Dacarbazin

Uses

Citric Acid Monohydrate contains the active ingredient Citric Acid Monohydrate which helps to reduce the dry cough and soothes the throat from any related discomfort and pain. Citric Acid is a demulcent which relieves irritation of the mucous membrane in the throat by forming a protective film. Citric Acid is absorbed after oral administration. It is found naturally in the body and is widely distributed.

Dacarbazine is used for the treatment of metastatic malignant melanoma. In addition, Dacarbazine is also used for Hodgkin’s disease as a second-line therapy when used in combination with other effective agents

Mannitol is principally used by IV infusion as an osmotic diuretic to preserve renal function in acute renal failure and to reduce raised intracranial and intraocular pressure. Mannitol is also used as an irrigating solution to prevent hemolysis and hemoglobin buildup during transurethral prostatic resection. It is useful in the management of acute drug poisoning where a route of elimination is through kidney. Besides these, it is also used in symptomatic relief of edema, reperfusion injury, termination of pregnancy, and bowel preparation. So, Mannitol is used for-

Renal insufficiency, Reperfusion injury, Raised intracranial pressure, Bladder irrigation, Raised intraocular presure, Bowel preparation, Edematous status, As a prophylactic in renal failure, Management of poisoning, Termination of Pregnancy

Dacarbazin is also used to associated treatment for these conditions: Acidosis, Catheter site calcification caused by appetite, Catheter site calcification caused by struvite, Gouty Arthritis, Headache, Heartburn, Kidney Stones, Metabolic Acidosis, Blood Specimen Collection, Blood sample storage, Bowel preparation therapy, Chemical contraception, Potassium placement, Urine alkalinization therapy, Cleansing of the colon as a preparation for colonoscopy, Oral antisepsisAdvanced Soft Tissue Sarcoma, Lymphoma, Hodgkins, Metastatic Melanoma, Pheochromocytomas, Advanced Medullary thyroid cancer, Advanced Pancreatic neuroendocrine tumorAcute Renal Failure (ARF), Cystic Fibrosis (CF), Edema of the cerebrum, Increased Intra Ocular Pressure (IOP), Bladder irrigation therapy

How Dacarbazin works

The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific.

Mannitol is an osmotic diuretic that is metabolically inert in humans and occurs naturally, as a sugar or sugar alcohol, in fruits and vegetables. Mannitol elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure, and cerebrospinal fluid volume and pressure may be reduced. As a diurectic mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes. Mannitol promotes the urinary excretion of toxic materials and protects against nephrotoxicity by preventing the concentration of toxic substances in the tubular fluid. As an Antiglaucoma agent mannitol levates blood plasma osmolarity, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure. As a renal function diagnostic aid mannitol is freely filtered by the glomeruli with less than 10% tubular reabsorption. Therefore, its urinary excretion rate may serve as a measurement of glomerular filtration rate (GFR).

The exact mechanism of action of inhaled mannitol in the symptomatic maintenance treatment of cystic fibrosis remains unclear. It is hypothesized that mannitol produces an osmotic gradient across the airway epithelium that draws fluid into the extracellular space and alters the properties of the airway surface mucus layer, allowing easier mucociliary clearance.

Dosage

Dacarbazin dosage

Age Dose Dose frequency

1-5 years 5 ml Upto 4 times daily

6-12 years 10 ml Upto 4 times daily

>12 years & Adults 20 ml 3-4 times daily

Malignant Melanoma: The recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals. An alternate recommended dosage is 250 mg/m²/day IV for 5 days. Treatment may be repeated every 3 weeks.

Hodgkin’s Disease: The recommended dosage of Dacarbazinein the treatment of Hodgkin’s disease is 150 mg/m²/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks. An alternative recommended dosage is 375 mg/m² on day 1, in combination with other effective drugs, to be repeated every 15 days.

The adult dose of Mannitol ranges from 50 to 100 gm by IV infusion. The rate of administration is usually adjusted to maintain a urine flow of at least 30 to 50 ml/hr. Total dosage, concentration and the rate of administration depends on fluid requirement, urinary output and the severity of the condition being treated

Renal insufficiency-

• Adults: 50 to 100 g of Mannitol administered at a rate adjusted to maintain a urine flow of at least 30 to 50 ml/hr.
• Children: 2 gm/kg or 60 gm/m2of body surface area administered over a period of 2 to 6 hrs.

Cerebral edema, elevated intracranial pressure, elevated intraocular pressure, Glaucoma-

• Adults: 1.5 to 2 gm/kgadministered over a period of 30 to 60 minutes.
• Children: 1 to 2 gm/kg body wt. or 30 to 60 gm/m2 of body surface area administered over a period of 30 to 60 mins.

Adjunctive therapy for removal of toxic substances-

• Adults: 50 to 200 g of Mannitol administered at a rate adjust to maintain a urine flow of at least 100 to 500 ml/hr.
• Children: 2 gm/kg or 60 gm/m2of body surface area

For termination of pregnancy 50 gm of Mannitol (250 ml of Mannitol) is instilled into the amniotic cavity which induces abortion in a high proportion of pregnancies.

Dacarbazine 200 mg/vial is reconstituted with 19.7 mL of Sterile Water for Injection. The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0. The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously. The reconstituted solution may be further diluted with 5% dextrose injection or sodium chloride injection and administered as an intravenous infusion. After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours. If the reconstituted solution is further diluted in 5% dextrose injection or sodium chloride injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.

