conjugated estrogens and medroxyprogesterone

Commonly used brand name(s)

In the U.S.

• Activella


• Alesse


• Angeliq


• Estinyl


• Hemocyte


• Loestrin 1/20


• Mircette


• Ortho-Novum


• Prefest


• Premphase

Available Dosage Forms:

• Tablet


• Tablet, Chewable

Uses For conjugated estrogens and medroxyprogesterone

Conjugated estrogens and medroxyprogesterone are estrogen and progestin hormones. Along with other effects, estrogens help females develop sexually at puberty and regulate the menstrual cycle. Progestin lowers the effect of estrogen on the uterus and keeps estrogen-related problems from developing.

Around the time of menopause, the ovaries produce less estrogen. Estrogens are given to:

• Relieve the signs of menopause (vasomotor symptoms of menopause), such as hot flashes and unusual sweating, chills, faintness, or dizziness.


• Treat inflammation of the vagina (atrophic vaginitis) and of the genital area (atrophy of the vulva) by keeping these areas from becoming too dry, itchy, or painful.


• Prevent the loss of bone that begins at the time of menopause. Keeping bones strong decreases the chance of developing weak bones that easily break (osteoporosis). Estrogen use is most effective when it is taken for more than 7 years while you are getting regular exercise and extra calcium. Protection from bone loss can then last for many years after you stop taking the medicine.

There is no medical evidence to support the belief that the use of estrogens will keep the patient feeling young, keep the skin soft, or delay the appearance of wrinkles. Nor has it been proven that the use of estrogens during menopause will relieve emotional and nervous symptoms, unless these symptoms are related to the menopausal symptoms, such as hot flashes.

Progestins are not needed if the uterus has been removed by a surgical method called hysterectomy. In that case, it may be better to receive estrogens alone without the progestin.

Conjugated estrogens and medroxyprogesterone are available only with your doctor's prescription.

Before Using conjugated estrogens and medroxyprogesterone

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Geriatric

Conjugated estrogens and medroxyprogesterone may increase your chance of having a stroke, memory problems, or breast cancer that spreads to other parts of your body.

Pregnancy

Conjugated estrogens and medroxyprogesterone are not recommended for use during pregnancy. Becoming pregnant or maintaining a pregnancy is not likely to occur around the time of menopause. Tell your doctor right away if you suspect you are pregnant.

Breast Feeding

Conjugated estrogens and medroxyprogesterone pass into the breast milk. conjugated estrogens and medroxyprogesterone is not recommended for use during breast-feeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

• Boceprevir

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Boceprevir


• Felbamate


• Isotretinoin


• Paclitaxel


• Paclitaxel Protein-Bound


• Theophylline


• Tizanidine


• Tranexamic Acid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Asthma or


• Epilepsy or


• Heart problems (congestive heart failure) or


• High blood pressure or


• Kidney problems, severe or


• Migraine headaches—Rarely, water retention caused by conjugated estrogens and medroxyprogesterone may make these conditions worse.

• Blood clotting problems, or history of with previous estrogen use or


• Breast cancer, estrogen-dependent, or history of or


• Breast cancer, or history of or


• Deep vein thrombosis (blood clot in the leg), active or history of or


• Heart attack, active or recent (within past year) or


• Liver disease, including jaundice, or history of or


• Pulmonary embolism (clot in the lung), active or history of or


• Stroke, active or recent (within past year) or


• Venous thromboembolism (clot in the veins), or history of—Conjugated estrogens and medroxyprogesterone should not be used in patients with these conditions.

• Bone cancer or


• Endometrial cancer (cancer of the uterus), active or suspected or


• Fibroid tumors of the uterus—Estrogens may interfere with the treatment of bone cancer, worsen cancer of the uterus, or increase the size of fibroid tumors.

• Changes in genital or vaginal bleeding of unknown causes—Estrogens may make these conditions worse; some irregular vaginal bleeding may be a sign that the lining of the uterus may be growing too much or is a sign of cancer of the uterus lining.

• Changes in vision—conjugated estrogens and medroxyprogesterone may cause changes in vision; your medicine may need to be stopped if these conditions become worse.

• Diabetes mellitus—Conjugated estrogens and medroxyprogesterone may slightly change the amount of blood sugar for some patients, but for most patients with diabetes, there is no change in blood sugar.

• Endometriosis or


• Gallbladder disease or gallstones, or history of or


• High cholesterol or triglycerides, or family history of or


• Memory loss (dementia) or


• Pancreatitis (inflammation of pancreas) or


• Porphyria (liver problem)—Conjugated estrogens and medroxyprogesterone may make these conditions worse; using estrogens can lower blood cholesterol in many patients with high cholesterol.

• Hypothyroidism (underactive thyroid)—A change in dose of thyroid medication may be needed.

• Low blood calcium, severe—Estrogens should be used with caution in patients with this condition.

Proper Use of conjugated estrogens and medroxyprogesterone

Conjugated estrogens and medroxyprogesterone usually come with patient directions. Read them carefully before taking conjugated estrogens and medroxyprogesterone.

Take conjugated estrogens and medroxyprogesterone only as directed by your doctor. Do not take more of it and do not take it for a longer period of time than your doctor ordered. The length of time you take the medicine will depend on the medical problem for which you are taking conjugated estrogens and medroxyprogesterone. Discuss with your doctor how long you will need to take these medicines.

If you are taking the estrogen or progestin hormones in a certain order (i.e., conjugated estrogens tablets followed by conjugated estrogens and medroxyprogesterone tablets), be sure you know in which order you need to take the medicines. If you have questions about this, ask your health care professional.

Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For conjugated estrogens, and conjugated estrogens and medroxyprogesterone


• For oral dosage form (tablets):
  
  • To prevent loss of bone (osteoporosis) or for treating itching or dryness of the genital area (atrophy of the vulva), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—One tablet (containing 0.625 mg conjugated estrogens) once a day on Days 1 through 14; then, one tablet (containing 0.625 mg conjugated estrogens and 5 mg medroxyprogesterone) once a day on Days 15 through 28. Repeat cycle.
    
