Page 1 of 14
`
`Frontier Therapeutics Exhibit 1009
`
`

`
`Antineoplastic Chemotherapy
`
`Methotrexate is active orally and parenterally. Methotrexate Injection 13.1’.
`may be given by the intramuscular, intravenous, intra-arterial or intrathecal
`routes. Dosage is related to the patient‘s body weight or surface area.
`Methotrexate has been used with beneficial effect
`in a wide variety of
`neoplastic diseases, alone and in combination with other cytotoxic agents.
`
`NOTE: Methotrexate Injection 1 g.’ 10ml and Sgf 50ml are hypertonic and
`thus it is not recommended for intrathecal use. in addition, the 500 mg/20 ml
`and l g/40 ml presentations are not suitable for intrathecal use.
`
`Chorlocareinotna and Similar Troplioblastic Diseases
`
`Methotrexate is administered orally or intramuscularly in doses of I5-30mg
`daily for a 5 day course. Such courses may be repeated 3-5 times as required,
`with rest periods of one or more weeks interposed between courses until any
`manifesting toxic symptoms subside.
`
`The effectiveness of therapy can be evaluated by 24 hours quantitative
`analysis of urinary chorionic gonadotrophin hormone (l-ICG). Combination
`therapy with other cytotoxic drugs, has also been reported as useful.
`
`Hydatidiform mole may precede or be followed by choriocarcinoma, and
`Methotrcxate has been used in similar doses for the treatment of hydatidiform
`mole and chorioadenoma destruens.
`
`Breast Carcinoma
`
`Prolonged cyclic combination with Cyclophosphamide, Methotrexate and
`Fluorouracil has given good results when used as adjuvant treatment to radical
`mastectomy in primary breast cancer with positive axillary lymph nodes.
`Methotnexate dosage was 4Omgfm2 intravenously on the first and eighth days.
`
`Leukaemia
`
`Acute granulocylic leukaemia is rare in children but common in adults and this
`form of leukaemia responds poorly to chemotherapy.
`
`Methotrexate is not generally a drug of choice for induction of remission of
`lymphoblastic
`leukaemia. Oral Methotrexate
`3.3mgltn2
`daily,
`and
`Prednisolonc 40-601ng/1112 daily for 4-6 weeks has been used. After a
`remission is attained, Methotrexate in a maintenance dosage of 20-301ngz‘m2
`orally or by l.M. injection has been administered twice weekly. Twice weekly
`doses
`appear
`to be more
`effective
`than daily drug administration.
`Alternatively, 2.5mg/kg has been administered LV. every 14 days.
`
`Meningeal Leukaemia
`
`Page 2 of 14
`Page 2 of 14
`
`

`
`Some patients with leukaemia are subject to leukaemic invasions of the central
`nervous system and the CSF should be examined in all leukaemia patients.
`
`Passage of Methotrexate from blood to the cerebrospinal fluid is minitnai and
`for adequate
`therapy the drug should be
`administered intrathecally.
`Methotrexate may be given in a prophylactic regimen in all cases of
`iymphoeytie leukaemia. The dose of intrathecai Methotrex.ate is constant
`regardless of age or body surface area in patients over the age of 3 years of
`age, the maximum intratheeal dose should be l21ng in such patients. Patients
`under the age of 3 yeais should be treated in accordance with combination
`chemotherapy protocols. The administration is at weekly intervals and is
`usually repeated until the cell count of cerebrospinal fluid returns to normal.
`At
`this point one additional dose is advised. Large doses may cause
`convulsions and untoward side effects may occur as with any intratheeal
`injection, and are commoniy neurological in character.
`
`NOTE: Methotrexate Injection I gt‘ 10ml and 5g! 50ml are not recommended
`for intratheeal use. In addition, the 500 mg/20 ml and 1 g/40 rnl presentations
`are not suitable for intratheeal use.
`
`Lymphomas
`
`In Burkitt’s Tumour, stages 1-2, Mcthotrexate has prolonged remissions in
`some cases. Recommended dosage is 10-25mg per day orally for 4 to 8 days.
`In stage 3, Methotrexate is commonly given eoncomitantiy with other
`antitumour agents. Treatment in all stages usually consists of several courses
`of the drug interposed with 7 to 10 day rest periods, and in stage 3 they
`respond to combined drug therapy with Methotrexate given in doses of
`0.62S:ng to
`2.5mg:"kg daily. Hodgkin’s Disease
`responds poorly to
`Methotrexate and to most types of chemotherapy.
`
`Myeosis Fungoides
`
`Therapy with Methotrexate appears to produce clinical remissions in one half
`of the cases treated. Recommended dosage is usually 2.5 to 10mg daily by
`mouth for weeks or months and dosage should be adjusted according to the
`patient’s response and haematological monitoring. Methotrexate has also been
`given intramuscularly in doses of 50mg once weekly or 25mg twice weekly.
`
`Psoriasis Chemotherapy
`
`Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy,
`have responded to weekly single, oral, I.M. or I.\/. doses of l0~25mg per
`week, adjusted according to the patient’s response. An initial test dose one
`week prior to initiation of therapy is recommended to detect any idiosyncrasy.
`A suggested dose range is 5-10mg parenterally.
`
`An alternative dosage schedule consists of 2.5 to Sing of Methotrexate
`administered orally at 12 hour intervals for 3 doses each week or at 8-hour
`intervais for 4 doses each week; weekly dosages should not exceed 30mg.
`
`Page 3 of 14
`Page 3 of 14
`
`

