PHUBUCT iNFORMATIOH
`
`ZANTACD
`(ranitldlne hydrochloride}
`Injection
`
`ZAN'I‘AC”
`(ranitldlne hydrochloride)
`injection Premixed
`
`s:
`
`4
`
`s
`8
`
`DESCRIPTION: The active ingredient in ZANTAC Injection and ZANTAC Injection
`Premixed is ranitldlne hydrochloride (H01). a histamine fig-receptor antagonist. Chemi-
`cally it is N[2-[j[5-[idimethylaminolmethyll~2~luranyljmefhyI]lhio]ethyl]-Irl‘-methyi-2-
`nrtro-t.1-ethenedramrne. hydrochloride. It has the following structure:
`
`[:3ng2 rsrcrr2
`
`/
`
`o
`
`\ CHQSCHQCHQNH
`
`\rrrvr-rt:r-ra . HCI
`
`CHN02
`
`
`
`
`Up toE
`Up 103
`
`basal gastric acid secretion as well as gastric acid secretron stimulated by betazole
`and pentagastrln. as shown in Table 2:
`Table 2: Ettect of Intravenous znnrnc on Gastric held Secretion
`
`% Inhibition of Gastric Acid Output
`
`
`
`Trme Alter
`by Intravenous Dose. mg
`
`
`Dose. h
`
`
`
`
`Betazole
`Pentagastrln
`
`
`in a group of 10 known hypersecretors, ranltidine plasma levels of 71. 100. and
`375 nglrnL inhibited basal acid secretion by 76%. 90%. and 99.5%. respectively.
`It appears that basal- and betazolestimuiated secretions are most sensitive to inhibi-
`tion by ZANTAC. while pentagastrin-stlmulated secretion is more difficult to suppress.
`2. Ellectc on Other Gastrointestinal Secretions:
`Pepsln:ZANTAC does not affect pepsin secretion. Total pepsin output rs reduced
`in proportion to the decrease in volume of gastric juice.
`intrinsic Factor:ZANTAO has no significant effect on pentagastrln-stimulated intrinsic
`factor secretion.
`Serum Gastrio:ZANTAC has little or no eflect on testing or postprandial serum gastrin.
`Other Phemracologic Actions:
`3. Gastric bacterial flora—increase in nitrate-reducing organisms. significance
`not known.
`a. Prolactin levels—no effect In recommended oral or intravenous (I'll) dosage. but
`small. transient. dose-related increases in serum prolactin have been reported after IV
`bolus rnjectrons of 100 mg or more.
`c. Other pituitary hormones-mo effect on serum gonadotropins. TSH. or Gl-l. Possible
`impairment of vasopressin release.
`it. No change in cortisol. aldosterone. androgen. or estrogen levels.
`a. No antlandrogenic action.
`1. No effect on count. motility. or morphology of sperm
`Pediatrics: The ranitldlne concentration necessary to suppress basal acid secre-
`tion by at least 90% has been reported to be 401d 60 nglmL in pediatric patients
`with duodenal or gastric ulcers.
`In a study of 20 critically ill pediatric patients receiving ranitldlne It! at 1 mgllrg
`every 6 hours. 10 patients with a baseline szal maintained this baseline throughout
`the study. Eight of the remaining 10 patients with a baseline of pHsz achieved was
`In roughout varying periods alter dosrng. It should be noted. however, that because
`these pharmacodynamic parameters were assessed in critically ill pediatric patients.
`the data should be interpreted with caution when dosing recommendations are
`made for a less seriously ill pediatric population.
`In another small study of neonatal patients in = 5] receiving ECMO. gastric pl-kat
`pretreatment increased to >4 after a 2 mglkg dose and remained above 4 for at least
`15 hours.