    
  
  

• For conjugated estrogens and medroxyprogesterone


• For oral dosage form (tablets):
  
  • To prevent loss of bone (osteoporosis) or for treating itching or dryness of the genital area (atrophy of the vulva), inflammation of the vagina (atrophic vaginitis), or symptoms of menopause:
    
    • Adults—One tablet (containing 0.3 mg conjugated estrogens and 1.5 mg medroxyprogesterone) once a day for twenty-eight days. Repeat cycle. If vaginal bleeding or spotting continues and it is undesired, your doctor may increase your dose to the next highest strength tablet (0.45 mg conjugated estrogens and 1.5 mg medroxyprogesterone). It should be taken once a day for twenty-eight days. Repeat cycle.
    
    
  
  

Missed Dose

If you miss a dose of conjugated estrogens and medroxyprogesterone, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using conjugated estrogens and medroxyprogesterone

It is very important that your doctor check your progress at regular visits to make sure conjugated estrogens and medroxyprogesterone does not cause unwanted effects. Plan on going to see your doctor every year, but some doctors require visits more often.

Although the risk for developing breast problems or breast cancer is low, it is still important that you regularly check your breasts for any unusual lumps or discharge, and report any problems to your doctor. You should also have a mammogram (x-ray pictures of the breasts) and breast examination done by your doctor whenever your doctor recommends it.

If your menstrual periods have stopped, they may start again once you begin taking conjugated estrogens and medroxyprogesterone. This effect will continue for as long as the medicine is taken. However, if taking the continuous treatment (0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone once a day), monthly bleeding usually stops within 10 months.

Also, vaginal bleeding between your regular menstrual periods may occur during the first 3 months of use. Do not stop taking your medicine. Check with your doctor if bleeding continues for an unusually long time, if your period has not started within 45 days of your last period, or if you think you are pregnant.

Tell the doctor in charge that you are taking conjugated estrogens and medroxyprogesterone before having any laboratory test, because some test results may be affected.

You may need to stop taking conjugated estrogens and medroxyprogesterone before having some kinds of surgery or while your doctor has ordered a long period of bedrest. Talk with your doctor about this.

conjugated estrogens and medroxyprogesterone Side Effects

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.

Healthy women rarely have severe side effects from taking conjugated estrogens or medroxyprogesterone to replace estrogen.

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

More common

• Itching of the vagina or genital area


• menstrual periods beginning again, including changing menstrual bleeding pattern for up to 6 months (spotting, breakthrough bleeding, prolonged or heavier vaginal bleeding, or vaginal bleeding completely stopping by 10 months)


• pain during sexual intercourse


• thick, white vaginal discharge

Less common

• Blurred vision


• breast lumps


• chest pain


• discharge from breast


• dizziness


• feeling faint, dizzy, or light-headed


• feeling of warmth or heat


• flushing or redness of skin, especially on face and neck


• headache


• heavy nonmenstrual vaginal bleeding


• pounding in the ears


• severe cramping of the uterus


• slow or fast heartbeat


• sweating

Rare

• Change in vaginal discharge


• pain or feeling of pressure in pelvis


• pain or tenderness in stomach, side, or abdomen


• yellow eyes or skin

Incidence not known

• Abdominal bloating


• acid or sour stomach


• belching


• backache


• full or bloated feeling or pressure in the stomach


• heartburn


• indigestion


• loss of appetite


• pelvic pain


• stomach discomfort, upset or pain


• stomach pain


• swelling of abdominal or stomach are

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:

More common

• Abdominal cramps


• back pain


• body aches or pain


• breast pain or tenderness


• congestion


• chills


• cough


• crying


• depersonalization


• diarrhea


• dryness or soreness of throat


• dysphoria


• enlarged breasts


• euphoria


• feeling faint, dizzy, or light-headedness


• feeling of warmth or heat


• fever


• flushing or redness of skin, especially on face and neck


• general feeling of discomfort or illness


• headache, severe and throbbing


• hoarseness


• increase in amount of clear vaginal discharge


• itching


• joint pain


• lack or loss of strength


• mental depression


• muscle aches and pains


• nausea


• pain


• pain or tenderness around eyes and cheekbones


• painful menstrual periods


• painful or difficult urination


• paranoia


• passing of gas


• quick to react or overreact emotionally


• rapidly changing moods


• runny nose


• shivering


• shortness of breath or troubled breathing


• sneezing


• sore throat


• stuffy nose


• stomach discomfort following meals


• tender, swollen glands in neck


• tightness of chest or wheezing


• trouble sleeping


• trouble in swallowing


• unusual tiredness


• voice changes


• vomiting

Less common

• Acne


• bloating or swelling of face, ankles, or feet


• cervix disorder


• crying


• depersonalization


• dysphoria


• euphoria


• increase in sexual desire


• leg cramps


• mental depression


• paranoia


• quick to react or overreact emotionally


• rapidly changing moods


• sleeplessness


• tense muscles


• trouble sleeping


• unable to sleep


• unusual weight gain or loss

Incidence not known

• Abdominal cramping


• bloody or cloudy urine


• bloody vaginal discharge


• difficult, burning, or painful urination


• frequent urge to urinate


• light vaginal bleeding between periods and after intercourse

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.

See also: conjugated estrogens and medroxyprogesterone side effects (in more detail)

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More conjugated estrogens and medroxyprogesterone resources

• Conjugated estrogens and medroxyprogesterone Side Effects (in more detail)
• Conjugated estrogens and medroxyprogesterone Use in Pregnancy & Breastfeeding
• Conjugated estrogens and medroxyprogesterone Drug Interactions
• Conjugated estrogens and medroxyprogesterone Support Group
• 6 Reviews for Conjugated estrogens and medroxyprogesterone - Add your own review/rating

Compare conjugated estrogens and medroxyprogesterone with other medications

• Atrophic Urethritis
• Atrophic Vaginitis
• Oophorectomy
• Osteoporosis
• Postmenopausal Symptoms
• Primary Ovarian Failure

Cosmegen

dactinomycin

Dosage Form: injection, powder, lyophilized, for solution
Cosmegen for Injection

(dactinomycin for injection)

(Actinomycin D)


Rx only

WARNING

Cosmegen® (dactinomycin for injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Due to the toxic properties of dactinomycin (e.g., corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently. Dactinomycin is extremely corrosive to soft tissue. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms.

DESCRIPTION

Dactinomycin is one of the actinomycins, a group of antibiotics produced by various species of Streptomyces. Dactinomycin is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. Unlike other species of Streptomyces, this organism yields an essentially pure substance that contains only traces of similar compounds differing in the amino acid content of the peptide side chains. The empirical formula is C62H86N12O16 and the structural formula is:

Cosmegen is a sterile, yellow to orange lyophilized powder for injection by the intravenous route or by regional perfusion after reconstitution. Each vial contains 0.5 mg (500 mcg) of dactinomycin and 20.0 mg of mannitol.