`
`A daily oral dosage schedule of 2 to Srng administered orally for 5 days
`followed by
`a rest period of at least 2 days may also be used. The daily dose should not
`exceed 6.25mg.
`
`The patient should be fully informed of the risks involved and the clinician
`should pay particular attention to the appearance of liver toxicity by carrying
`out liver function tests before starting Methotrexate treatment, and repeating
`these at 2 to 4 month intervals during therapy. The aim oftherapy should be to
`reduce the dose to the lowest possible level with the longest possible rest
`period. The use of Mcthotrexate may permit the return to conventional topical
`therapy which Should be encouraged.
`
`4.3.
`
`Contraindications
`
`Significantly impaired renal function.
`
`Significantly impaired hepatic function
`
`Pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia,
`thrombocytopenia or anaemia.
`
`Methotrexate is contraindicated in pregnancy.
`
`Because of the potential for serious adverse reactions from methotrexate in breast fed
`infants, breast feeding is contra-indicated in women taking methotrexate.
`
`Patients with a known allergic hypersensitivity to methotrexate should not receive
`rriethotrexate.
`
`4.4.
`
`Special warnings and precautions for use
`
`Warnings
`
`Methotrexate must be used only by physicians experienced in antinictabolite
`chemotherapy.
`
`Because ofthe possibility of fatal or severe toxic reactions, the patient should be fully
`informed by the physician of the risks involved and be under his constant supervision.
`
`Acute or chronic interstitial pnemonitis, often associated with blood eosinophilia, may
`occur and deaths have been reported. Symptoms typically include dyspnoea, cough
`(especially a dry non-productive cough) and fever for which patients should be
`monitored at each follow-up visit. Patients should be informed of the risk of
`pneumonitis and advised to contact their doctor immediately should they develop
`persistent cough or dyspnoea.
`
`Page 4 of 14
`Page4 of 14
`
`

