1440 (cid:9)
`
`Merck Sharp & Dohme—Cont.
`
`Literature reports suggest an apparent association between
`use of corticosteroids and left ventricular free wall rupture
`after a recent myocardial infarction; therefore, therapy with
`corticosteroids should be used with great caution in these
`patients.
`
`PRECAUTIONS
`
`Following prolonged therapy, withdrawal of corticosteroids
`may result in symptoms of the corticosteroid withdrawal
`syndrome including fever, myalgia, arthralgia, and malaise.
`This may occur in patients even without evidence of adrenal
`insufficiency.
`There is an enhanced effect of corticosteroids in patients
`with hypothyroidism and in those with cirrhosis.
`Corticosteroids should be used cautiously in patients
`with ocular herpes simplex because of possible corneal
`perforation.
`The lowest possible dose of corticosteroid should be used to
`control the condition under treatment, and when reduction
`in dosage is possible, the reduction should be gradual.
`Psychic derangements may appear when corticosteroids are
`used, ranging from euphoria, insomnia, mood swings, per-
`sonality changes, and severe depression, to frank psychotic
`manifestations. Also, existing emotional instability or psy-
`chotic tendencies may be aggravated by corticosteroids.
`Aspirin should be used cautiously in conjunction with corti-
`costeroids in hypoprothrombinemia.
`Steroids should be used with caution in nonspecific ulcer-
`ative colitis, if there is a probability of impending perfora-
`tion, abscess, or other pyogenic infection, diverticulitis, fresh
`intestinal anastomoses, active or latent peptic ulcer, renal
`insufficiency, hypertension, osteoporosis, and myasthenia
`gravis. Signs of peritoneal irritation following gastrointesti-
`nal perforation in patients receiving large doses of corticoste-
`roids may be minimal or absent. Fat embolism has been re-
`ported as a possible complication of hypercortisonism.
`When large doses are given, some authorities advise that
`corticosteroids be taken with meals and antacids taken be-
`tween meals to help to prevent peptic ulcer.
`Growth and development of infants and children on pro-
`longed corticosteroid therapy should be carefully observed.
`Steroids may increase or decrease motility and number of
`spermatozoa in some patients.
`Phenytoin, phenobarbital, ephedrine, and rifampin may
`enhance the metabolic clearance of corticosteroids, resulting
`in decreased blood levels and lessened physiologic activity,
`thus requiring adjustment in corticosteroid dosage.
`The prothrombin time should be checked frequently in pa-
`tients who are receiving corticosteroids and coumarin anti-
`coagulants at the same time because of reports that cortico-
`steroids have altered the response to these anticoagulants.
`Studies have shown that the usual effect produced by adding
`corticosteroids is inhibition of response to coumarins, al-
`though there have been some conflicting reports of potentia-
`tion not substantiated by studies.
`When corticosteroids are administered concomitantly with
`potassium-depleting diuretics, patients should be observed
`closely for development of hypokalemia.
`
`ADVERSE REACTIONS
`Fluid and Electrolyte Disturbances
`Sodium retention
`Fluid retention
`Congestive heart failure in susceptible patients
`Potassium loss
`Hypokalemic alkalosis
`Hypertension
`Musculoskeletal
`Muscle weakness
`Steroid myopathy
`Loss of muscle mass
`Osteoporosis
`Vertebral compression fractures
`Aseptic necrosis of femoral and humeral heads
`Pathologic fracture of long bones
`Tendon rupture
`Gastrointestinal
`Peptic ulcer with possible perforation and hemorrhage
`Perforation of the small and large bowel, particularly in
`patients with inflammatory bowel disease
`Pancreatitis
`Abdominal distention
`Ulcerative esophagitis
`Dermatologic
`Impaired wound healing
`Thin fragile skin
`Petechiae and ecchymoses
`Erythema
`
`Physicians' Desk Reference@ (cid:9)
`Increased sweating
`May suppress reactions to skin tests
`Other cutaneous reactions, such as allergic dermatitis,
`urticaria, angioneurotic edema
`Neurologic
`Convulsions
`Increased intracranial pressure with papilledema (pseudo-
`tumor cerebri), usually after treatment
`Vertigo
`Headache
`Psychic disturbances
`Endocrine
`Menstrual irregularities
`Development of cushingoid state
`Suppression of growth in children
`Secondary adrenocortical and pituitary unresponsiveness,
`particularly in times of stress, as in trauma, surgery, or
`illness
`Decreased carbohydrate tolerance
`Manifestations of latent diabetes mellitus
`Increased requirements for insulin or oral hypoglycemic
`agents in diabetics
`Hirsutism
`Ophthalmic
`Posterior subcapsular cataracts
`Increased intraocular pressure
`Glaucoma
`Exophthalmos
`Metabolic
`Negative nitrogen balance due to protein catabolism
`Cardiovascular
`Myocardial rupture following recent myocardial infarc-
`tion (see WARNINGS).