CLINICAL PHARMACOLOGY

Action: Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases.

Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implants. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.

Pharmacokinetics and Metabolism: Results of a study in patients with malignant melanoma indicate that dactinomycin (3H actinomycin D) is minimally metabolized, is concentrated in nucleated cells, and does not penetrate the blood-brain barrier. Approximately 30% of the dose was recovered in urine and feces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.

CLINICAL STUDIES

A wide variety of single agent and combination chemotherapy regimens with Cosmegen have been studied. Because chemotherapeutic regimens are constantly changing, the decision to employ Cosmegen should be directly supervised by physicians familiar with current oncologic practices and new advances in therapy.

Wilms' Tumor: The neoplasm responding most frequently to Cosmegen is Wilms' tumor. Data from the National Wilms' Tumor Studies (NWTS 1, NWTS 2, NWTS 3 and NWTS 4) support the use of Cosmegen in Wilms' tumor. The NWTS 3 evaluated results in 1,439 patients randomized to various regimens incorporating Cosmegen (see table below).1

The Third National Wilms' Tumor Study

Stage	Regimen	4 Year Relapse Free Survival (%)	4 Year Overall Survival (%)
L = Cosmegen and vincristine (10 weeks) EE = Cosmegen and vincristine (26 weeks) DD = Cosmegen, doxorubicin, and vincristine (65 weeks) DD1 = Cosmegen, doxorubicin, and vincristine (65 weeks) preceded by radiation therapy (1000 rads) DD2 = Cosmegen, doxorubicin, and vincristine (65 weeks) preceded by radiation therapy (2000 rads) DD-RT = Cosmegen, doxorubicin, and vincristine (65 weeks) preceded by radiation therapy (dose according to age) K = Cosmegen and vincristine (65 weeks) K1 = Cosmegen and vincristine (65 weeks) preceded by radiation therapy (1000 rads) K2 = Cosmegen and vincristine (65 weeks) preceded by radiation therapy (2000 rads) J = Cosmegen, doxorubicin, cyclophosphamide, and vincristine (65 weeks)
I (favorable histology)	L EE	89.0 91.8	95.6 97.4
II (favorable histology)	DD DD2 K K2	87.9 86.9 87.4 90.1	93.6 89.6 91.1 94.9
III (favorable histology)	DD1 DD2 K1 K2	82.0 85.9 71.4 76.8	90.9 86.7 85.2 85.1
IV (favorable histology)	DD-RT J	71.9 77.9	78.4 86.6
I-III (unfavorable histology)	DD-RT J	67.1 62.4	68.3 68.4
IV (unfavorable histology)	DD-RT J	58.3 52.9	58.3 52.3

It should be noted that the complete results from NWTS 4 have not yet been published. Changes in NWTS 4 and NWTS 5 have consisted of alterations in duration as well as dose intensity of Cosmegen. As a consequence, appropriate consultation with physicians experienced in the management of Wilms' tumor should be sought.

Childhood Rhabdomyosarcoma: The Third Intergroup Rhabdomyosarcoma Study (IRS III) studied 1,062 previously untreated pediatric patients and young adults (≤21 years of age) and compared outcomes amongst a number of treatment regimens.

Cosmegen was included in all arms as a standard component of the treatment regimen; thus, comparative data are not available from this study. Nevertheless, it does provide information on treatment outcomes in a large group of closely studied patients. For treatment purposes, patients were stratified according to clinical group, histologic subtype, and site of disease. Patients in most strata were randomized, but clinical group I patients with favorable histology were not randomized and treated according to a single regimen.2

The Third Intergroup Rhabdomyosarcoma Study

Group	Number of Arms	Chemotherapy Regimen	5 Year Progression Free Survival (%) (mean±SEM)	5 Year Overall Survival (%) (mean±SEM)
VA = vincristine/Cosmegen VADRC = vincristine/doxorubicin/cyclophosphamide VAC = vincristine/Cosmegen/cyclophosphamide CDDP = Cisplatin VP 16 = Etoposide RT = radiation therapy
I (favorable histology)	1 (non randomized)	cyclic sequential VA (1 year)	83±3	93±2
II (favorable histology, excluding orbit, head and paratesticular sites)	2 (randomized)	VA, doxorubicin and RT (1 year) VA and RT (1 year)	77±6 56±10	89±5 54±13
III (excluding special pelvic, orbit, scalp, parotid, oral cavity, larynx, oropharynx and cheek)	3 (randomized)	pulsed VAC and RT (2 years) pulsed VADRC VAC, CDDP and RT (2 years) pulsed VADRC VAC, CDDP, VP 16 and RT (2 years)	70±6 62±5 56±4	70±6 63±5 64±5
IV (all)	3 (randomized)	pulsed VAC and RT (2 years) pulsed VADRC VAC, CDDP and RT (2 years) pulsed VADRC VAC, CDDP, VP 16 and RT (2 years)	27±8 27±8 30±6	27±6 31±6 29±7

Metastatic Nonseminomatous Testicular Cancer: Combinations of vinblastine, cyclophosphamide, Cosmegen, bleomycin and cisplatin (VAB 6 regimen) have been employed in the treatment of metastatic nonseminomatous testicular cancer.3,4 In a retrospective analysis of 142 evaluable patients with primary advanced stage II or clinical stage III testicular cancer 112 (79%) achieved a complete response (CR) after treatment with VAB 6 alone or in combination with surgery. Relapses were uncommon (12%) and 117 of 166 patients (71%) were categorized as alive without evidence of disease during the four years covered by the study.

