Melphalan 2

Each film-coated tablet contains:

Melphalan I.P.  2 mg

Excipients     q.s

Colour: Approved color

Melphalan 5

Each film-coated tablet contains:

Melphalan I.P.          5 mg

Excipients       q.s

Colour: Approved color

Melphalan is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2- chloroethyl groups enables alkylation through covalent binding with the 7-nitrogen of guanine on DNA, cross-linking Iwo DNA strands and thereby preventing cell replication. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.

In a study of 18 patients administered melphalan 0.2 to 0.25 mg/kg body weight orally, a maximum plasma concentration (range 87 to 350 ng/mL) was reached within 0.5 to 2.0 hours. The mean elimination half-life was 1.12+ 0.15 hours.

The steady-state volume of distribution of melphalan is 0.5 like. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges torn 60% to 93%. Serum albumin is the major binding protein, while of-acid glycoprotein appears to account for about 20% of the plasma protein binding. Approximately 30% of the drug is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.

Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low. one study noted an increase in the occurrence of severe leucopenia in patients with elevated blood urea nitrogen (BUN) after 10 weeks of therapy.

Melphalan is indicated for the palliative treatment of multiple rnyeloma and advanced ovarian adenocarcinorna. Melphalan has a significant therapeutic effect in a proportion of patients suffering from advanced breast carcinoma and may be used in the treatment of policythaemia vera.

The usual oral dose is 6 mg (3 tablets) daily. The entire daily dose may be given at one time. The dose is adjusted, as required, on the basis of blood counts done at approximately weekly intervals. After 2 to 3 weeks of treatment, the drug should be discontinued for up to 4 weeks, during which time the blood count should be followed carefully. When the white blood cell and platelet counts are rising, a maintenance dose of 2 mg daily rimy be instituted. Because of the patient-to-patient variation in melphalan plasma levels following oral administration of the drug. several investigators have recommended that the dosage of Melphalan be cautiously escalated until some rnyelosuppression is observed in order to assure that potentially therapeutic levels of the drug have been reached.

Other dosage regimens have been used by various investigators. 0sserm an and Takatsuki have used an initial coursed 10 mg/day for 7 to 10 days. They report Mat maximal suppression of the leukocyte and platelet counts occurs within 3 to 5 weeks arid recovery within 4 to a week5. Continuous maintenance therapy with 2 mg/day is instituted when the white blood cell count is greater than 4,000 cells/mcL and the platelet count is greater than 100,000 cells/mcL. Dosage is adjusted to between land 3 mglday depending upon the hematological response. II is desirable to tni to maintain a significant degree of bone marrow depression sass to keep the leukocyte count in the range of 3,000 to 3,500 cells/mcL.

Hoogstraten et el have started treatment with 0,15 mg/kg/day for 7 days. This is followed by rest period of at least 14 days, but it may be as Icing as 5 to 6 weeks. Maintenance therapy is started when the white blood cell and platelet counts are rising. The maintenance dose is 0.05 mg/kg/day or less and readjusted according tote blood count.

Available evidence suggests that about one third to one half of the patients with multiple rnyeloma show a favorable response to oral administration of the drug.

One study by Alexanian el al has shown that the use of Melphalan in combination with prednisone significantly improves the percentage of patients with multiple myeloma who achieve palliation. One regimen has been to administer courses of Melphalan at 0.25 mg/kg/day ay for 4 consecutive days (or, 0.20 mg/kg/day for 5 consecutive days) for a total time of I mg/kg/course. These 4- to 5-day courses are then repeated every 4 to 6 weeks if the granulocyte count and the platelet count have returned to normal levels.

It is to be emphasized that response may be very gradual over many months: it is important that repeated courses or continuous therapy be given since improvement may continue slowly over many months, and the maximum benefit maybe missed if treatment is abandoned too soon.

In patients with moderate to severe renal impairment, currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction to those patients, but it may be prudent to use a reduced dose initially.

Epithelial Ovarian Cancer: One commonly employed regimen for the treatment of ovarian carcinoma has been to administer Melphalan at a dose of 0.2 mg/kg daily for 5 days as a single course. Courses are repeated every 4 to 5 weeks depending upon hematologic tolerance.

Melphalan Is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Provided the outer coating of the tablet Is intact, there is no risk in handling Melphalan tablets.

Melphalan tablets should not be divided. Do not break, crust or chew the tablets. Since Melphalan is a potent myelosuppressive agent, it is essential that careful attention should be paid to the monitoring of blood counts to avoid the possibility of excessive rnyelosuppression and the risk of irreversible bone marrow aplasia. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent course of Melphalan: platelet count, haemoglobin, white blood cell count, and differential.