`Other
`Hypersensitivity
`Thromboembolism
`Weight gain
`Increased appetite
`Nausea
`Malaise
`Psychic disturbances
`
`OVERDOSAGE
`
`Reports of acute toxicity and/or death following overdosage
`of glucocorticoids are rare. In the event of overdosage, no
`specific antidote is available; treatment is supportive and
`symptomatic.
`The intraperitoneal LD50 of cortisone acetate in female mice
`was 1405 mg/kg.
`
`DOSAGE AND ADMINISTRATION
`
`For' oral administration
`DOSAGE REQUIREMENTS ARE VARIABLE AND MUST
`BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE
`AND THE RESPONSE OF THE PATIENT. (cid:9)
`•
`The initial dosage varies from 25 to 300 mg a day depending
`on the disease being treated. In less severe diseases doses
`lower than 25 mg may suffice, while in severe diseases doses
`higher than 300 mg may be required. The initial dosage
`should be maintained or adjusted until the patient's re-
`sponse is satisfactory. If satisfactory clinical response does
`not occur after a reasonable period of time, discontinue
`CORTONE Acetate tablets and transfer the patient to other
`therapy.
`After a favorable initial response, the proper maintenance
`dosage should be determined by decreasing the initial dosage
`in small amounts to the lowest dosage that maintains an
`adequite clinical response.
`Patients should be observed closely for signs that might re-
`quire dosage adjustment, including changes in clinical sta-
`tus resulting from remissions or exacerbations of the disease,
`individual drug responsiveness, and the effect of stress (e.g.,
`surgery, infection, trauma). During stress it may be neces-
`sary to increase dosage temporarily.
`If the drug is to be stopped after more than a few days of
`treatment, it usually should be withdrawn gradually.
`
`HOW SUPPLIED
`
`No. 7063—Tablets Cortone Acetate, 25 mg each, are white,
`round, scored, compressed tablets, coded MSD 219. They are
`supplied as follows:
`NDC 0006-0219-68 in bottles of 100.
`Shown in Product Identification Section, page 419
`A.H.F.S. Category: 68:04
`DC 7411828 Issued March 1988
`
`Consult 1992 Supplements for revisions
`
`COSMEGEN® Injection
`(Dactinomycin, MSD),
`
`WARNING
`
`Dactinomycin is extremely corrosive to soft tissue. If
`extravasation occurs during intravenous use, severe
`damage to soft tissues will occur. In at least one in-
`stance, this has led to contracture of the arms.
`
`DOSAGE
`
`The dosage of COSMEGEN (Dactinomycin, MSD) is
`calculated in micrograms (mcg). The usual adult dosage
`is 500 micrograms (0.5 mg) daily intravenously for a
`maximum of five days. The dosage for adults or children
`should not exceed 15 mcg/kg or 400-600 meg/square
`meter of body surface daily intravenously for five days.
`Calculation of the dosage for obese or edematous pa-
`tients should be on the basis of surface area in an effort
`to relate dosage to lean body mass.