Ewing's Sarcoma: Cosmegen in conjunction with vincristine, doxorubicin, cyclophosphamide and radiotherapy has been used in the management of both metastatic and non-metastatic Ewing's sarcoma. Of 120 previously untreated patients with non-metastatic disease treated with Cosmegen as part of maintenance therapy in the United Kingdom Children's Cancer Study Group Ewing's Tumor Study (ET 1), 49 (41%) were free of disease at 5 years and 53 (44%) were alive at 5 years.5 Outcomes in regional and metastatic disease for previously untreated patients administered Cosmegen resulted in 31 of 44 patients (70%) achieving a CR after a median time on study of 83 weeks. Eight of 44 (18%) patients achieved a partial response (PR) and the remaining 5 (11%) demonstrated no response to the regimen.6

Gestational Trophoblastic Neoplasia: Single agent Cosmegen has been used in the management of nonmetastatic gestational trophoblastic neoplasia. In a series of 31 patients with nonmetastatic disease, complete and sustained remissions were achieved with Cosmegen alone in 94% of treated patients.7 Alternating combination regimens incorporating Cosmegen in conjunction with etoposide, methotrexate, vincristine and cyclophosphamide (EMA CO regimen)8 have also been used in the treatment of poor prognosis gestational trophoblastic neoplasia. Administration of EMA CO to 148 women with poor prognosis gestational trophoblastic neoplasia resulted in 110 (80%) complete and 25 (18%) partial responses after a mean follow-up of 50.4 months. Overall survival during the study period was 85% and relapses were uncommon (5.4%). Meticulous monitoring of beta hCG (human chorionic gonadotropin) must be incorporated into the treatment regimen.

Regional Perfusion in Locally Recurrent and Locoregional Solid Malignancies: Cosmegen, as a component of regional perfusion, has been administered as palliative treatment and as an adjunct to tumor resection in the management of locally recurrent and locoregional sarcomas, carcinomas and adenocarcinomas.

INDICATIONS AND USAGE

Cosmegen, as part of a combination chemotherapy and/or multi-modality treatment regimen, is indicated for the treatment of Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma and metastatic, nonseminomatous testicular cancer.

Cosmegen is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia.

Cosmegen, as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.

CONTRAINDICATIONS

Hypersensitivity to any component of this product.

Cosmegen should not be given at or about the time of infection with chickenpox or herpes zoster because of the risk of severe generalized disease which may result in death.

WARNINGS

Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as Cosmegen. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.

Pregnancy Category D

Cosmegen may cause fetal harm when administered to a pregnant woman. Cosmegen has been shown to cause malformations and embryotoxicity in rat, rabbit, and hamster when given in doses of 50 100 mcg/kg (approximately 0.5 - 2 times the maximum recommended daily human dose on a body surface area basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential must be warned to avoid becoming pregnant.

PRECAUTIONS

General

This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see boxed warning and HOW SUPPLIED, Special Handling). Since Cosmegen is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling Cosmegen. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse (see HOW SUPPLIED, Special Handling).

As with all antineoplastic agents, Cosmegen is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with Cosmegen. The possibility of an anaphylactoid reaction should be borne in mind.

It is extremely important to observe the patient daily for toxic side effects when combination chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe hematopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.

Veno-occlusive Disease: Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months. (See ADVERSE REACTIONS, Hepatic.)

Cosmegen (dactinomycin for injection) and Radiation Therapy: An increased incidence of gastrointestinal toxicity and marrow suppression has been reported with combined therapy incorporating Cosmegen and radiation. Moreover, the normal skin, as well as the buccal and pharyngeal mucosa, may show early erythema. A smaller than usual radiation dose administered in combination with Cosmegen causes erythema and vesiculation, which progress more rapidly through the stages of tanning and desquamation. Healing may occur in four to six weeks rather than two to three months. Erythema from previous radiation therapy may be reactivated by Cosmegen alone, even when radiotherapy was administered many months earlier, and especially when the interval between the two forms of therapy is brief. This potentiation of radiation effect represents a special problem when the radiotherapy involves the mucous membrane. When irradiation is directed toward the nasopharynx, the combination may produce severe oropharyngeal mucositis. Severe reactions may ensue if high doses of both Cosmegen and radiation therapy are used or if the patient is particularly sensitive to such combined therapy.

Particular caution is necessary when administering Cosmegen within two months of irradiation for the treatment of right-sided Wilms' tumor, since hepatomegaly and elevated AST levels have been noted. In general, Cosmegen should not be concomitantly administered with radiotherapy in the treatment of Wilms' tumor unless the benefit outweighs the risk.

Cosmegen (dactinomycin for injection) and Regional Perfusion Therapy: Complications of the perfusion technique are related mainly to the amount of drug that escapes into the systemic circulation and may consist of hematopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing, and superficial ulceration of the gastric mucosa. Other side effects may include edema of the extremity involved, damage to soft tissues of the perfused area, and (potentially) venous thrombosis.

Laboratory Tests

Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving Cosmegen. Renal, hepatic, and bone marrow functions should be assessed frequently.

Dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as Cosmegen. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.

The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumors occurred in male F344 rats given intraperitoneal injections of 50 mcg/kg, 2 to 5 times per week for 18 weeks. The first tumor appeared at 23 weeks.

Dactinomycin has been shown to be mutagenic in a number of test systems in vitro and in vivo including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat. Adequate fertility studies have not been reported, although, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.

Pregnancy: Pregnancy Category D

(See WARNINGS.)

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cosmegen, a decision should be made as to discontinuation of nursing and/or drug, taking into account the importance of the drug to the mother.

Pediatric Use

The greater frequency of toxic effects of Cosmegen in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.

Geriatric Use

Clinical studies of Cosmegen did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, a published meta-analysis of all studies performed by the Eastern Cooperative Oncology Group (ECOG) over a 13 year period suggests that administration of Cosmegen to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Toxic effects (excepting nausea and vomiting) usually do not become apparent until two to four days after a course of therapy is stopped, and may not peak until one to two weeks have elapsed. Deaths have been reported. However, adverse reactions are usually reversible on discontinuance of therapy. They include the following:

Miscellaneous: malaise, fatigue, lethargy, fever, myalgia, proctitis, hypocalcemia, growth retardation, infection.

Oral: cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis.

Lung: pneumonitis.

Gastrointestinal: anorexia, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal ulceration. Nausea and vomiting, which occur early during the first few hours after administration, may be alleviated by the administration of anti-emetics.

Hepatic: liver toxicity including liver function test abnormalities, ascites, hepatomegaly, hepatitis, hepatic failure with reports of death, hepatic veno-occlusive disease which may be associated with intravascular clotting disorder and multi-organ failure (see PRECAUTIONS, Veno-occlusive Disease).

Hematologic: anemia, even to the point of aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia. Platelet and white cell counts should be performed frequently to detect severe hematopoietic depression. If either count markedly decreases, the drug should be withheld to allow marrow recovery. This often takes up to three weeks.