`
`Methotrexate should be withdrawn from patients with pulmonary symptoms and a
`thorough investigation should be made to exclude infection. If methotrexate induced
`lung disease is suspected treatment with corticosteroids should be initiated and
`treatment with methotrexate should not be restarted.
`
`Deaths have been reported with the use of Methotrexate in the treatment of psoriasis.
`
`In the treatment of psoriasis, Methotrexate should be restricted to severe recalcitrant,
`disabling psoriasis which is not adequately responsive to other forms of therapy, but
`only when the diagnosis has been established by biopsy andfor after dermatological
`consultation.
`
`Full blood counts should be closely monitored before, during and after
`1.
`treatment. Ifa clinically significant drop in wl1ite—cell or platelet count develops,
`methotrexate should be withdrawn immediately. Patients should be advised to report
`all symptoms or signs suggestive of infection.
`
`Methotrexate may be hepatotoxic, particularly at hi gh dosage or with
`2.
`prolonged therapy. Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal
`fibrosis have been reported. Since changes may occur without previous signs of
`gastrointestinal or haematological toxicity, it is imperative that hepatic function be
`determined prior to initiation of treatment and monitored regularly throughout
`therapy. If substantial hepatic function abnormalities develop, methotrexate dosing
`should be suspended for at least 2 weeks. Special caution is indicated in the presence
`of pre-existing liver damage or impaired hepatic function, Concomitant use of other
`drugs with hepatotoxic potential (including alcohol) should be avoided.
`
`Methotrexate has been shown to be teratogenic; it has caused foetal death
`3.
`and/or congenital anomalies. Therefore it is not recommended in women of
`childbearing potential unless there is appropriate medical evidence that the benefits
`can be expected to outweigh the considered risks. Pregnant psoriatic patients should
`not receive Methotrexate.
`
`Renal function should be closely monitored before, during and after treatment.
`4.
`Caution should be exercised if significant renal impairment is disclosed. Reduce dose
`of methotrexate in patients with renal impairment. High doses may cause the
`precipitation of methotrexate or its metabolites in the renal tubules. A high fluid
`throughput and alkalinisation ofthc urine to pH 6.5 — 7.0, by oral or intravenous
`administration of sodium bicarbonate (5 x 625mg tablets every three hours) or
`acetazolamide (500mg orally four times a day) is recommended as a preventative
`measure . Methotrexate is excreted primarily by the kidneys. Its use in the presence of
`impaired renal function may result in accumulation of toxic amounts or even
`additional renal damage.
`
`Diarrhoea and ulcerative stornatitis are frequent toxic effects and require
`5.
`interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal
`perforation may occur.
`
`Page 5 of 14
`Page 5 of 14
`
`

`
`Methotrexate affects gametogenesis during the period ofits administration and
`6.
`may result in decreased fertility which is thought to be reversible on discontinuation
`of therapy. Conception should be avoided during the period of Methotrexate
`administration and for at least 6 months thereafter. Patients and their partners should
`be advised to this effect.
`
`Methotrexate has some immunosuppressive activity and immunological
`7.
`responses to concurrent vaccination may be decreased. The immunosuppressive effect
`of Methotrexate should be taken into account when irnrnune responses of patients are
`important or essential.
`
`Pleural effusions and ascites should be drained prior to initiation of
`8.
`methotrexate therapy.
`
`Deaths have been reported with the use of methotrexate. Serious adverse
`9.
`reactions including deaths have been reported with concomitant administration of
`rnclhotrexatc (usually in high doses) along with some nonosteroidal anti-
`inflamrnatory drugs (NSAIDS).
`
`Concomitant administration of rotate antagonists such as
`10.
`trimethoprimfsulphamethoxazole has been reported to cause an acute tnegaloblastic
`pancytopenia in rare instances.
`11.
`Systemic toxicity may occur following intratheeal administration. Blood
`counts should be nionitored closely.
`
`12.
`
`13.
`
`A chest X-ray is recommended prior to initiation of methotrexate therapy.
`
`If acute niethotrexatc toxicity occurs, patients may require folinic acid.
`
`Precautions
`
`Mcthotrcxate has a high potential toxicity, usually dose related, and should be used
`only by physicians experienced in antitnetabolite chemotherapy, in patients under
`their constant supervision. The physician should be familiar with the various
`characteristics ofthe drug and its established clinical usage.
`
`Before beginning methotrexate therapy or reinstitutin g methotrexate after a rest
`period, assessment of renal function, liver function and blood eienients should be
`made by history, physical examination and laboratory tests.
`
`It should he noted that intrathecal doses are transported into the cardiovascular system
`and may give rise to systemic toxicity. Systemic toxicity of rnetliotrexate may also be
`enhanced in patients with renal dysfunction, aseites, or other effusions due to
`prolongation of serum half—liFe.
`
`Carcinogenesis, mutagenesis, and irnpairrnent of fertility: Animal carcinogenicity
`studies have demonstrated metliotrexate to be free of carcinogenic potential. Although
`metliotrexate has been reported to cause chromosomal damage to animal somatic celis
`and bone marrow cells in humans, these effects are transient and reversible. In
`
`Page 6 of 14
`Page 6 of 14
`
`

