (54 versus 35 hours).

Patients with hepatic impairment

The clearance of Colhidrol and doxorubicinol was reduced in patients with elevation in serum bilirubin .

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Colhidrol hydrochloride treatment results in an increased risk of secondary malignancies based on postmarketing reports . Colhidrol hydrochloride was mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay.

Colhidrol hydrochloride decreased fertility in female rats at the doses of 0.05 and 0.2 mg/kg/day (approximately 0.005 and 0.02 times the recommended human dose, based on body surface area).

A single intravenous dose of 0.1 mg/kg Colhidrol hydrochloride (approximately 0.01 times the recommended human dose based on body surface area) was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and oligospermia/hypospermia in rats. Colhidrol hydrochloride induces DNA damage in rabbit spermatozoa and dominant lethal mutations in mice.

14. CLINICAL STUDIES

The clinical efficacy of Colhidrol hydrochloride-containing regimens for the post-operative, adjuvant treatment of surgically resected breast cancer was evaluated in a meta-analysis conducted by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG meta-analyses compared cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7523 patients) and Colhidrol hydrochloride-containing regimens with CMF as an active control (6 trials including 3510 patients). Data from the meta-analysis of trials comparing CMF to no therapy were used to establish the historical treatment effect size for CMF regimens. The major efficacy outcome measures were disease-free survival (DFS) and overall survival (OS).

Of the 3510 women (2157 received Colhidrol hydrochloride-containing regimens and 1353 received CMF treatment) with early breast cancer involving axillary lymph nodes included in the six trials from the meta-analyses, approximately 70% were premenopausal and 30% were postmenopausal. At the time of the meta-analysis, 1745 first recurrences and 1348 deaths had occurred. The analyses demonstrated that Colhidrol hydrochloride-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS with a hazard ratio (HR) of 0.91 (95% CI, 0.82 to 1.01) and on OS with a HR of 0.91 (95% CI, 0.81 to 1.03). Results of these analyses for both DFS and OS are provided in Table 2 and Figures 1 and 2.

Abbreviations: DFS = disease free survival; OS = overall survival; AC = Colhidrol hydrochloride, cyclophosphamide; AVbCMF = Colhidrol hydrochloride, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, Colhidrol hydrochloride; FAC = 5-fluorouracil, Colhidrol hydrochloride, cyclophosphamide; FACV = 5-fluorouracil, Colhidrol hydrochloride, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval

* Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF.

** a hazard ratio of less than 1 indicates that the treatment with Colhidrol hydrochloride-containing regimens is associated with lower risk of disease recurrences or death compared to the treatment with CMF.

† Patients received alternating cycles of AVb and CMF.


Study

(starting year)


Regimens


No. of Cycles


No. of Patients


Doxorubicin -Containing

Regimens vs. CMF HR**

(95% CI)


DFS


OS


NSABP B-15

(1984)


AC


4


1562*


0.93 (0.82 to 1.06)


0.97 (0.83 to 1.12)


CMF


6


776


SECSG 2

(1976)


FAC


6


260


0.86 (0.66 to 1.13)


0.93 (0.69 to 1.26)


CMF


6


268


ONCOFRANCE

(1978)


FACV


12


138


0.71 (0.49 to 1.03)


0.65 (0.44 to 0.96)


CMF


12


113


SE Sweden BCG A

(1980)


AC


6


21


0.59 (0.22 to 1.61)


0.53 (0.21 to 1.37)


CMF


6


22


NSABC Israel Br0283

(1983)


AVbCMF†


4


55


6


0.91 (0.53 to 1.57)


0.88 (0.47 to 1.63)


CMF


6


50


Austrian BCSG 3

(1984)


CMFVA


6


121


1.07(0.73 to 1.55)


0.93 (0.64 to 1.35)


CMF


8


124


Combined Studies


Doxorubicin -Regimens CMF


Containing


2157


0.91 (0.82 to 1.01)


0.91 (0.81 to 1.03)


1353


Figure 1. Meta-analysis of Disease-Free Survival

Figure 2. Meta-analysis of Overall Survival

fig-1 fig-2

15. REFERENCES

  • "Hazardous Drugs". OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16. HOW SUPPLIED/STORAGE AND HANDLING

Colhidrol Hydrochloride for Injection, USP is supplied as a sterile red-orange lyophilized powder for intravenous use only, is available in single dose flip-top vials in the following package strengths:

NDC 67457-478-10: 10 mg vial; individually boxed.