Dermatologic: alopecia, skin eruptions, acne, flare up of erythema or increased pigmentation of previously irradiated skin.

Soft tissues: Dactinomycin is extremely corrosive. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms. Epidermolysis, erythema, and edema, at times severe, have been reported with regional limb perfusion.

Laboratory Tests: Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving Cosmegen. Renal, hepatic, and bone marrow functions should be assessed frequently.

To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck Inc. at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Dactinomycin was lethal to mice and rats at intravenous doses of 700 and 500 mcg/kg, respectively (approximately 3.8 and 5.4 times the maximum recommended daily human dose on a body surface area basis, respectively). The oral LD50 of dactinomycin is 7.8 mg/kg and 7.2 mg/kg in the mouse and rat, respectively.

Manifestations of overdose in patients have included nausea, vomiting, diarrhea, mucositis including stomatitis, gastrointestinal ulceration, skin disorders including exanthema, desquamation and epidermolysis, severe hematopoietic depression, veno-occlusive disease, acute renal failure, and death. No specific information is available on the treatment of overdosage with Cosmegen. Treatment is symptomatic and supportive. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic, and bone marrow functions frequently.

DOSAGE AND ADMINISTRATION

Not for oral administration: Toxic reactions due to Cosmegen are frequent and may be severe (see ADVERSE REACTIONS), thus limiting in many instances the amount that may be administered. However, the severity of toxicity varies markedly and is only partly dependent on the dose employed.

Careful calculation of the dosage should be performed prior to administration of each dose.

Intravenous Use: The dosage of Cosmegen varies depending on the tolerance of the patient, the size and location of the neoplasm, and the use of other forms of therapy. It may be necessary to decrease the usual dosages suggested below when additional chemotherapy or radiation therapy is used concomitantly or has been used previously.

The dosage for Cosmegen is calculated in micrograms (mcg). The dose intensity per 2 week cycle for adults or children should not exceed 15 mcg/kg/day or 400 600 mcg/m2/day intravenously for five days. Calculation of the dosage for obese or edematous patients should be performed on the basis of surface area in an effort to more closely relate dosage to lean body mass.

A wide variety of single agent and combination chemotherapy regimens with Cosmegen may be employed. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of physicians familiar with current oncologic practices and new advances in therapy. The following suggested regimens are based upon a review of current literature concerning therapy with Cosmegen and are on a per cycle basis.

Wilms' Tumor, Childhood Rhabdomyosarcoma and Ewing's Sarcoma: Regimens of 15 mcg/kg intravenously daily for five days administered in various combinations and schedules with other chemotherapeutic agents have been utilized in the treatment of Wilms' tumor1, rhabdomyosarcoma2 and Ewing's sarcoma.5,6

Metastatic Nonseminomatous Testicular Cancer: 1000 mcg/m2 intravenously on Day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.3

Gestational Trophoblastic Neoplasia: 12 mcg/kg intravenously daily for five days as a single agent.7

500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.8

Regional Perfusion in Locally Recurrent and Locoregional Solid Malignancies: The dosage schedules and the technique itself vary from one investigator to another; the published literature, therefore, should be consulted for details. In general, the following doses are suggested:

50 mcg (0.05 mg) per kilogram of body weight for lower extremity or pelvis.

35 mcg (0.035 mg) per kilogram of body weight for upper extremity.

It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.

Preparation of Solution for Intravenous Administration: This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see boxed warning and HOW SUPPLIED, Special Handling). Since Cosmegen is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling Cosmegen. Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse. (See HOW SUPPLIED, Special Handling.)

Reconstitute Cosmegen by adding 1.1 mL of Sterile Water for Injection (without preservative) using aseptic precautions. The resulting solution of Cosmegen will contain approximately 500 mcg (0.5 mg) per mL.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, Cosmegen is a clear, gold-colored solution.

Once reconstituted, the solution of Cosmegen can be added to infusion solutions of Dextrose Injection 5 percent or Sodium Chloride Injection either directly or to the tubing of a running intravenous infusion.

Although reconstituted Cosmegen is chemically stable, the product does not contain a preservative and accidental microbial contamination might result. Any unused portion should be discarded. Use of water containing preservatives (benzyl alcohol or parabens) to reconstitute Cosmegen for Injection, results in the formation of a precipitate.

Partial removal of Cosmegen from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported.

Since dactinomycin is extremely corrosive to soft tissue, precautions for materials of this nature should be observed.

If the drug is given directly into the vein without the use of an infusion, the "two-needle technique" should be used. Reconstitute and withdraw the calculated dose from the vial with one sterile needle. Use another sterile needle for direct injection into the vein.

Discard any unused portion of the Cosmegen solution.

Management of Extravasation: Care in the administration of Cosmegen will reduce the chance of perivenous infiltration (see boxed warning and ADVERSE REACTIONS). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of Cosmegen, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 minutes q.i.d. for 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.9

HOW SUPPLIED

Cosmegen for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear, gold-colored and essentially free from visible particles. Cosmegen for Injection is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol.

NDC 67386-811-55

Storage: Store at 20-25°C (68-77°F). See USP controlled room temperature. Protect from light and humidity.

Special Handling: Animal studies have shown dactinomycin to be corrosive to skin, irritating to the eyes and mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic, embryotoxic and teratogenic. Due to the drug's toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of Cosmegen for parenteral administration. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet.10 Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be used based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing.

Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.11-16

Accidental Contact Measures: Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION, Preparation of Solution for Intravenous Administration).

REFERENCES

1. D'Angio, G.J.; et al: Treatment of Wilms' Tumor: Results of the Third National Wilms' Tumor Study. Cancer 64: 349-360, 1989.

2. Crist, W.; et al: The Third Intergroup Rhabdomyosarcoma Study. J. Clin. Oncol. 13: 610-630, 1995.

3. Vugrin, D.; et al: VAB-6 Combination Chemotherapy in Disseminated Cancer of the Testis. Ann. Intern. Med. 95: 59-61, 1981.

4. Bosl, G.J.; et al: VAB-6: An Effective Chemotherapy Regimen for Patients With Germ-Cell Tumors. J. Clin. Oncol. 4: 1493-1499, 1986.

5. Craft, A.W.; et al: Long-Term Results from the First UKCCSG Ewing's Tumour Study (ET-1). Eur. J. Cancer 33: 1061-1069, 1997.