`
`patients treated with methotrexate, evidence is insufficient to permit conclusive
`evaluation of any increased risk of neoplasia.
`
`Mcthotrexate has been reported to cause impairment of fertility, oligospermia,
`menstrual dysfunction and amenorrhoea in humans, during and for a short period after
`cessation of therapy. In addition, rnethotrexate causes, ernbryotoxicity, abortion and
`foetal defects in humans. Therefore the possible risks of effects on reproduction
`should be discussed with patients of childbearing potential (see ‘Warnings').
`
`Patients undergoing therapy should be subject to appropriate supervision so that signs
`or symptoms of possible toxic effects or adverse reactions may be detected and
`evaluated with minimal delay. Pretreatrnent and periodic haematological studies are
`essential to the use ot'l\/Icthotrexate in chemotherapy because of its common effect of
`haematopoietic suppression. This may occur abruptly and on apparent safe dosage,
`and any profound drop in blood cell count indicates immediate stopping of the drug
`and appropriate therapy. In patients with malignant disease who have pre-existing
`bone marrow aplasia, leukopenia, thrornbocytopcnia or anaemia, methotrex ate should
`be used with caution, if at all.
`
`In general, the following laboratory tests are recommended as part ofessentiai clinical
`evaluation and appropriate monitoring of patients chosen for or receiving
`Mcthotrcxate therapy: complete haernogram; hacmatocrit; urinalysis; renal function
`tests; liver function tests and a chest X—ray.
`
`The purpose is to determine any existing organ dysfunction or system impairment.
`The tests should be performed prior to therapy, at appropriate periods during therapy
`and after termination of th erapy.
`
`Liver biopsy may be considered after cumulative doses 3-1.5g have been given, if
`hepatic impairment is suspected.
`
`Methotrexate is bound in part to serum albumin after absorption, and toxicity may be
`increased because of displacement by certain drugs such as salicylates,
`sulphonamides, phenytoin, and some antibacterials such as tetracycline,
`chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and
`sulphonamides, wlrether antibacterial, hypoglycaemic or diuretic, should not be given
`concurrently until the significance of these findings is established.
`
`Vitamin preparations containing fol ic acid or its derivatives may alter response to
`Methotrexate.
`
`Methotrexate should be used with extreme caution in the presence of infection, peptic
`ulcer, ulccrative colitis, dcbility, and in extreme youth and old age. If profound
`leukopenia occurs during therapy, bacterial infection may occur or become a threat.
`Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe
`bone marrow depression, blood or platelet transfus ions may be necessary.
`
`Since it is reported that Methotrex-ate may have an immunosupprcssive action, this
`factor must be taken into consideration in evaluating the use of the drug where
`immune responses in a patient may be important or essential.
`
`Page 7 of 14
`Page 7 of 14
`
`

`
`In all instances where the use of Methotrexate is considered for chemotherapy, the
`physician must evaluate the need and usefulness of the drug against the risks oftoxic
`effects or adverse reactions. Most such adverse reactions are reversible if detected
`
`ear! y. When such effects or reactions do occur, the drug should be reduced in dosage
`or discontinued and appropriate corrective measures should be taken according to the
`clinical judgement of the physician. Reinstitution of Methotrexate therapy should be
`carried out with caution, with adequate consideration of further need for the drug and
`alertness as to the possible recurrence of toxicity.
`
`Methotrexate given concomitantly with radiotherapy may inc1'ease the risk of soft
`tissue necrosis and osteonecrosis.
`
`4.5.
`interaction
`
`Interaction with other medicinal products and other forms of
`
`Methotrexate is extensively protein bound and may be displaced by certain drugs such
`as salicylatcs, hypoglycaeinics, diuretics, sulphonarnides, diphenylhydantoins,
`tetracyclines, chloramphenicol, p-an-iinobenzoic acid, and the acidic anii~
`inflammatory agents, so causing a potential for increased toxicity when used
`concurrently.
`
`Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including
`alcohol) should be avoided.
`
`Vitamin preparations containing folic acid or its derivatives may decrease the
`effectiveness of methotrexate.
`
`Caution should be used when NSAIDS and salicylates are administered concomitantly
`with metholrexate. These drugs have been reported to reduce the tubular secretion of
`methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and
`saiicylates has been associated with fatal niethotrexate toxicity.
`
`However, patients using constant dosage regimens of NSAEDS have received
`concurrent doses of methotrexate without problems observed.
`
`Renal tubular transport is also diminished by probenecid and penicillins; use of these
`with methotrexate should be carefully monitored.
`
`Severe bone marrow depression has been reported following the concurrent use of
`methotrexate and eo—tri1noxazole or trirnethopriin. Concurrent use should probably be
`avoided.
`
`Metholrexate—induced stomatitis and other toxic effects may be increased by the use
`ofnitrous oxide.
`
`An increased risk of hepatitis has been reported following the use of methotrexate and
`the acitrezin metabolite, etretinate. Consequently, the concomitant use of methotrcxate
`and acitretin should be avoided.
`
`Page 8 of 14
`Page 8 of 14
`
`