NDC 67457-436-50: 50 mg vial; individually boxed.

Store unreconstituted vial at controlled room temperature, between 20°C to 25°C (68°F to 77°F). Protect vials from light. Retain in carton until time of use. Discard unused portion.

Reconstituted Solution Stability

After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 7 days at room temperature and under normal room light (100 foot-candles) and 15 days under refrigeration (2° to 8°C). It should be protected from exposure to sunlight. Discard any unused solution from the 10 mg and 50 mg single dose vials.

Handling and Disposal

Handle and dispose of Colhidrol Hydrochloride for Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

17. PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information).

Inform patients of the following:

  • Colhidrol hydrochloride can cause irreversible myocardial damage. Advise patients to contact a healthcare provider for symptoms of heart failure during or after treatment with Colhidrol hydrochloride .
  • There is an increased risk of treatment-related leukemia from Colhidrol hydrochloride .
  • Colhidrol hydrochloride can reduce the absolute neutrophil count resulting in an increased risk of infection. Advise patients to contact a healthcare provider for new onset fever or symptoms of infection .
  • Colhidrol hydrochloride can cause fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Colhidrol hydrochloride and for 6 months after treatment, and to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Colhidrol hydrochloride .
  • Colhidrol hydrochloride may induce chromosomal damage in sperm, which may lead to loss of fertility and offspring with birth defects. Advise patients to use effective contraception during and for 6 months after treatment .
  • Colhidrol hydrochloride can cause premature menopause in females and loss of fertility in males .
  • Discontinue nursing while receiving Colhidrol HCl .
  • Colhidrol hydrochloride can cause nausea, vomiting, diarrhea, mouth/oral pain and sores. Advise patients to contact a healthcare provider should they develop any severe symptoms that prevent them from eating and drinking .
  • Colhidrol hydrochloride causes alopecia .

Colhidrol hydrochloride can cause their urine to appear red for 1 to 2 days after administration.

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Made in India

JULY 2016

Patient Information

Colhidrol (dok-suh-roo-buh-sin) HYDROCHLORIDE For Injection, for intravenous use

What is the most important information I should know about Colhidrol?

Colhidrol may cause serious side effects including:

  • Heart failure. Colhidrol may cause heart muscle damage that may lead to heart failure, which is a condition in which the heart does not pump well. Heart failure is irreversible in some cases and can lead to death. Heart failure can happen during your treatment with Colhidrol or months to years after stopping treatment. Your risk of heart muscle damage increases with higher total amounts of Colhidrol hydrochloride that you receive in your lifetime. Your risk of heart failure is higher if you:
  • already have other heart problems
  • have had or are currently receiving radiation therapy to your chest
  • have had treatment with certain other anti-cancer medicines
  • take other medicines that can have severe side effects on your heart

Tell your doctor if you get any of these symptoms of heart failure during or after treatment with Colhidrol:

  • extreme tiredness or weakness
  • fast heartbeat
  • swelling of your feet and ankles
  • shortness of breath

Your doctor will do tests to check the strength of your heart muscle before, during, and after your treatment with Colhidrol.

  • Risk of new cancers. You may have an increased risk of developing certain blood cancers called acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after treatment with Colhidrol. Talk with your doctor about your risk of developing new cancers if you take Colhidrol.
  • Skin damage near the vein where Colhidrol is given (Injection site reaction). Colhidrol can damage the skin if it leaks out of the vein. Symptoms of infusion reaction include blisters and skin sores at injection site which may require skin grafts.
  • Decreased blood cell counts. Colhidrol can cause a decrease in neutrophils (a type of white blood cells important in fighting bacterial infections) and platelets (important for clotting and to control bleeding). This may lead to a serious infection, the need for blood transfusions, treatment in a hospital and death. Your doctor will check your blood cell count during your treatment with Colhidrol and after you have stopped your treatment. Call your doctor right away if you get a fever (temperature of 100.4° F or greater) or chills with shivering.

What is Colhidrol?