6. Vietti, T.J.; et al: Multimodal Therapy in Metastatic Ewing's Sarcoma: An Intergroup Study. Nat. Cancer Inst. Monogr. 56: 279-284, 1981.

7. Osathanondh, R.; et al: Actinomycin D as the Primary Agent for Gestational Trophoblastic Disease, Cancer. 36: 863-866, 1975.

8. Newlands, E.S.; et al: Results with the EMA/CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, Vincristine) Regimen in High Risk Gestational Trophoblastic Tumours, 1979 to 1989. Br. J. Obstet. Gynaecol. 98: 550-557, 1991.

9. Rudolph, R.; Larson, D.L.: Etiology and Treatment of Chemotherapeutic Agent Extravasation Injuries: A Review. J. Clin. Oncol. 5: 1116-1126, 1987.

10. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.

11. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA 253: 1590-1592, 1985.

12. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

13. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med. J. Australia 1: 426-428, 1983.

14. Jones, R. B.; et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, Ca- A Cancer Journal for Clinicians, Sept/Oct, 258-263, 1983.

15. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am. J. Hosp. Pharm. 47: 1033-1049, 1990.

16. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am. J. Health-Syst. Pharm. 53: 1669-1685, 1996.

Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany

For: Lundbeck Inc., Deerfield, IL 60015, U.S.A.

® Trademark of Lundbeck Inc., Deerfield, IL 60015, U.S.A.

Revised: September 2009

750-03231-x

PRINCIPAL DISPLAY PANEL

67386-811-55

Cartons:

Vial:

   

Cosmegen  dactinomycin  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 67386-811 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DACTINOMYCIN (DACTINOMYCIN) DACTINOMYCIN 0.5 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 67386-811-55 1 VIAL In 1 CARTON contains a VIAL 1 1 mL In 1 VIAL This package is contained within the CARTON (67386-811-55)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA050682	12/10/1964

Labeler - Lundbeck Inc. (018343595)

Registrant - Lundbeck Inc. (018343595)

Establishment
Name	Address	ID/FEI	Operations
Baxter Oncology GmbH		344276063	MANUFACTURE

Revised: 05/2010Lundbeck Inc.

More Cosmegen resources

• Cosmegen Side Effects (in more detail)
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• Cosmegen Drug Interactions
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Capastat

capreomycin sulfate

Dosage Form: injection, powder, for solution
Capastat® SULFATE

CAPREOMYCIN FOR INJECTION, USP


For Intramuscular and Intravenous Infusion Only


NOT FOR PEDIATRIC USE

Warnings

The use of Capastat® Sulfate (Capreomycin for Injection, USP) in patients with renal insufficiency or preexisting auditory impairment must be undertaken with great caution, and the risk of additional cranial nerve VIII impairment or renal injury should be weighed against the benefits to be derived from therapy.

Refer to ANIMAL PHARMACOLOGY for additional information.

Since other parenteral antituberculosis agents (streptomycin, viomycin) also have similar and sometimes irreversible toxic effects, particularly on cranial nerve VIII and renal function, simultaneous administration of these agents with Capastat Sulfate is not recommended. Use with nonantituberculosis drugs (polymyxin A sulfate, colistin sulfate, amikacin, gentamicin, tobramycin, vancomycin, kanamycin, and neomycin) having ototoxic or nephrotoxic potential should be undertaken only with great caution.

Usage in Pregnancy: The safety of the use of Capastat Sulfate in pregnancy has not been determined.

Pediatric Usage: Safety and effectiveness in pediatric patients have not been established.

Capastat Description

Capastat Sulfate is a polypeptide antibiotic isolated from Streptomyces capreolus. It is a complex of 4 microbiologically active components which have been characterized in part; however, complete structural determination of all the components has not been established.

Capreomycin is supplied as the disulfate salt and is soluble in water. In complete solution, it is almost colorless.

Each vial contains the equivalent of 1 g capreomycin activity.

The structural formula is as follows:

Capastat - Clinical Pharmacology

Human Pharmacology

Capreomycin is not absorbed in significant quantities from the gastrointestinal tract and must be administered parenterally. In 2 studies of 10 patients each, peak serum concentrations following 1 g of capreomycin given intramuscularly were achieved 1 to 2 hours after administration, and average peak levels reached were 28 and 32 μg/mL respectively (range, 20 to 47 μg/mL). Low serum concentrations were present at 24 hours. However, 1 g of capreomycin daily for 30 days or more produced no significant accumulation in subjects with normal renal function. Two patients with marked reduction of renal function had high serum concentrations 24 hours after administration of the drug. When a 1–g dose of capreomycin was given intramuscularly to normal volunteers, 52% was excreted in the urine within 12 hours.

Lehmann, et al, examined the pharmacokinetics of single dose capreomycin (1.0 g) administered intramuscularly and by intravenous infusion (1 hour) in 6 healthy volunteers. The area under the serum concentration versus time curve was similar for the two routes of administration. Capreomycin peak concentrations after intravenous infusion were 30 ± 47% higher than after intramuscular administration.1, 2

Paper chromatographic studies indicated that capreomycin is excreted essentially unaltered. Urine concentrations averaged 1.68 mg/mL (average urine volume, 228 mL) during the 6 hours following a 1–g dose.

Microbiology

Capreomycin is active against strains of Mycobacterium tuberculosis found in humans.

Susceptibility Tests

The in vitro susceptibility of strains of M. tuberculosis to capreomycin varies with the media and techniques employed. In general, the minimum inhibitory concentrations for M. tuberculosis are lowest in liquid media that are free of egg protein (7H10 or Dubos) and range from 1 to 5 µg/mL when the indirect method is used. Comparable inhibitory concentrations are obtained when 7H10 agar is used for direct susceptibility testing. When indirect susceptibility tests are performed on standard tube slants with 7H10 media, susceptible strains are inhibited by 10 to 25 μg/mL capreomycin. Egg-containing media, such as Löwenstein-Jensen or ATS, require concentrations of 25 to 50 μg/mL to inhibit susceptible strains.

Cross–Resistance

Frequent cross-resistance occurs between capreomycin and viomycin. Varying degrees of cross-resistance between capreomycin and kanamycin and neomycin have been reported. No cross-resistance has been observed between capreomycin and isoniazid, aminosalicylic acid, cycloserine, streptomycin, ethionamide, or ethambutol.