`Clinical Trials: Active Duodenal Ulcer? In a multicenter. double-blind, controlled. US
`study ol endoscopicaily diagnosed duodenal ulcers. earlier healing was seen in the
`patients treated with oral ZANTAC as shown in Table 3:
`Table 3: Duodenal Ulcer Patient Heeling Rates
`
`_ralZANTAC— Oral Placebo
`
`
`
`Number H—ledrrEntered _valuable
`
`NumberEntered
`HealedlEvaluable
` Outpatients
`69l182
`
`
`{Birth}1
`
`1377107
`Week at
`(1’3“an
`
`
`'All patients were permitted p.r.n. antacids for relief of pain.
`1P<0.0001.
`
`
`
`Week 2
`
`
`
`The empirical formula is Crstszoss'HCi. representing a molecular weight of 350.81
`Flanitidine HCl is a white to pale yellow. granular substance that is soluble in water.
`ZANTAD Injection is a clear. colorless to yellow. nonpyrogenrc liqurd. The yellow
`color of the liquid tends to intensity without adversely affecting potency. The pH of the
`injection solution is 6.?to 13.
`Sterile Injection for intramuscular or Intravenous Administration: Each 1 mL of
`aqueous solution contains ranitldlne 25 mg (as the hydrochloride}; phenol 5 mg as
`preservative; and 0.06 mg of monobasic potassium phosphate and 2.4 mg of dlbasic
`sodium phosphate as buffers.
`sterile. Premixed Solution for Intravenous Administration in Single-Dose. Flexible
`Plastic Containers: Each 50 mL contains ranitldlne HCI equivalent to 50 mg of ranitldlne.
`sodium chloride 225 mg. and citric acid 15 mg and dibasic sodium phosphate 90 mg
`as buffers in water for injection. it contains no preservatives. The osmolarity of this
`solution is 100 mOsmlL (approx). and the pH Is 6.? to 7.3.
`The flexrble plastrc container is fabricated from a specially formulated. nonplasticlzed.
`thermoplastic co-polyester (CR3). Water can permeate item inside the container Into
`the overwrap but not in amounts sufficient to about the solution significantly. Solutions
`inside the plastic container also can teach out certain of the chemical components in
`very small amounts before the expiration period is adorned. However. the safety of the
`plastic has been confirmed by tests in animals according to USP biological standards
`for plastic containers.
`CLINICAL PHAHMflCOLOGY: ZANTAG is a competitive. reversible Inhibitor of the
`action of histamine at the histamine Hyreceptors. including receptors on the gastric
`cells. ZANTAC does not lower serum Ca++ In hypercalcemic states. ZANTAC is not an
`anticholinergic agent.
`Pharmaenkinetlcs: Absorption: ZANTAC ls absorbed very rapidly after Intramuscu-
`lar (flirt) injection. Mean peak levels of are ngtmL occur within 15 minutes or less
`tollowino a Sit-mg lllr‘l dose. Absorption from 1M sites is virtually complete. with a
`bloavailabillty of 90% to 100% compared with intravenous (Ill) administration.
`Following oral administration. the bloavailabillty of ZANTAC Tablets is 50%.
`Distribution: The volume of distribution is about 14 um. Serum protein binding
`averages 15%.
`Metabolism: In humans. the N-oxrde is the principal metabolite in the urine;
`however. this amounts to <4% ot the dose. Other metabolites are the S-oriide it"s)
`and the desmetl'ryl ranitldlne (1%). The remainder of the administered dose is found
`in the stool. Studies in patients with hepatic dysfunction (compensated cirrhosis]
`indicate that there are mrnor. but clinically insignrilcant. alterations in ranitldlne
`hall—lite. distribution clearance. and bioavailability.
`Excretion: Following iv injection. approximately toes of the dose rs recovered in
`the urine as unchanged drug. Renal clearance averages 530 miJmiri. with a total
`clearance of 1'60 lemin. The elimination half-life Is 20 to 2.5 hours.
`Four patients with clinically significant renal function impairment (creatinirre clear-
`ance 25 to 35 lemin) administered 50 mg of ranitldlne intravenously had an aver-
`age plasma half-lite 014.8 hour. a ranitldlne clearance of 29 er‘mln. and a volume of
`distribution of 1.76 Lllrg. In general. these parameters appear to be altered in propor-
`tion to creatinine clearance (see DOSAGE AND ADMINISTRATION).