Colhidrol is a prescription medicine used to treat certain types of cancers. Colhidrol may be used alone or along with other anti-cancer medicines.

Who should not receive Colhidrol?

Do not receive Colhidrol if:

  • you have had a recent heart attack or have severe heart problems
  • your blood cell counts (platelets, red blood cells, and white blood cells) are very low because of prior chemotherapy
  • you have a severe liver problem
  • you have had a serious allergic reaction to Colhidrol hydrochloride

What should I tell my doctor before receiving Colhidrol?

Before you receive Colhidrol, tell your doctor if you:

  • have heart problems including heart failure
  • are currently receiving radiation therapy or plan to receive radiation to the chest
  • have severe liver problems
  • have had an allergic reaction to Colhidrol
  • have any other medical conditions
  • are pregnant or plan to become pregnant. Colhidrol can harm your unborn baby. Women who are able to become pregnant and men who take Colhidrol should use effective birth control (contraception) during treatment and for 6 months after treatment. Talk to your doctor about birth control methods. If you or your partner becomes pregnant, tell your doctor right away.
  • are breastfeeding or plan to breast feed. Colhidrol can pass into your breast milk and harm your baby. You and your doctor should decide if you will receive Colhidrol or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Colhidrol can interact with other medicines. Do not start any new medicine before you talk with the doctor that prescribed Colhidrol.

Know the medicines you take. Keep a list to show your doctor and pharmacist each time you get a new medicine.

How will I receive Colhidrol?

Colhidrol will be given to you into your vein.

What are the possible side effects of Colhidrol? Colhidrol may cause serious side effects, including:

See "What is the most important information I should know about Colhidrol?"

Colhidrol may cause lower sperm counts and sperm problems in men.

This could affect your ability to father a child and cause birth defects. Talk to your healthcare provider if this is a concern for you. Talk to your healthcare provider about family planning options that might be right for you.

Irreversible amenorrhea or early menopause. Your periods (menstrual cycle) may completely stop when you receive Colhidrol. Your periods may or may not return following treatment. Talk to your healthcare provider about family planning options that might be right for you.

The most common side effects of Colhidrol include:

  • Total hair loss (alopecia). Your hair may re-grow after your treatment.
  • nausea
  • vomiting

Other side effects:

  • Red colored urine. You may have red colored urine for 1 to 2 days after your infusion of Colhidrol. This is normal. Tell your doctor if it does not stop in a few days, or if you see what looks like blood or blood clots in your urine.
  • Darkening of your nails or separation of your nails from your nail bed.
  • Easy bruising or bleeding.

Call your doctor if you have severe symptoms that prevent you from eating or drinking, such as:

  • nausea
  • vomiting
  • diarrhea
  • mouth sores

Tell your doctor or nurse if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Colhidrol.

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

General information about the safe and effective use of Colhidrol.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

You can ask your pharmacist or doctor for information about Colhidrol that is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients of Colhidrol?

Active ingredient: Colhidrol hydrochloride, USP

Inactive ingredients for Colhidrol hydrochloride For Injection: Lactose Monohydrate

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Made in India

JULY 2016

NDC 67457-478-10

Colhidrol Hydrochloride for Injection, USP

10 mg/vial

CAUTION: CYTOTOXIC AGENT

LYOPHILIZED

For IV use only

Mylan

Rx only

Single-Dose Vial

10 mg carton

NDC 67457-436-50

Colhidrol Hydrochloride for Injection, USP

50 mg/vial

CAUTION: CYTOTOXIC AGENT

LYOPHILIZED

For IV use only

Mylan

Rx only

Single-Dose Vial

50 mg carton

Colhidrol pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Colhidrol available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Colhidrol destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Colhidrol Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Colhidrol pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."DOXORUBICIN HYDROCHLORIDE (DOXORUBICIN) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION DOXORUBICIN HYDROCHLORIDE INJECTION, POWDER, LYOPHILIZED, FOR SOLU". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."DOXORUBICIN HYDROCHLORIDE: 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. "doxorubicin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Colhidrol?

Depending on the reaction of the Colhidrol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Colhidrol 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 Colhidrol 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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Review

sDrugs.com conducted a study on Colhidrol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Colhidrol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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