Indications and Usage for Capastat

Capastat Sulfate, which is to be used concomitantly with other appropriate antituberculosis agents, is indicated in pulmonary infections caused by capreomycin–susceptible strains of M. tuberculosis when the primary agents (isoniazid, rifampin, ethambutol, aminosalicylic acid, and streptomycin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli.

Susceptibility studies should be performed to determine the presence of a capreomycin–susceptible strain of M. tuberculosis.

CONTRAINDICATION

Capastat Sulfate is contraindicated in patients who are hypersensitive to capreomycin.

Precautions

General

Audiometric measurements and assessment of vestibular function should be performed prior to initiation of therapy with Capastat Sulfate and at regular intervals during treatment.

Renal injury, with tubular necrosis, elevation of the blood urea nitrogen (BUN) or serum creatinine, and abnormal urinary sediment, has been noted. Slight elevation of the BUN and serum creatinine has been observed in a significant number of patients receiving prolonged therapy. The appearance of casts, red cells, and white cells in the urine has been noted in a high percentage of these cases. Elevation of the BUN above 30 mg/100 mL or any other evidence of decreasing renal function with or without a rise in BUN levels calls for careful evaluation of the patient, and the dosage should be reduced or the drug completely withdrawn. The clinical significance of abnormal urine sediment and slight elevation in the BUN (or serum creatinine) observed during long-term therapy with Capastat Sulfate has not been established.

The peripheral neuromuscular blocking action that has been attributed to other polypeptide antibiotics (colistin sulfate, polymyxin A sulfate, paromomycin, and viomycin) and to aminoglycoside antibiotics (streptomycin, dihydrostreptomycin, neomycin, and kanamycin) has been studied with Capastat Sulfate. A partial neuromuscular blockade was demonstrated after large intravenous doses of Capastat Sulfate. This action was enhanced by ether anesthesia (as has been reported for neomycin) and was antagonized by neostigmine.

Caution should be exercised in the administration of antibiotics, including Capastat Sulfate, to any patient who has demonstrated some form of allergy, particularly to drugs.

Laboratory Tests

Regular tests of renal function should be made throughout the period of treatment, and reduced dosage should be employed in patients with known or suspected renal impairment.

Renal function studies should be made both before therapy with Capastat Sulfate is started and on a weekly basis during treatment.

Since hypokalemia, hypomagnesemia and hypocalcemia may occur during therapy, these serum electrolyte levels should be determined frequently.

Drug Interactions

For neuromuscular blocking action of this drug, see PRECAUTIONS, GENERAL.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed to determine potential for carcinogenicity, mutagenicity, or impairment of fertility.

Usage in Pregnancy — Pregnancy Category C

Capastat Sulfate has been shown to be teratogenic in rats when given in doses 3 1/2 times the human dose. There are no adequate and well-controlled studies in pregnant women. Capastat Sulfate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see boxed WARNINGS and ANIMAL PHARMACOLOGY).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Capastat Sulfate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see boxed WARNINGS).

Geriatric Use

Clinical studies of Capastat Sulfate did not analyze the safety and efficacy of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Capastat Sulfate is known to be substantially excreted by the kidney (see CLINICAL PHARMACOLOGY), and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, Laboratory Tests). Patients with reduced renal function should have dosage reduction based on creatinine clearance using the guidelines included in Table 1 (see DOSAGE AND ADMINISTRATION).

The geriatric population is also more likely to have impaired hearing at baseline. Audiometric measurements and assessment of vestibular function should be performed prior to initiation of therapy with Capastat Sulfate and at regular intervals during treatment (see PRECAUTIONS, General).

Adverse Reactions

Nephrotoxicity: In 36% of 722 patients treated with Capastat Sulfate, elevation of the BUN above 20 mg/100 mL has been observed. In many instances, there was also depression of PSP excretion and abnormal urine sediment. In 10% of this series, the BUN elevation exceeded 30 mg/100 mL.

Toxic nephritis was reported in 1 patient with tuberculosis and portal cirrhosis who was treated with Capastat Sulfate (1 g) and aminosalicylic acid daily for 1 month. This patient developed renal insufficiency and oliguria and died. Autopsy showed subsiding acute tubular necrosis.

Electrolyte disturbances including hypokalemia, hypomagnesemia and hypocalcemia, sometimes serious in nature, have been reported.

Ototoxicity: Subclinical auditory loss was noted in approximately 11% of 722 patients undergoing treatment with Capastat Sulfate. This was a 5– to 10–decibel loss in the 4000– to 8000–CPS range. Clinically apparent hearing loss occurred in 3% of the 722 subjects. Some audiometric changes were reversible. Other cases with permanent loss were not progressive following withdrawal of Capastat Sulfate.

Tinnitus and vertigo have occurred.

Liver: Serial tests of liver function have demonstrated a decrease in BSP excretion without change in AST (SGOT) or ALT (SGPT) in the presence of preexisting liver disease. Abnormal results in liver function tests have occurred in many persons receiving Capastat Sulfate in combination with other antituberculosis agents that also are known to cause changes in hepatic function. The role of Capastat Sulfate in producing these abnormalities is not clear; however, periodic determinations of liver function are recommended.

Blood: Leukocytosis and leukopenia have been observed. The majority of patients treated have had eosinophilia exceeding 5% while receiving daily injections of Capastat Sulfate. This has subsided with reduction of the Capastat Sulfate dosage to 2 or 3 g weekly.

Pain and induration at the injection site have been observed. Excessive bleeding at the injection site has been reported. Sterile abscesses have been noted. Rare cases of thrombocytopenia have been reported.

Hypersensitivity: Urticaria and maculopapular skin rashes associated in some cases with febrile reactions have been reported when Capastat Sulfate and other antituberculosis drugs were given concomitantly.

Overdosage

Signs and Symptoms

Nephrotoxicity following the parenteral administration of Capastat Sulfate is most closely related to the area under the curve of the serum concentration versus time graph. The elderly patient, patients with abnormal renal function or dehydration, and patients receiving other nephrotoxic drugs are at much greater risk for developing acute tubular necrosis.

Damage to the auditory and vestibular divisions of cranial nerve VIII has been associated with Capastat Sulfate given to patients with abnormal renal function or dehydration and in those receiving medications with additive auditory toxicities. These patients often experience dizziness, tinnitus, vertigo, and a loss of high–tone acuity.

Neuromuscular blockage or respiratory paralysis may occur following rapid intravenous infusion.