`Pediatrics: There are no significant dlfierences in the pharmacoklnetlc parameter
`values for ranitldlne rn pediatric patients {from 1 month up to 16 years of age} and
`healthy adults when correction is made for body weight. The pharmacokinetlcs oi
`ZANTAD in pediatric patients are summarized 'n Table 1.
`Table 1. Ranitidlne Pharmacolrlnetlcs in
`Pediatric Patients Following III Dosing
`
`
`Peptic ulcer disease
`
`11.41
`{<6 years}
`.
`3.95
`{6-119 years)
`1.14
`
`9.09
`{>12 years}
`0.98
`
`Adults
`1.04
`err
`
`
`Peptic ulcer disease
`(35-16 years)
`2.3
`7’95 mL/minl
`1.?3lm‘
`
`
` Children in
`intensive care
`
`it day . 12.0
`
`years)
`
`Neonates
`receiving ECMO
`Tm = Terminal half—life: CLp = Plasma clearance of ranitldlne.
`ECMD : extracorporeai membrane oxygenation.
`Plasma clearance rrr neonatal patients (less than 1 month of agar receivrng EGMO was
`considerably lower {3 to 4 mLimrnllig) than observed in children or adults. The elimination
`hall—lite in neonates average 0.6 hours as compared to approximately 2 hours in adults and
`pediatric patients.
`Pharrnacodynarnics: Serum concentrations necessary to rrrhioit 50% of stimulated gastric
`acid secretion are estimated to be 36 to 94 rrglmL. Following srngle Ill or IM 507mg doses.
`serum concentrations of ZANTAC are in this range for 6 to 0 hours.
`Antisecretory Activity: 1'. Effects on Acid Secretion: ZANTAC injection inhibits
`
`In these studies. patients treated wrth oral ZANTAC reported a reduction in both
`daytime and noctumal pain. and they also consumed less antacid than the placebo-
`treated patients.
`
`
`
`
`
`
`Ulcer Not Heated
`0 l1
`1.113
`
`Table 4: Mean Daily Doses of Antacid
`Ulcer Healed
`
`0.05
`Oral ZAIIITAC
`
`D_7‘l
`Oral placebo
`
`Pathological Hypersecretory Conditions {soon as Zollinger—Ellieorr syndrome).-
`ZAI‘ITAC inhibits gastric acid secretion and reduces occurrence of diarrhea. anorexia.
`and pain in patients with pathological hypersecretlon associated with Zollinger—Ellison
`syndrome. systemic mastocytosls. and other pathological hypersecretory conditions
`leg. postoperative. "shortgut" syndrome. idiopathic). Use of oral EANTAC was followed
`by healing of ulcers in 8 ol 19 (42%) patients who were intractable to prevrous therapy.
`In a retrospective review of 52 Zolllnger-Ellison patients given ZANTAC as a continuous
`I‘ll infusion for up to 15 days. no patients developed complrcations oi acid-peptic disease
`such as bleeding or perforation. Acid output was controlled to 510 mEoih.
`INDICnTIONs AND USAGE: ZANTAC Injection and ZANTAC Injection Premixed are
`indicated in some hospitalized patients with pathological hypersecretory conditions or
`lntractable duodenal ulcers. or as an alternative to the oral dosage form for short-tenn
`use in patients who are unable to take oral medication.
`CONTRAINDICATIONS: thliITAC Injection and ZANTAC Injection Premixed are contra-
`indicated lor patients known to have hypersensltrvity to the drug.
`PRECAUTIONS:
`General: 1. Symptomatic response to therapy with ZANTAC does not preclude the
`presence of gastric malignancy.
`2. Since ZANTAC is excreted primarily by the kidney. dosage should be adjusted in
`patients with impaired renal function (see DOSAGE AND ADMINISTRATION). Caution
`should be observed in patients with hepatic dysfunction since ZANTAC is metabolized
`in the liver.
`3.