`
`Pregnancy and lactation
`4.6.
`Abortion, foetal death, and/or congenital anomalies have occurred in pregnant
`women receiving Methotrcxatc, especially during the ‘lirst trimester of pregnancy.
`Methotrexale is contraindicated in the management of psoriasis or rheumatoid arthritis
`in pregnant women. Women of childbearing potential should not receive
`Methotrexate until pregnancy is excluded. For the management of psoriasis or
`rheumatoid arthritis, Melhotrexate therapy in women should be started immediately
`following a menstrual period and appropriate measures should be taken in men or
`women to avoid conception during and for at least 6 months following cessation of
`Methotrexate therapy.
`
`Both men and women receiving Methotrexate should be informed ofthe potential risk
`of adverse effects on reproduction. Women of childbearing potential should be fully
`informed of the potential hazard to the foetus should they become pregnant during
`Methotrexate therapy. in cancer chemotherapy, Methotrexate should not be used in
`pregnant women or women of childbearing potential who might become pregnant
`unless the potential benefits to the mother outweigh the possible risks to the foetus.
`
`Defective oogcnesis or spermatogcnesis, transient oligosperrnia, menstrual
`dysfunction, and infertility have been reported in patients receiving Methotrexate.
`
`Methozrcxate is distributed into breast milk. Because of the potential for serious
`adverse reactions to Methotrcxate in nursing infants, a decision should be made
`whether to discontinue nursing or the drug, taking into account the importance of the
`drug to the woman.
`
`Effects on ability to drive and use machines
`4.7.
`Not applicable.
`
`4.8.
`
`Undesirablc effects
`
`The most common adverse reactions include ulcerative stomatitis, leukopenia,
`nausea and abdominal distress. Although very rare, anaphylaclic reactions to
`methotrexate have occurred. Others reported are malaise, undue fatigue, chills and
`fever, dizziness and decreased resistance to infection. In general, the incidence and
`severity of side effects are considered to be dose-related. Adverse reactions as
`reported for the various systems are as follows:
`
`Skin: Stevens-Iohnson syndrome, epidermal necrolysis, erythematous rashes, pruritus,
`urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia,
`acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure
`to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion
`of psoriatic plaques have been reported. The recall phenomenon has been reponed in
`both radiation and solar damaged skin.
`
`Blood: Bone marrow depression, ieukopcnia, thrombocytopenia, anaemia,
`hypogarnrnaglobulinaemia, haemorrhage from various sites, septicaemia.
`
`Page 9 of 14
`Page 9 of 14
`
`