Thrombocytopenia and/or leucopoenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis or blood counts at the nadir and day of treatment should be considered. See DOSAGEANDADMINISTRATION.

Although controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation, severe bone marrow suppression with resulting infection or bleeding fray occur Melphalan should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy or whose marrow function is recovering horn previous cytotoxic therapy.

Renal impairment: Melphalan clearance may be reduced in patients with renal impairment, who may also haye uraemic bone marrow suppression. Dosage reduction may therefore be necessary (see Dosage and Administration), and these patients should be closely observed.

Administration Precautions: Procedures For proper handling and disposal of anticancer drugs should be considered.

Haematologic: The most common side-effect is bone marrow depression leading to leucopenia, thrombocytopenia and anemia. White blood oell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been reported. Acute leukemia has also been reported.(See Mutagenicity and carcinogenicity).

Gastrointestinal: Gastro-intestinal effects such as nausea and vomiting occur in up to 30 per cent of patients receiving conventional oral doses of Melphalan. Diarrhoea is very common.0ral uIceration occurs infrequently. Stomatitis occurs rarely following conventional doses of Melphalan. At high doses stomatitis is very common.

Hypersensitivity: Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of425 patients receiving Melphalan for Injection for myeloma (see PRECAUTIONS AND WARNINGS). These reactions were characterized by urticaria, pruritis, skin rashes, oedema, and in some patients, tachycardia, bronchospasm, dyspnoea, and hypotension These patients appeared to respond to antihistamine and corticosteroid therapy If a hypersensitivity reaction occurs, IV or oral melphalan should not be re-administered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been imported rarely in association with such events.

Miscellaneous: Other reported adverse reactions include skin hypersensitivity, skin necrosis rarely requiring skin grafting, maculopapular rashes, pruritus, vasculitis, allergic reaction, and interstitial pneumonitis.

Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and Jaundice have been reported. Veno-occlusive disease has been reported in association with these cases.

Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage. There have been case reports of interstitial pneumonitis and pulmonary fibrosis. There have also been case reports of fatal pulmonary fibrosis and haemolytic anaemia occurring after melphalan treatment.

Alopecia is very common at high doses and common at conventional doses.

CLINICAL TRIALS

A randomized trial compared prednisone plus IV melphalan to prednisone plus oral melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the two formulations after week 22 are impossible to make.

Both arms received oral prednisone starting at 0.8 mg/kg per day with doses tapered over 6 weeks. Melphalan doses in each arm were:

Arm 1: Oral melphalan 0.15 mg/kg per day x 7 followed by 0.05 mg/kg per day when WBC began to rise.

Arm 2: IV melphalan 16 mg/m2 once every 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.

Doses of melphalan were adjusted according to the following criteria:

Table 1: Criteria for Dosage Adjustment in a Randomized Clinical Trial

107 patients were randomised to the oral melphalan and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumour load (51% versus 34%) on the oral compared to the IV arm(P<0.04). Response rates at week 22 are shown in the following table.

Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.

Severe myelotoxicity (WBC ≤1000 and/or platelets ≤ 25,000) was more common in the IV melphalan am (28%) than the oral melphalan arm (11%).

An association was holed between poor renal function and myelosuppression; Consequently, an amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was 30 mg/DI (≥10.71 mmol/L). The rate of severe leucopenia in the I\/ am in the patents with BUN over 30 mg/DI (≥10.71 mmol/L) decreased horn 50% (8/16) before protocol amendment to11%  (3/108) (P = 0.01) after the amendment.

Before the dosing amendment, there was a 10% (8/77) incidence of drug related death in the IV arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug- related death in the oral arm.

: Simultaneous administrator of nalidixic acid with melphalan should be avoided if possible. Nalidixic acid together with high dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.

Cyclosporin and high dose melphalan is a potentially dangerous combination. A deterioration of renal function was associated win simultaneous use of these drugs, bat not with melphalan alone.

Cisplatin may affect melphalan kinetics by inducing renaI dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for Carmustine lung toxicity.

Vaccinations with live organism vaccines are not recommended in imrrurocor1p+omised individuals (See PRECAUTIONS AND WARNINGS}:

MUTAGENICITY AND CARCINOGENICITY: Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.

Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic in man. There been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macrogIobuIinaemia, cold agglutinin syndrome and ovarian cancer.

A comparison of patients with ovarian cancer who received alkylating agent with those who did not showed that the use of alkylating agents, including melphalan, significantly increased the incidence of acute leukaemia. The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.

Secondary malignancies, including acute nonlymphocytic leukaemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylaling agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukaemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukaemia in patients who have received melphalan (and other alkylating agents) suggest trial the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. The potential benefits from Melphalan therapy must be weighed on an individual basis against the possible risk of the inductor of a second malignancy.