`in controlled studies in normal volunteers. elevations in SGPT have been observed
`when Hg—antagonlsts have been administered lntravenously at greater than recommended
`dosages for 5 days or longer. Therefore. it seems prudent in patients receiving l‘u‘
`ranitldlne at dosages 2100 mg old. for periods of 5 days or longer to monrtor SGPT
`daily (tron: day 5) for the remainder of IV therapy.
`4. Bradycardia in association with rapid administration of ZANTAG Injection has been
`reported rarely. usually in patients with iactors predisposing to cardiac rhythm distur-
`bances. Recommended rates of administration should not be exceeded (see DOSAGE
`AN D ADMINISTRATION}.
`5. Rare reports suggest that ZAlIlTAC may precipitate acute porphyrlc attacks in
`Datients with acute porphyria. ZANTAG should therefore be avoided in patients with a
`history of acute porphyria.
`laboratory Tests: Falsepositive tests for urine protein with litULTISTIX01 may occur dur-
`ing therapy with ZANTAC. and therefore testing with sulfosalicylic acidrs recommended
`
`Sandoz
`
`ExhibitiOiO Pagei
`
`
`
`
`
`CLp
`(mUmlnikgl
`
`11.?
`
`
`
`
`1.8
`4.3
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`Sandoz Exhibit 1010 Page 1
`
`

`

`
`
`ZAIITACP (ranitidine hydrochloride) Injection
`
`Zillrl'ITrlIC® [ranitidine hydrochloride) Injection Premixed
`
`Drug Interactions: Although ZANTAC has been reported to bind weakly to cytochrome
`P—450 in vitro. recommended doses of the drug do not inhibit the action of the cyto-
`chrome P-450—linlred oxygenase enzymes in the liver. However. there have been isolated
`reports of drug interactions that suggest that ZANTAC may affect the bioavailability of
`certain drugs by some mechanism as yet unidentified log. a pH-dependent effect on
`absorption or a change in volume of distribution).
`Increased or decreased prothrombin times have been reported during concurrent use
`of ranitidine and warfarin. However. in human pharmacolrinetic studies with dosages
`of ranitidine up to 400 mgr‘day. no interaction occurred: ranitidine had no effect on
`warfarin clearance or prothrombin time. The possibility of an interaction with warfarin
`at dosages of ranitidine higher than 400 mgrday has not been investigated.
`In a ranitidine-triazolam drug-drug interaction study. lriazolam plasma concentrations
`were higher during bid, dosing of ranitidine than triazolam given alone. The mean area
`under the triazolam concentration-time curve lAUCl values. in to— to 60-year-old subjects
`were 10% and 28% higher following administration of TS-mg and tSC-rng ranitidine
`tablets. respectively. than trrazolam given alone. In subjects older than 60 years of age.
`the mean AUG values were approximately 30% higher following administration of
`75-mg and 150-mg ranitidine tablets. It appears that there were no changes in pharma-
`Coltinetics ottrlaaolarn and or-hydroxytriazolarn. a major metabolite. and in their elimi—
`nation. Reduced gastrrc acidity due to ranitidine may have resulted in an increase in the
`availability of triazolam. The clinical significance of this triazolam and ranitidine pharma-
`cokinetic interaction is unknown.
`Carcinogenesis. Mulagenesis. Impairment of Fertility: There was no indication of
`tumorigenic or carcinogenic effects in lifespan studies in mice and rats at oral dosages
`up to 2000 mgr’kg per day.
`Hanitidine was not mutagenic in standard bacterial tests (Salmonella. Escherichia cold
`for mutagehicity at concentrations up to the maximum recommended for these assays.
`to a dominant lethal assay, a single oral dose of 1000 mgrlrg to male rats was without
`effect on the outcome of two matings per week for the next 9 weeks.
`Pregnancy: Torafogenfc Effects: Pregnancy Category B: Reproduction studies have
`been performed in rats and rabbits at oral doses up to 150 times the human oral dose
`and have revealed no evidence of impaired fertility or harm to the fetus due to ZANTAC.