`
`Alimentary System: Gingivitis, pharyngitis, stomatitis, anorexia, vomiting, diarrhoea,
`haentatemesis, melaena, gastrointestinal ulceration and bleeding, enteritis, hepatic
`toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal
`fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal
`mucosa has led to matabsorption or toxic megacolon.
`
`Ilcpatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute
`fiver atrophy, necrosis, fatty metamorphosis, peripoital fibrosis or cirrhosis or death
`may occur, usually following chronic administration.
`
`Urogenital System: Renal failure, azotaemia, cystitis, hacrnaturia, defective oogenesis
`or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility,
`abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis,
`haematuria and nephropathy have also been reported.
`
`Pulmonary System: Acute or chronic interstitial pneumonitis, often associated with
`blood cosinophilia, may occur and deaths have been reported (see Section 4.4 Special
`warnings and special precautiosn for use). Acute pulmonary oedema has also been
`reported after oral and intrathecal use. Pulmonary fibrosis is rate. A syndrome
`consisting of pleuritic pain and pleural thickening has been reported following high
`doses.
`
`Central Nervous System: Headaches, drowsiness. blurred vision, aphasia, hemiparcsis
`and convulsions have occurred possibly related to haemorrhage or to complications
`from intra-arterial catlieterisation. Convulsion, paresis, Guillain-Barre syndrome and
`increased cerebrospinal fluid pressure have followed intratheeal administration.
`
`Other reactions related to, or attributed to the use of Methotrexate such as
`pneuruonitis, metabolic changes, precipitation of diabetes, osteoporotic effects,
`abnormal changes in tissue cells and even sudden death have been reported.
`
`There have been reports of leukoencephalopathy following intravenous methotrexate
`in high doses, or low doses following cranial-spinal radiation.
`
`Adverse reactions following intralhecal metholrexate are generally classified into
`three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis
`manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The
`subacute form may include paresis, usually transient, paraplegia, nerve palsies, and
`cerebellar dysfunction. The chronic fonn is a lcukoencephalopathy manifested by
`irritability, confusion. ataxia, spaslicity, occasionally convulsions, dementia,
`soinnolence, coma, and rarely, death. There is evidence that the combined use of
`cranial radiation and intrathecal methotrcxate increases the incidence of
`
`leukoencephalopath y.
`
`Additional reactions related to or attributed to the use oftnethotrexate such as
`
`osteoporosis, abnormal (usually megaioblastic) red cell morphology, precipitation of
`diabetes, other metabolic changes, and sudden death have be en reported.
`
`4.9.
`
`Overdose
`
`Page 10 of 14
`Page10of14
`
`

`
`Calcium Folinate (Caicium Leucovorin) is a potent agent for neutralising the
`immediate toxic effects of Mcthotrexate on the haernatopoietic system. Where
`large doses or overdoses are given, Calcium Folinatc may be administered by
`intravenous infusion in doses up to 75mg within 12 hours, followed by 12mg
`intramuscularly every 6 hours
`for 4 doses. Where average doses of
`Methotrexate appear to have an adverse effect 6-12mg of Calcium l-‘olinate
`may be given intramuscularly every 6 hours for 4 doses.
`In general, where
`overdosage is suspected, the dose of Calcium Folinate should be equai to or
`higher than, the offending dose of Methotrexate and should be administered as
`soon as possible; preferably within the first hour and cenainly within 4 hours
`after which it may not be effective.
`
`Other supporting therapy such as blood transfusion and renal dialysis may be
`required. Effective clearance of methotrexate has been reported with acute,
`intermittent haemodialysis using a high flux dialyser.
`
`5.
`
`PHARMACOLOGICAL PROPERTIES
`
`5.1
`
`Pharmacedynamic properties
`
`Methotrexate is an antirnetabolite which acts principally by competitively
`inhibiting the enzyine, dihydrofoiate reductase.
`In the process of DNA
`synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic
`acid by this enzyme, and inhibition by Methotrexate interfers with tissue cell
`reproduction. Actively proliferating tissues such as maiignant cells are
`generally more sensitive to this effect of Methotrexate.
`It also inhibits
`antibody synthesis.
`
`Metliotrexate also has immunosuppressive activity, in part possibly as a result
`of inhibition of lymphocyte multiplication. The rnechanisni(s) of action in the
`management of rheumatoid arthritis of the drug is not known, aithough
`suggested rnechanisins have
`included immunosuppressive andfor
`anti-
`inflammatory effect.
`
`Pharrnacokinetic properties
`5.2
`In doses of [Llmg (of Methotrexate) per kg, Methotrexate is completely absorbed
`from the G.l. tract; larger oral doses may be incompletely absorbed. Peak serum
`concentrations are achieved within 0.5 ~ 2 hours following I.V., IM. or inn-a-arterial
`administration. Serum concentrations following oral administration of Methotrexate
`may be slightly lower than those following I.V. injection.
`
`Mcthotrexate is actively transported across cell membranes. The drug is widely
`distributed into body tissues with highest concentrations in the kidneys, gali bladder,
`
`Page 11 of 14
`Page11of14
`
`