`
`DESCRIPTION
`
`Dactinomycin is one of the actinomycins, a group of antibiot-
`ics produced by various species of Streptomyves. Dactinomy-
`cin is the principal component of the mixture of actinomy-
`cins produced by Streptomyces parvullus. Unlike other spe-
`cies 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 C62H86N12016and the structural
`formula is:
`
`0 (cid:9)
`I
`
`CH(CH3)2
`FOC-414
`NCH3
`v,rcirsine
`L. line
`Dyalino
`CO
`1 CH—CH
`CH3 (cid:9)
`11H
`CO
`
`CH(CH3)2
`-00---1
`iliCH3
`
`arc ne esi
`L Lino (cid:9)
`
`0
`I
`
`
`
`D tlirm (cid:9)
`0 414---61 (cid:9)
`
`NH (cid:9)
`Co
`
`CH,
`
`N143
`0
`
`H3 (cid:9)
`
`CH3
`
`COSMEGEN is a sterile, yellow lyophilized powder for injec-
`tion by the intravenous route or by regional perfusion after
`reconstitution. Each vial contains 0.5 mg (500 mcg) of dac-
`tinomycin 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 treat-
`ment of infectious diseases.
`Because the actinomycins are cytotoxic, they have an anti-
`neoplastic effect which has been demonstrated in experi-
`mental animals with various types of tumor implant. This
`cytotoxic action is the basis for their use in the palliative
`treatment of certain types of cancer.
`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 ter-
`minal plasma half-life for radioactivity was approximately
`36 hours.
`
`INDICATIONS AND USAGE
`
`Wilms' Tumor
`The neoplasm responding most frequently to COSMEGEN is
`Wilma' tumor. With low doses of both dactinomycin and ra-
`diotherapy, temporary objective improvement may be as
`good as and may last longer than with higher doses of each
`given alone. In the National Wilms' Tumor study, combina-
`tion therapy with dactinomycin and vincristine together
`with surgery and radiotherapy, was shown to have signifi-
`cantly improved the prognosis of patients in groups H and
`HI. Dactinomycin and vincristine were given for a total of
`seven cycles, so that maintenance therapy continued for
`approximately 15 months.
`
`NOVARTIS EXHIBIT 2114
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`
`(cid:9)
`

`
`1460 (cid:9)
`
`Merck Sharp & Dohme—Cont.
`
`font. Nevertheless, caution should be exercised when topical
`corticosteroids are administered to a nursing woman.
`Pediatric Use
`Pediatric patients may demonstrate greater susceptibility to
`topical corticosteroid-induced HPA axis suppression and
`Cushing's syndrome than mature patients because of a larger
`skin surface area to body weight ratio.
`Hypothalamic-pituitary-adrenal (HPA) axis suppression,
`Cushing's syndrome, and intracranial hypertension have
`been reported in children receiving topical corticosteroids.
`Manifestations of adrenal suppression in children include
`linear growth retardation, delayed weight gain, low plasma
`cortisol levels, and absence of response to ACTH stimulation.
`Manifestations of intracranial hypertension include bulging
`fontanelles, headaches, and bilateral papilledema.
`Administration of topical corticosteroids to children should
`be limited to the least amount compatible with an effective
`therapeutic regimen. Chronic corticaderoid therapy may
`interfere with the growth and development of children.
`
`ADVERSE REACTIONS
`
`The following adverse reactions are reported infrequently
`with topical corticosteroids, but may occur more frequently
`with the use of occlusive dressings. These reactions are listed
`in an approximate decreasing order of occurrence:
`Burning
`Itching
`Irritation
`Dryness
`Folliculitis
`Hypertrichosis
`Acneiform eruptions
`Hypopigmentation
`Perioral dermatitis
`Allergic contact dermatitis
`Maceration of the skin
`Secondary infection
`Skin atrophy
`Striae
`Miliaria
`
`OVERDOSAGE
`
`Topically applied corticosteroids can be absorbed in suffi-
`cient amounts to produce systemic effects (See PRECAU-
`TIONS).
`
`DOSAGE AND ADMINISTRATION
`
`Patients should be instructed in the correct way to use
`DECASPRAY. The preparation is readily applied, even on
`hairy areas. It does not have to be rubbed into the skin.
`Optimal effects will be obtained with DECASPRAY when
`these directions are followed:
`1. Keep the affected area clean to reduce the possibility of
`infection.
`2. Shake the container gently once or twice each time before
`using. Hold it about six inches from the area to be treated.