`There are. however. no adequate and well~controlled studies in pregnant women. Because
`animal reproduction studies are not always predictive of human response. this drug
`should be used during pregnancy only it clearly needed.
`Nursing Mothers: ZANTAC i5 secreted in human miltr, Caution should be exercised when
`ZANTAC is administered to a nursing mother.
`Pediatric Use: The safety and effectiveness of ZANTAC Injection have been estab-
`lished in the age-group ol 1 month to to years for the treatment of duodenal ulcer.
`Use of ZANTAC in this age-group is supported by adequate and well-controlled stud-
`ies in adults. as well as additional pharmacoltrnetic data in pediatric patients. and an
`analysis of the published literature.
`Safety and effectiveness in pediatric patients for the treatment of pathological
`hypersecretory conditions have not been established
`Limited data in neonatal patients (less than one month of age) receiving ECMO
`suggest that ZANTAC may be useful and safe for increasing gastric pH for patients
`at rislr of gastrointestinal hemorrhage.
`Use in Elderly Patients: Ulcer heating rates in elderly patients (65 to 82 years of age)
`treated with oral ZANTAC were no different from those in younger ageegroups. The
`incidence rates for adverse events and laboratory abnormalities were also not different
`from those seen in other age~groups
`ADVERSE REACTIONS: Transient pain at the site of IM injection has been reported.
`Transient local burning or itching has been reported with IV administration of ZANTAC.
`The following have been reported as events in clinical trials or in the routine manage-
`ment of patients treated with oral or parenteral ZANTAC. The relationship to therapy
`with ZANTAC has been unclear in many cases. Headache. sometimes severe. seems to
`be related to administration of ZANTAC.
`Central Nervous System: Rarely, malaise. dizziness. somnolence. insomnia. and vertigo.
`Rare cases of reversible mental confusion. agitation. depression. and hallucinations have
`been reported. predominantly in severely ill elderly patients. Rare cases of reversible
`blurred vision suggestive of a change in accommodation have been reported. Rare reports
`of reversible involuntary motor disturbances have been received.
`Cardiovascular: its with other Hg-blocirers. rare reports of arrhythmias such as tachy-
`cardia. bradycardla. asystole. atrioventricular block. and premature ventricular beats.
`Gastrointestinal: Constipation. diarrhea. nausearvomiting. abdominal discomfortlpaln.
`and rare reports of pancreatitls.
`Hepatic: in normal volunteers. SGPT values were increased to at least twice the pretreat-
`ment levels in 5 of 12 subjects receiving 100 mg q.l.d. intravenously for ? days. and in
`4 of 24 subjects receiving 50 mg old. intravenously for 5 days. There have been occa-
`sional reports of hepatocellular. cholestatic. or mixed hepatitis. with or without jaundice.
`In such circumstances. ranitidine should be immediately discontinued. These events
`are usually reversible. but in rare circumstances death has occurred. Flare cases of
`hepatic failure have also been reported.
`Musculoslteletal: Rare reports oi arthralgias and myalgias.
`Hematologic: Blood count changes {Ieukopenla granulocylopenra. and thrombocytopenia)
`have occurred in a few patients. These were usually reversible. Flare cases of agranulo-
`cytosls. pancytopenia. sometimes with marrow hypoplasia. and aplastic anemia and
`exceedingly rare cases of acquired immune hemolytic anemia have been reported.
`Endocrine: Controlled studies in animals and humans have shown no stimulation at any
`pituitary hormone by ZANTAC and no antiandrogenic activity. and cimetidine-induced
`gynecomastia and impotence in hypersecretory patients have resolved when ZANTAC
`has been substituted. However. occasional cases of gynecomastia. impotence. and loss
`of libido have been reported in male patients receiving ZANTAC. but the incidence did
`not difter from that in the general population.
`Inlegumontary: Rash. including rare cases of erythema multiforme. and. rarely. alopecia.
`Other: Flare cases of hypersensitivity reactions leg. bronchospasm. fever. rash. eosino—
`phiiia). anaphylaxis. angioneurotic edema. and small increases in serum creatinine.