`
`spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and
`for months in the liver. Sustained serum concentrations and tissue accumulation may
`result from repeated daily doses. Methotrexate crosses the placental barrier and is
`distributed into breast milk. Approximately 50% oftlie drug in the blood is bound to
`serum proteins.
`
`In one study, Methotrexatc had a serum half-life of 2-4 hours following LM.
`administration. Following oral doses of 0.06mg!kg or more, the drug had a serum
`half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10
`hours when oral doses of 0.03?'mg/kg were given.
`
`Methotrexate does not appear to be appreciably inetabolised. The drug is excreted
`primarily by the kidneys via glomerular filtration and active transport. Small amounts
`are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion
`pattern. If Methotrexate excretion is impaired accumulation will occur more rapidly in
`patients with impaired renal function. In addition, simultaneous administration of
`other weak organic acids such as salicylates may suppress Methotrexate clearance.
`
`5.3
`
`Preclinical safety data
`
`None stated.
`
`6.
`
`PHARMACEUTICAL PARTICULARS
`
`6.! .
`
`List of excipients
`
`Sodium Hydroxide and Water for Injections.
`
`lncompatibilitics
`6.2
`Immediate precipitation or turbidity results when combined with certain
`concentrations of Droperidol, Heparin Sodium, Metoclopramide Hydrochloride,
`Ranitidine Hydrochloride in syringe.
`
`6.3
`
`Shelf-life
`
`As packaged for sale — 30 months.
`
`After dilution — Chemical and physical in—use stability has been demonstrated in
`dextrose 5% and sodium chloride 0.9% infusion solutions for 30 days at 4°C in PVC
`containers when protected from light.
`
`From a microbiological point ofvicw the product should be used immediately. If not
`used immediately, in-use storage times and conditions prior to use are Lhe
`
`Page 12 of 14
`Page12of14
`
`

`
`responsibility of the user and would not normally be longer than 24 hours at 2-8°C,
`unless dilution has taken place in controlled and validated aseptic conditions.
`
`Special precautions for storage
`6.4
`As packaged for sale-
`Do not store above 25°C. Do not freeze. Keep container in the outer canon.
`
`After dilution — sec 6.3.
`
`6.5.
`
`Nature and contents of container
`
`- Conventional, or Once-Tain® Type 1 glass vial with rubber
`lgflfl ml
`stopper, aluminium seal and plastic ‘flip-off’ top, or Onco-Vial® Type I glass
`vials with rubber stopper. Packs containing 1 vial.
`
`5g;'50 ml — Conventional, or Onco-Tain® Type I glass via] with rubber
`stopper, aluminium seal and plastic ‘flip-off’ top, or Onco-Vial® Type 1 glass
`vials with rubber stopper. Packs containing 1 vial.
`
`Not all presentations and pack sizes may be marketed.
`
`6.6.
`
`Instruction for Use, handling and disposal
`
`Single use only. Discard any unused contents.
`
`Onco-Vials should be used with an appropriate Fauldirtg administration
`device.
`
`7
`
`MARKETING AUTHORISATION HOLDER
`
`I-lospira UK Limited
`Quccnsway
`Royal Leamington Spa
`Warwickshirc
`CV31 3RW
`UK
`8.
`
`MARKETING AUTHORISATION NUMBER
`
`PL 045510038
`
`Page 13 of 14
`Page13of14
`
`

`
`DATE OF FIRST AUTHORISATION.-’RENEW‘AL OF
`9.
`AU"I'HORlSA'l‘lON
`
`13th March 198?‘ I 7th June 1994
`
`10
`
`DATE OF REVISION OF THE TEXT
`
`2271 H2005
`
`Page 14 of 14
`Page14of14