`Effective medication may be obtained with the container
`held either upright or inverted, since it is fitted with a
`special valve that dispenses approximately the same dos-
`age in either position.
`3. Spray each four inch square of affected area for one or two
`seconds three or four times a day, depending on the nature
`of the condition and the response to therapy.
`4. When a favorable response is obtained, reduce dosage
`gradually and eventually discontinue.
`5. Occlusive dressings may be used for the management of
`psoriasis or recalcitrant conditions.
`
`HOW SUPPLIED
`
`No. 7623X—DECASPRAY is supplied as follows:
`NDC 0006-7623-25 in a 25 g pressurized container.
`A.H.F.S. Category: 84:06
`DC 6005318 Issued April 1983
`COPYRIGHT © MERCK & CO., Irsic., 1983
`All rights reserved
`
`DEMSER® Capsules
`(Metyrosine, MSD), U.S.P.
`
`DESCRIPTION
`
`DEMSER® (Metyrosine, MSD) is (—)-a-methyl-L -tyrosine
`or (a-MPT). It has the following structural formula:
`[See chemical formula at top of next column.]
`Metyrosine is a white, crystalline compound of molecular
`weight 195. It is very slightly soluble in water, acetone, and
`methanol, and insoluble in chloroform and benzene. It is
`
`Physicians' Desk Reference® (cid:9)
`
`Consult 1992 Supplements for revisions
`
`CH3
`
`HO
`
`CH2 —C —COOH
`
`HH2
`
`soluble in acidic aqueous solutions. It is also soluble in alka-
`line aqueous solutions, but is subject to oxidative degrada-
`tion under these conditions.
`DEMSER is supplied as capsules, for oral administration.
`Each capsule contains 250 mg metyrosine. Inactive ingredi-
`ents are colloidal silicon dioxide, gelatin, hydroxypropyl
`cellulose, magnesium stearate, and titanium dioxide. The
`capsules may also contain any combination of D&C Red 33,
`D&C Yellow 10, FD&C Blue 1, and FD&C Blue 2.
`
`CLINICAL PHARMACOLOGY
`
`DEMSER inhibits tyrosine hydroxylase, which catalyzes the
`first transformation in catecholamine biosynthesis, i.e., the
`conversion of tyrosine to dihydroxyphenylalanine (DOPA).
`Because the first step is also the rate-limiting step, blockade
`of tyrosine hydroxylase activity results in decreased endoge-
`nous levels of catecholamines, usually measured as de-
`creased urinary excretion of catecholamines and their me-
`tabolites.
`In patients with pheochromocytoma, who produce excessive
`amounts of norepinephrine and epinephrine, administration
`of one to four grams of DEMSER per day has reduced cate-
`cholamine biosynthesis from about 35 to 80 percent as mea-
`sured by the total excretion of catecholamines and their me-
`tabolites (metanephrine and vanillylmandelic acid). The
`maximum biochemical effect usually occurs within two to
`three days, and the urinary concentration of catecholamines
`and their metabolites usually returns to pretreatment levels
`within three to four days after DEMSER is discontinued. In
`some patients the total excretion of catecholamines and cate-
`cholamine metabolites may be lowered to normal or near
`normal levels (less than 10 mg/24 hours). In most patients
`the duration of treatment has been two to eight weeks, but
`several patients have received DEMSER for periods of one to
`10 years.
`Most patients with pheochromocytoma treated with
`DEMSER experience decreased frequency and severity of
`hypertensive attacks with their associated headache, nau-
`sea, sweating, and tachycardia. In patients who respond,
`blood pressure decreases progressively during the first two
`days of therapy with DEMSER; after withdrawal, blood pres-
`sure usually increases gradually to pretreatment values
`within two to three days.
`Metyrosine is well absorbed from the gastrointestinal tract.
`From 53 to 88 percent (mean 69 percent) was recovered in
`the urine as unchanged drug following maintenance oral
`doses of 600 to 4000 mg/24 hours in patients with pheochro-
`mocytoma or essential hypertension. Less than 1% of the
`dose was recovered as catechol metabolites. These metabo-
`lites are probably not present in sufficient amounts to con-
`tribute to the biochemical effects of metyrosine. The quanti-
`ties excreted, however, are sufficient to interfere with accu-
`rate determination of urinary catecholamines determined
`by routine techniques.