`OVERDOSAGE: There has been virtually no experience with overdosage with ZAlIlTAC
`Injection and limited experience with oral doses of ranitidine Reponed acute ingestions
`of up to 18 g orally have been associated with transient adverse effects similar to those
`encountered in normal clinical experience jsee ADVERSE REACTIONS)
`In addition.
`abnormalities of gait and hypotension have been reported.
`When overdosage occurs. clinical monitoring and supportive therapy should
`be employed.
`Studies in dogs receiving dosages of ZANTAC in excess of 225 mglirg per day have
`shown muscular tremors. vomiting. and rapid respiration. Single oral doses of
`1000 mgi'lrg in mice and rats were not lethal. Intravenous L059 values in mice and rats
`were i? and 83 mgjltg. respectively.
`DOSAGE AND AIMIIIISTFIATION:
`Parenteral Administration: In some hospitalized patients with pathological hyper-
`secretory conditions or intractable duodenal ulcers. or in patients who are unable
`to talre oral medication. ZANTAC may be administered parenterally according to the
`following recommendations:
`intramuscular injection: 50 mg {2 mL) every 5 to 8 hours. {No dilution necessary.)
`intermittent intravenous injection:
`a. lntennittenl Bolus: 50 mg (2 le every 6 to 0 hours. Dilute ZANTAC Injection.
`50 mg. in 0.9% sodium chloride injection or other compatible Iv solution (see Stability)
`to a concentration no greater than 2.5 mgrmL [20 mL). Inject at a rate no greater than
`4 er'min (5 minutes).
`
`o. infennfftonf infusion: 50 mg (2 mt.) every 6 to 3 hours. Dilute KANTAC Injection.
`50 mg, in 5% dextrose Injection or other compatible IV solution (see Stability) to a
`concentration no greater than 0.5 mgrmL {100 mL). Infuse at a rate no greater than
`5 to 7 rnL/min (15 to 20 minutes).
`ZAIIITAC Injection Premixed solution. 50 mg. in 0.45% sodium chloride. 50 mL. requires
`no dilution and should be infused over 15 to 20 minutes.
`In some patients it may be necessary to increase dosage. When this is necessary. the
`increases should be made by more frequent administration of the close. but generally
`should not exceed 400 mglday.
`Continuous intravenous infusion: Add ZANTAC Injection to 5% dextrose injection or
`other compatible I‘ll solution (see Stability). Deliverat a rate of 6.25 mgih le.g.. 150 mg
`[6 mL] of ZANTAC Injection in 250 mL of 5% dextrose injection at 10.? mL./h).
`For ZollingervEllison patients. dilute ZANTAC injection in 5% dextrose injection or
`other compatible I'v' solution {see Stability) to a concentration no greater than 2.5 ngmL.
`Start the infusion at a rate of 1.0 mgr’kg per hour. If after 4 hours either a measured
`gastric acid output rs >10 mEtyh or the patient becomes symptomatic, the dose should
`be adjusted upward in 0.5-mgrlrg per hour increments. and the acid output should be
`remeasured. Dosages up to 2.5 mgrl-rg per hour and infusion rates as high as 220 mgfh
`have been used.
`Pediatric Use: While limited data exist on the administration of Iv ranitidine to
`children. the recommended dose in pediatric patients is for a total daily dose of 2 to
`4 mgflrg. to be divided and administered every 6 to 8 hours. up to a maximum of
`50 mg given every 6 to 8 hours. This recommendation is derived from adult clinical
`studies and pharmacoiunetic data in pediatric patients. Limited data in neonatal
`patients [less than one month of age) receiving ECMD have shown thata close of
`2 mglltg Is usually sufficient to increase gastric pH to >4 for at least 15 hours.
`Therefore. doses of 2 rngilrg given every 12 to 24 hours or as a continuous infusion
`should be considered.