Side Effects

There are no known side effects from using this medicine when used as directed. If taken excessively above the stated dose, glycerol present in the medicine may cause headache, stomach upset and diarrhea.

Symptoms of anorexia, nausea and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses. The vomiting lasts 1 to 12 hours and is incompletely and unpredictably palliated with phenobarbital and/or prochlorperazine. Rarely, intractable nausea and vomiting have necessitated discontinuance of therapy with Dacarbazine for Injection. Rarely, Dacarbazine for Injection has caused diarrhea. Some helpful suggestions include restricting the patient’s oral intake of food for 4 to 6 hours prior to treatment. The rapid toleration of these symptoms suggests that a central nervous system mechanism may be involved, and usually these symptoms subside after the first 1 or 2 days.

The most common side effects associated with Mannitol intravenous infusion is fluid and electrolytes imbalance including circulatory overload and acidosis at high doses. Other side effects include nausea, vomiting, thirst, headache, dizziness, fever, tachycardia, chest pain, hyponatraemia, dehydration, blurred vision, urticaria, and hypertension or hypotension.

Toxicity

ORAL (LD50): Acute: 5040 mg/kg [Mouse]. 3000 mg/kg [Rat].

LD₅₀=350mg/kg (orally in mice)

Mannitol overdose may result in bronchoconstriction and should be counteracted using a short-acting bronchodilator and other symptomatic and supportive care, as necessary.

Precaution

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Hospitalization is not always necessary but adequate laboratory study capability must be available. Extravasation of the drug subcutaneously during intravenous administration may result in tissue damage and severe pain. Local pain, burning sensation and irritation at the site of injection may be relieved by locally applied hot packs. Carcinogenicity of dacarbazine was studied in rats and mice. Proliferative endocardial lesions, including fibrosarcomas and sarcomas were induced by dacarbazine in rats. In mice, administration of dacarbazine resulted in the induction of angiosarcomas of the spleen.

Careful monitoring of rate of administration of Mannitol is necessary to avoid fluid and electrolyte imbalance and circulatory overloading. The infusion should be discontinued if the patient develops signs of progressive renal dysfunction, heart failure or pulmonary congestion. Mannitol should not be administered with whole blood.

Interaction

Increased metabolism when used with enzyme inducers (e.g. barbiturates, rifampicin, phenytoin). May potentiate the effect of mercaptopurine, azathioprine, allopurinol. May impair immune response to vaccines. May enhance the effects of methoxsalen due to photosensitisation.

Increased nephrotoxicity with ciclosporin.

Volume of Distribution

Mannitol administered intravenously has a volume of distribution of 34.3 L.

Elimination Route

Erratic, slow and incomplete.

Approximately 7% of ingested mannitol is absorbed during gastrointestinal perfusion in uremic patients.

Inhalation of 635 mg of mannitol powder yields a plasma C_max of 13.71 μg/mL in 1.5 hours (T_max) and a mean systemic AUC of 73.15 μg*h/mL.

Half Life

5 hours

Mannitol has an elimination half-life of 4.7 hours following oral administration; the mean terminal elimination half-life is similar regardless of administration route (oral, inhalation, and intravenous.

Clearance

Intravenous administration of mannitol yields a total clearance of 5.1 L/hr and renal clearance of 4.4 L/hr.

Elimination Route

Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine.

Mannitol is primarily excreted unchanged in the urine. Following oral inhalation of 635 mg of mannitol in healthy volunteers, 55% of the total dose was recovered unchanged in the urine; following oral or intravenous administration of 500 mg, the corresponding values were 54 and 87%, respectively.

Pregnancy & Breastfeeding use

There are no or limited amount of data from the use of Citric Acid Monohydrate in pregnant women. There is insufficient information on the excretion of Citric Acid Monohydrate & its metabolites in human milk.

Pregnancy Category C. Dacarbazine for Injection has been shown to be teratogenic in rats when given in doses 20 times the human daily dose on day 12 of gestation. Dacarbazine when administered in 10 times the human daily dose to male rats (twice weekly for 9 weeks) did not affect the male libido, although female rats mated to male rats had higher incidence of resorptions than controls. In rabbits, dacarbazine daily dose 7 times the human daily dose given on Days 6 to 15 of gestation resulted in fetal skeletal anomalies. There are no adequate and well controlled studies in pregnant women. Dacarbazine for Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 tumorigenicity shown for Dacarbazine for Injection in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety of Mannitol intravenous infusion in pregnancy has not been established yet. No information is available on the excretion of mannitol in breast milk and should be administered after careful consideration of risk-benefit ratio.

Contraindication

Dacarbazine is contraindicated in patients who have demonstrated a hypersensitivity to it in the past.

Mannitol intravenous infusion is contraindicated in patients with pulmonary edema or congestive heart failure. It is also contraindicated during inadequate urine flow, dehydration or acidosis, intracranial bleeding and in patients with renal failure unless a test dose has produced a diuretic response

Acute Overdose

Give supportive treatment and monitor blood cell counts.

Storage Condition

Keep in a cool and dry place, away from light. Keep out of the reach of children.

Store in a refrigerator 2°C to 8°C

Mannitol should be stored at a temperature of 20° to 30°. Exposure to lower temperatures may cause deposition of crystals, which should be dissolved by warming the bottle in hot water for about 30 minutes. Cool to body temperature before using. If all crystals can not be dissolved, the solution should not be used. The content of open containers should be used promptly. Unused contents should be discarded.

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