`Plasma half-life of metyrosine determined over an 8-hour
`period after single oral doses was 3.4-3.7 hours in three
`patients.
`For further information, refer to: Sjoerdsma, A.; Engelman,
`K.; Waldman, T. A.; Cooperman, L H.; Hammond, W. G.:
`Pheochromocytoma: Current concepts of diagnosis and treat-
`ment, Ann. Intern. Med. 65: 1302-1326, Dec. 1966.
`
`INDICATIONS AND USAGE
`
`DEMSER is indicated in the treatment of patients with pheo-
`chromocytoma for
`1. Preoperative preparation of patients for surgery
`2. Management of patients when surgery is contraindicated
`3. Chronic treatment of patients with malignant pheochro-
`mocytoma.
`DEMSER is not recommended for the control of essential
`hypertension.
`
`CONTRAINDICATIONS
`
`DEMSER is contraindicated in persons known to be hyper-
`sensitive to this compound.
`
`WARNINGS
`
`Maintain Fluid Volume During and After Surgery
`When DEMSER is used preoperatively, alone or especially in
`combination with alpha-adrenergic blocking drugs, adequate
`intravascular volume must be maintained intraoperatively
`(especially after tumor removal) and postoperatively to avoid
`hypotension and decreased perfusion of vital organs result-
`ing from vasodilatation and expanded volume capacity. Fol-
`lowing tumor removal, large volumes of plasma may be
`
`needed to maintain blood pressure and central venous pres-
`sure within the normal range.
`In addition, life-threatening arrhythmias may occur during
`anesthesia and surgery, and may require treatment with a
`beta blocker or lidocaine. During surgery, patients should
`have continuous monitoring of blood pressure and electro-
`cardiogram.
`Intraopemtive Effects
`While the preoperative use of DEMSER in patients with
`pheochromocytoma is thought to decrease intraoperative
`problems with blood pressure control, DEMSER does not
`eliminate the danger of hypertensive crises or arrhythmias
`during manipulation of the tumor, and the alpha-adrenergic
`blocking drug, phentolamine, may be needed.
`Interaction with Alcohol
`DEMSER may add to the sedative effects of alcohol and other
`CNS depressants, e.g., hypnotics, sedatives, and tranquiliz-
`ers. (See PRECAUTIONS, Information for Patients and Drug
`Interactions)
`
`PRECAUTIONS
`
`General
`Metyrosine Crystalluria: Crystalluria and urolithiasis have
`been found in dogs treated with DEMSER (Metyrosine, MSD)
`at doses similar to those used in humans, and crystalluria
`has also been observed in a few patients. To minimize the
`risk of crystalluria, patients should be urged to maintain
`water intake sufficient to achieve a daily urine volume of
`2000 mL or more, particularly when doses greater than 2 g
`per day are given. Routine examination of the urine should be
`carried out Metyrosine will crystallize as needles or rods. If
`metyrosine crystalluria occurs, fluid intake should be in-
`creased further. If crystalluria persists, the dosage should be
`reduced or the drug discontinued.
`Relatively Little Data Regarding Long-term Use: The total
`human experience with the drug is quite limited and few
`patients have been studied long-term. Chronic animal stud-
`ies have not been carried out. Therefore, suitable laboratory
`tests should be carried out periodically in patients reqdiring
`prolonged use of DEMSER and caution should be observed in
`patients with impaired hepatic or renal function.
`Information for Patients
`When receiving DEMSER, patients should be warned about
`engaging in activities requiring mental alertness and motor
`coordination, such as driving a motor vehicle or operating
`machinery. DEMSER may have additive sedative effects
`with alcohol and other CNS depressants, e.g., hypnotics,
`sedatives, and tranquilizers.
`Patients should be advised to maintain a liberal fluid intake.
`(See PRECAUTIONS, General.)
`Drug Interactions
`Caution should be observed in administering DEMSER to
`patients receiving phenothiazines or haloperidol-because the
`extrapyramidal effects of these drugs can be expected to be
`potentiated by inhibition of catecholamine synthesis.