Although adequate and well-controlled carcinogenicity studies have not been conducted In animals, there is clear evidence from animal studies that melphalan is carcinogenic. Intraperitoneal (IP) administration of melphalan in rats (5.4 or 10.8 mg/m2) and mice (2.25 or 4.5 mg/m2) three tlmes per week for 6 months followed by a 12 months post-dose observation produced peritoneal sarcoma in rats, and lung tumors and lymphosarcomas (males) in mice.

Lung tumours were also increased in two other studies in mice (total dose: 144 mg/m2 dermal given as 10 infections over a period of 10 weeks; 3.2-51 mg/m2 IP given as 12 injections over a period of 4 weeks) while in one of these studies (dermal), skin papillomas were increased although non-significantly.

Chromosome aberrations have been observed in patents being treated with Melphalan. Melphalan has been shown to cause chromatid and chromosome damage in human lymphocytes at a single dose of 20 mg IV (-10.6 mg/m2,  comparable to a therapeutic dose of 16 mg/m2/ and In rat bone marrow cells at a single intramuscular dose  of 6 mg/m2. Melphalan also showed mutagenic effect on germ cells in male mice at 17.1-21.9 mg/m2.

Effects on fertility: Melphalan causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.

No fertility studies have been conducted in animals. However, there is evidence from some animal studies that melphalan can have an adverse effect on spermatogenesis. Therefore, it is possible that Melphalan may cause temporary or permanent sterility in male patient.

Use in Pregnancy: Category D.

As with other cytotoxic agents, Melphalan can produce spontaneous abortion, foetal loss and birth defects. The teratogenic potential of Melphalan has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that melphalan could cause congenital defects in the offspring of patients treated with the drug.

As with  all cytotoxic chemotherapy, adequate contraceptive precautions should be practiced when either partner is receiving Melphalan.

The use of Melphalan should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.

Melphalan has been shown to be teratogenic and embryogenic in animaIs studies. A singIe  dose of 5 mg/kg IP(30 mg/m2) given on day 6 or day 9 of gestation in the rat was embryolethal and teratogenic, and a single dose of 3 mg/kg IP (18 mg/m2) was teratogenic when administered on day 6. Malformations resulting from melphalan administration included alterations of the brain (underdevelopment, deformation, meningocele and encephaiocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as exomphaly (umbilical hernia).

In a repeat-dose embryotoxicity study in rats, (0.33, 1 and 3 mg/kg/day PO on gestation days 7-17; total doses: 22. 66 and 198 mg/m2 PO, respectively; at clinical dose of 16 mg/m2 IV), all doses were maternotoxic reduced weight gain, and mortality occurred at the high dose).

Intrauterine deaths, reduced foetal and pup weights and pup weight gain over the lactation period were seen in the mid and high dose groups but pup survival over the lactation period was reduced at all doses. Melphalan showed a reduction in ossification at >1mg/kg/day and an Increased incidence of rib anomalies and impairment of pup development (delayed eruption of incisors, significantly different open field behaviour) at the high dose. No animal studies have been conducted to investigate the peri- and post-natal effects of melphalan.

Lactation: It is not known whether this drug is excited in human milk. Mothers receiving Melphalan should not breastfeed.

CONTRAINDICATIONS:

Melphalan should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan.

Overdose:

Signs and Symptoms: Overdoses insulting in death have been reported. Overdoses, including doses up to 290 mg/m2, have produced the following symptoms: severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis. and cholinomimetic effects. Damage to the gastrointestinal lining may also ensue. Severe mucositis, stomatitis, colitis, diarrhoea, and haemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m2). Elevations in liver enzymes and veno-occlusive disease occur infrequently.

Significant hyponatremia caused by an associated inappropriate secretion of  antiduretic hormone (ADH) syndrome  has been observed  Nephrotoxicity and adult respiratory distress  syndrome  have been reported rarely.

Management: The principal toxic effect is bone marrow suppression, leading to leucopenia, thrornbocytopenia and anaemia. Hematologic parameters should be closely followed for at least 4 weeks following mellow until there is evidence of recovery. An uncontrolled study suggests that administration of autologous bone marrow or haematopoietic growth factors (filgrastim) may shorten the period of pancytopenla. General supportive measures together with appropriate blood and platelet transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by haemodialysis or haernoperfusion. A paediatric patient survived a 254-mg/rn2 overdose treated with standard supportive care.

Store at a temperature between 2°C to 8°C (36°F to 46’F)

Protect from light.

Melphalaz 2

Bottle containing 30 tablets.

Melphalaz 5

Bottle containing 25 tablets.