If capreomycin is ingested, toxicity would be unlikely because it is poorly absorbed (less than 1%) from an intact gastrointestinal system.

Hypokalemia, hypocalcemia, hypomagnesemia, and an electrolyte disturbance resembling Bartter’s syndrome have been reported to occur in patients with capreomycin toxicity.

The subcutaneous median lethal dose in mice was 514 mg/kg.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

Patients who have received an overdose of capreomycin and have normal renal function should be carefully hydrated to maintain a urine output of 3 to 5 mL/kg/h. Fluid balance, electrolytes, and creatinine clearance should be carefully monitored.

Hemodialysis may be effectively used to remove capreomycin in patients with significant renal disease.

Capastat Dosage and Administration

Capastat Sulfate may be administered intramuscularly or intravenously following reconstitution. Reconstitution is achieved by dissolving the vial contents (1 g) in 2 mL of 0.9% Sodium Chloride Injection or Sterile Water for Injection. Two to 3 minutes should be allowed for complete dissolution.

Intravenously— For intravenous infusion, reconstituted Capastat Sulfate should be diluted in 100 mL of 0.9% Sodium Chloride Injection and administered over 60 minutes.

Intramuscularly— Reconstituted Capastat Sulfate should be given by deep intramuscular injection into a large muscle mass, since superficial injection may be associated with increased pain and the development of sterile abscesses.

For administration of a 1–g dose, the entire contents of the vial should be given. For doses lower than 1 g, the following dilution table may be used.

DILUTION TABLE

* Equivalent to capreomycin activity. Approximated concentration takes into account the retention volume.
Diluent Added to 1-g, 10-mL Vial	Volume of Capastat Sulfate Solution	Concentration (Approx)
2.15 mL	2.85 mL	370 mg*/mL
2.63 mL	3.33 mL	315 mg*/mL
3.3 mL	4 mL	260 mg*/mL
4.3 mL	5 mL	210 mg*/mL

The solution may acquire a pale straw color and darken with time, but this is not associated with loss of potency or the development of toxicity. After reconstitution, all solutions of Capastat Sulfate may be stored for up to 24 hours under refrigeration.

Capreomycin is always administered in combination with at least 1 other antituberculosis agent to which the patient’s strain of tubercle bacilli is susceptible. The usual dose is 1 g daily (not to exceed 20 mg/kg/day) given intramuscularly or intravenously for 60 to 120 days, followed by 1 g by either route 2 or 3 times weekly. (Note — Therapy for tuberculosis should be maintained for 12 to 24 months. If facilities for administering injectable medication are not available, a change to appropriate oral therapy is indicated on the patient’s release from the hospital.)

Patients with reduced renal function should have dosage reduction based on creatinine clearance using the guidelines included in Table 1. These dosages are designed to achieve a mean steady–state capreomycin level of 10 μg/mL.

Table 1. Estimated Dosages to Attain Mean Steady-State Serum Capreomycin Concentration of 10 µg/mL (Based on Creatinine Clearance)

* For patients with renal impairment, initial maintenance dose estimates are given for optional dosing intervals; longer dosing intervals are expected to provide greater peak and lower trough serum capreomycin levels than shorter dosing intervals. † The usual dosage for patients with normal renal function is 1000 mg daily, not to exceed 20 mg/kg/day, for 60 to 120 days, then 1000 mg 2 to 3 times weekly.
	Capreomycin		Dose* (mg/kg) for the Following
CrCl	Clearance	Half-life	Dosing Intervals
(mL/min)	(L/kg/h x 10 –2)	(hours)	24 h	48 h	72 h
0	0.54	55.5	1.29	2.58	3.87
10	1.01	29.4	2.43	4.87	7.30
20	1.49	20.0	3.58	7.16	10.7
30	1.97	15.1	4.72	9.45	14.2
40	2.45	12.2	5.87	11.7
50	2.92	10.2	7.01	14.0
60	3.40	8.8	8.16
80	4.35	6.8	10.4†
100	5.31	5.6	12.7†
110	5.78	5.2	13.9†

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How is Capastat Supplied

Capastat® Sulfate, Capreomycin for Injection, USP, is available in:

Vials: 1 g1, 10 mL size (No. 718) (1s) NDC 0002-1485-01

_________

1

Equivalent to capreomycin activity.

Store at controlled room temperature 15° to 30°C (59° to 86°F) prior to reconstitution.

Animal Pharmacology

In addition to renal and cranial nerve VIII toxicity demonstrated in animal toxicology studies, cataracts developed in 2 dogs on doses of 62 mg/kg and 100 mg/kg for prolonged periods.

In teratology studies, a low incidence of “wavy ribs” was noted in litters of female rats treated with daily doses of 50 mg/kg or more of capreomycin.

REFERENCES

1. 
   

   Lehmann CR, Garrett LE, Winn RE, Springberg PD, Vicks S, Porter DK, Pierson WP, Wolny JD, Brier GL, Black HR. Capreomycin kinetics in renal impairment and clearance by hemodialysis. Am Rev Respir Dis 1988;138/5:1312–3.

   
   


2. 
   

   Unpublished data on file at Lilly.

   
   

Literature revised January 14, 2008

Eli Lilly and Company

Indianapolis, IN 46285, USA

Copyright © 1971, 2008 Eli Lilly and Company. All rights reserved.

PV 4801 AMP

LABEL – Capastat 1g vial

1 VIAL

NDC 0002-1485-01

VIAL No. 718

Capastat® Sulfate

Capreomycin For Injection, USP

Equivalent to 1 g

Capreomycin Activity

Rx Lilly

For INTRAMUSCULAR AND INTRAVENOUS INFUSION ONLY

Lilly

Capastat SULFATE  capreomycin sulfate  injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0002-1485 Route of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Capreomycin sulfate (Capreomycin) Capreomycin sulfate 1 g  in 2 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0002-1485-01 2 mL In 1 VIAL None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA050095	10/01/1971

Labeler - Eli Lilly and Company (006421325)

Establishment
Name	Address	ID/FEI	Operations
Eli Lilly and Company Limited (Speke)		230761368	API MANUFACTURE, ANALYSIS

Establishment
Name	Address	ID/FEI	Operations
Eli Lilly and Company (Indianapolis)		006421325	MANUFACTURE, ANALYSIS

Revised: 02/2010Eli Lilly and Company

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