`Concurrent use of DEMSER with alcohol or other CNS de-
`pressants can increase their sedative effects. (See WARN-
`INGS and PRECAUTIONS, Information for Patients)
`Laboratory Test Interference
`Spurious increases in urinary catecholamines may be ob-
`served in patients receiving DEMSER due to the presence of
`metabolites of the drug.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Long-term carcinogenic studies in animals and studies on
`mutagenesis and impairment of fertility have not been per-
`formed with metyrosine.
`Prey
`Pregnancy Category C Animal reproduction studies have not
`been conducted with DEMSER. It is also not known whether
`DEMSER can cause fetal harm when administered to a preg-
`nant woman or can affect reproduction capacity. DEMSER
`should be given to a pregnant woman only if clearly needed.
`Nursing Mothers
`It is not known whether DEMSER is excreted in human
`milk. Because many drugs are excreted in human milk, cau-
`tion should be exercised when DEMSER is administered to a
`nursing woman.
`Pediatric Use
`Safety and effectiveness in children under 12 years of age
`have not been established.
`
`ADVERSE REACTIONS
`
`Central Nervous System
`Sedation: The most common adverse reaction to DEMSER
`is moderate to severe sedation, which has been observed in
`almost all patients. It occurs at both low and high dosages.
`Sedative effects begin within the first 24 hours of therapy,
`are maximal after two to three days, and tend to wane dur-
`ing the next few days. Sedation usually is not obvious after
`one week unless the dosage is increased, but at dosages
`greater than 2000 mg/day some degree of sedation or fatigue
`may persist.
`
`NOVARTIS EXHIBIT 2114
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`Page 152 of 303
`
`(cid:9)
`

`
`Consult 1992 Supplements for revisions (cid:9)
`
`Physicians' Desk Reference® (cid:9)
`
`1461
`
`In most patients who experience sedation, temporary
`changes in sleep pattern occur following withdrawal of the
`drug. Changes consist of insomnia that may last for two or
`three days and feelings of increased alertness and ambition.
`Even patients who do not experience sedation while on
`DEMSER may report symptoms of psychic stimulation when
`the drug is discontinued.
`Extrapyramidal Signs: Extrapyramidal signs such as drool-
`ing, speech difficulty, and tremor have been reported in ap-
`proximately 10 percent of patients. These occasionally have
`been accompanied by trismus and frank parkinsonism.
`Anxiety and Psychic Disturbances: Anxiety and psychic
`disturbances such as depression, hallucinations, disorienta-
`tion, and confusion may occur. These effects seem to be dose-
`dependent and may disappear with reduction of dosage.
`Diarrhea
`Diarrhea occurs in about 10 percent of patients and may be
`severe. Anti-diarrheal agents may be required if continua-
`tion of DEMSER is necessary.
`Miscellaneous
`Infrequently, slight swelling of the breast, galactorrhea,
`nasal stuffiness, decreased salivation, dry mouth, headache,
`nausea, vomiting, abdominal pain, and impotence or failure
`of ejaculation may occur. Crystalluria (see PRECAUTIONS)
`and transient dysuria and hematuria have been observed in
`a few patients. Hematologic disorders (including eosinophi-
`lia, anemia, thrombocytopenia, and thrombocytosis), in-
`creased SCOT levels, peripheral edema, and hypersensitiv-
`ity reactions such as urticaria and pharyngeal edema have
`been reported rarely.
`
`OVERDOSAGE
`Signs of metyrosine overdosage include those central ner-
`vous system effects observed in some patients even at low
`dosages.
`At doses exceeding 2000 mg/day, some degree of sedation or
`feeling of fatigue may persist. Doses of 2000-4000 mg/day
`can result in anxiety or agitated depression, neuromuscular
`effects (including fine tremor of the hands, gross tremor of
`the trunk, tightening of the jaw with trismus), diarrhea, and
`decreased salivation with dry mouth.
`Reduction of drug dose or cessation of treatment results in
`the disappearance of these symptoms.
`The acute toxicity of metyrosine was 442 mg/kg and 752
`mg/kg in the female mouse and rat respectively.
`
`DOSAGE AND ADMINISTRATION
`The recommended initial dosage of DEMSER for adults and
`children 12 years of age and older is 250 mg orally four times
`daily. This may be increased by 250 mg to 500 mg every day
`to a maximum of 4.0 g/day in divided doses. When used for
`preoperative preparation, the optimally effective dosage of
`DEMSER should be given for at least five to seven days.
`Optimally effective dosages of DEMSER usually are between
`2.0 and 3.0 g/day, and the dose should be titrated by monitor-
`ing clinical symptoms and catecholamine excretion. In pa-
`tients who are hypertensive, dosage should be titrated to
`achieve normalization of blood pressure and control of clini-
`cal symptoms. In patients who are usually normotensive,
`dosage should be titrated to the amount that will reduce uri-
`nary metanephrines and/or vanillylmandelic acid by 50
`percent or more.
`If patients are not adequately controlled by the use of
`DEMSER, an alpha-adrenergic blocking agent (phenoxyben-
`zamine) should be added.
`Use of DEMSER in children under 12 years of age has been
`limited and a dosage schedule for this age group cannot be
`given.
`
`HOW SUPPLIED
`No. 3355—Capsules DEMSER, 250 mg, are opaque, two-
`toned blue capsules coded MSD 690 on one side and
`DEMSER on the other. They are supplied as follows:
`NDC 0006-0690-68 bottles of 100.
`Shown in Product Identification Section, page 419
`A.H.F.S. Category: 92.00
`DC 7111505 Issued September 1985
`COPYRIGHT© MERCK & CO., INC., 1985
`All rights reserved
`
`DIUPRES® Tablets
`(Reserpine-Chlorothiazide, MSD), U.S.P.
`
`WARNING
`
`This fixed combination drug is not indicated for initial
`therapy of hypertension. Hypertension requires ther-
`apy titrated to the individual patient. lithe fixed combi-
`nation represents the dosage so determined, its use may
`be more convenient in patient management. The treat-
`ment of hypertension is not static, but must be re-evalu-
`ated as conditions in each patient warrant.
`
`DESCRIPTION
`
`DIUPRES® (Reserpine-Chlorothiazide, MSD) combines two
`antihypertensives: DIURILO (Chlorothiazide, MSD) and
`reserpine.
`Chlorothiazide
`Chlorothiazide is a diuretic and antihypertensive. Its
`chemical name is 6-chloro-2H-1,2,4-benzothiadiazine- 7-
`sulfonamide 1,1-dioxide. Its empirical formula is
`C1H6C1N304S2 and its structural formula is:
`
`Chlorothiazide is a white, or practically white, crystalline
`powder with a molecular weight of 295.72, which is very
`slightly soluble in water, but readily soluble in dilute aque-
`ous sodium hydroxide. It is soluble in urine to the extent of
`about 150 mg per 100 mL at pH 7.
`Reserpine
`The chemical name of reserpine is 11,17a-dimethoxy-18/3-
`[(3, 4, 5-trimethoxybenzoyl)oxy] -3/3,20a-yohimban- 16 p-
`carboxylic acid methylester. It is a crystalline alkaloid de-
`rived from Rauwolfia serpentine. Its empirical formula is
`C33H4oN209 and its structural formula is:
`
`00C
`
`CH30
`
`Reserpine is a white or pale buff to slightly yellowish, odor-
`less, crystalline powder with a molecular weight of 608.69, is
`insoluble in water and freely soluble in glacial acetic acid.
`DIUPRES is supplied as tablets in two strengths for oral use:
`DIUPRES-250, contains 250 mg of chlorothiazide and 0.125
`mg of reserpine.
`DIUPRES-500, contains 500 mg of chlorothiazide and 0.125
`mg of reserpine.
`Each tablet contains the following inactive ingredients:
`FD&C Red 3, gelatin, lactose, magnesium stearate, starch
`and talc.
`
`CLINICAL PHARMACOLOGY
`
`Chlorothiazide
`The mechanism of the antihypertensive effect of thiazides is
`unknown. Chlorothiazide does not usually affect normal
`blood pressure.
`Chlorothiazide affects the distal renal tubular mechanism of
`electrolyte reabsorption. At maximal therapeutic dosage all
`thiazides are approximately equal in their diuretic efficacy.
`Chlorothiazide increases excretion of sodium and chloride in
`approximately equivalent amounts. Natriuresis may be ac-
`companied by some loss of potassium and bicarbonate.
`After oral use diuresis begins within 2 hours, peaks in about
`4 hours and lasts about 6 to 12 hours.
`
`Reserpine
`Reserpine has antihypertensive, bradycardic, and tranquil-
`izing properties. It lowers arterial blood pressure by deple-
`tion of catecholamines. Reserpine is beneficial in relieving
`anxiety, tension, and headache in the hypertensive patient.
`It acts at the hypothalamic level of the central nervous sys-
`tem to promote relaxation without hypnosis or analgesia.
`The sleep pattern shown by the electroencephalogram fol-
`lowing barbiturates does not occur with this drug. In labora-
`tory animals spontaneous activity and response to external
`stimuli are decreased, but confusion or difficulty of move-
`ment is not evident.
`The bradycardic action of reserpine promotes relaxation and
`may eliminate sinus tachycardia. It is most pronounced in
`subjects with sinus tachycardia and usually is not prominent
`in persons with a normal pulse rate.
`Miosis, relaxation of the nictitating membrane, ptosis, hypo-
`thermia, and increased gastrointestinal activity are noted in
`animals given reserpine, sometimes in subclinical doses.
`None of these effects, except increased gastrointestinal activ-
`ity, has been found to be clinically significant in man with
`therapeutic doses.
`
`Pharmacokinetics and Metabolism
`Chlorothiazide
`Chlorothiazide is not metabolized but is eliminated rapidly
`by the kidney. The plasma half-life of chlorothiazide is
`45-120 minutes. After oral doses, 20-24 percent is excreted
`unchanged in the urine. Chlorothiazide crosses the placental
`but not the blood-brain barrier and is excreted in breast
`milk.
`Reserpine
`Oral reserpine is rapidly absorbed from the gastrointestinal
`tract. Methylreserpate and trimethoxybenzoic acid are the
`primary metabolites which result from the hydrolytic cleav-
`age of reserpine. Maximal blood levels are achieved approxi-
`mately 2 hours after the oral dosage of 3H-reserpine to six
`normal volunteers; within 96 hours approximately 8 percent
`was excreted in urine and 62 percent in feces. Reserpine ap-
`pears in human breast milk. Reserpine crosses the placental
`barrier in guinea pigs.
`
`INDICATION AND USAGE
`
`Hypertension (see box warning).
`Use in Pregnancy. Routine use of diuretics during normal
`pregnancy is inappropriate and exposes mother and fetus to
`unnecessary hazard. Diuretics do not prevent development
`of toxemia of pregnancy and there is no satisfactory evidence
`that they are useful in the treatment of toxemia.
`Edema during pregnancy may arise from pathologic causes
`or from the physiologic and mechanical consequences of
`pregnancy. Thiazides are indicated in pregnancy when
`edema is due to pathologic causes, just as they are in the
`absence of pregnancy (see PRECAUTIONS, Pregnancy ).
`Dependent edema in pregnancy, resulting from restriction of
`venous return by the gravid uterus, is properly treated
`through elevation of the lower extremitieiand use of support
`stockings. Use of diuretics to lower intravaacular volume in
`this instance is illogical and unnecessary. During normal
`pregnancy there is hypervolemia which is not harmful to the
`fetus or the mother in the absence of cardiovascular disease.
`However, it may be associated with edema, rarely general-
`ized edema. If such edema causes discomfort, increased re-
`cumbency will often provide relief. Rarely this edema may
`cause extreme discomfort which is not relieved by rest. In
`these instances, a short course of diuretic therapy may pro-
`vide relief and be appropriate.
`
`CONTRAINDICATIONS
`Chlorothiazide is contraindicated in anuria.
`DIUPRES is contraindicated in hypersensitivity to chloro-
`thiazide or other sulfonamide-derived drugs or to reserpine.
`Electroshock