`ZANTAC Injection Premixed In Flexible Plastic Containers: Instructions for Use:
`To Open: Tear outer wrap at notch and remove solution container. Check for minute
`Iealrs by squeezing container firmly. li leaks are found. discard unit as sterility may
`be impaired.
`Preparation forddrninislreifon: Use aseptic technique.
`1. Close flow control clamp of administration set.
`2. Remove cover from outlet port at bottom of container.
`3. Insert piercing pin of administration set into port with a twisting motion until the pin
`is firmly seated. NOTE: See full directions on administration set canon.
`4. Suspend container from hanger.
`5. Squeeze and release drip chamber to establish proper fluid level in chamber during
`infusion of ZAI‘ITAC Injection Premixed.
`5. Open flow control clamp to expel air from set. Close clamp.
`i'. Attach set to venipuncture device.
`If device is not Indwelling. prime and
`make venipuncture.
`8. Perform venipuncture.
`9. Regulate rate of administration with flow control clamp.
`Caution: ZANTAC Injection Premixed in flexible plastic containers is to be adminis
`lured by slow IV drip Infusion only. Additives should not be introduced Into this solu-
`tion. It used with a primary IV fluid system. the primary solution should be discontinued
`during ZANTAC Injection Premixed infusion.
`Do not administer unless solution is clear and container is undamaged.
`Warning: Do not use flexible plastic container in series connections.
`Dosage Adjustment for Patients With Impaired Renal Function: The administration
`of ranitidine as a continuous infusion has not been evaluated in patients with impaired
`renal function. 0n the basis of experience with a group of subjects with severely impaired
`renal function treated with ZANTAC. the recommended dosage in patients with a creat—
`inine clearance <50 mUmin is 50 mg every 18 to 24 hours. Should the patient's con-
`dition require. the frequency of closing may be increased to every 12 hours or even
`tunher with caution. Hemodialysis reduces the level of circulating ranitidine. Ideally.
`the dosing schedule should be adjusted so that the timing of a scheduled dose coin—
`cides with the end of hemodialysis.
`Stability: Llndiluted. LANTAC injection tends to exhibit a yellow color that may intensity
`over time without adversely affecting potency. ZANTAC Injection is stable for 40 hours
`at room temperature when added to or diluted with most commonly used IV solutions.
`e.g.. 0.9% sodium chloride injection. 5% dextrose injection. 10% dextrose injection.
`lactated ringer's injection. or 5% sodium bicarbonate injection.
`ZANTAC Injection Premixed in flexible plastic containers is sterile through the expiration
`date on the label when stored under recommended conditions.
`Note: Parenteral drug products should be inspected visually for particulate matter and
`discoloration before administration whenever solution and container permit.
`HOW SUPPLIED:
`ZANTAC Injection. 25 mgrmL. containing phenol 0.5% as preservative. is avaiiable
`as follows:
`NDC 0173-0362-38 2-mL single-dose vials (Tray of ‘10)
`NBC 0173-0303-01 S-mL multldose vials (Singles)
`Store between 4° and SIM: [39" and 36°F). Protect from light.
`ZANTAC Injection Premixed. 50 mgl50 mL. in 0.45% sodium chloride. is available
`as a sterile. premixed solution for it! administration in single-dose. flexible plastic con-
`tainers (N00 0173-0441-00) (case of 24). It contains no preservatives.
`Store between 2“ and 25°C (36° and 77°F). Protect from light.
`Exposure of pharmaceutical products to heat should be minimized. Avoid exceseive
`heat: however, brief exposure up to 40°C does not adversely affect the product. Protect
`from freezing.
`
`GlaxoWellcome
`Glaxo Wellcome inc.
`Research Triangle Park. NC 27709
`
`Zl‘rNTACcm Injection:
`Glaxo Wellcome Inc.
`Research Triangle Park. NC 27709
`
`ZANTACG“ Injection Premixed:
`Manufactured for Glaxo Wellcome Inc.
`Research Triangle Park. NC 2??09
`by Abbott Laboratories. North Chicago. IL 50064
`US Patent No. 4.585390
`
`©Copyrigl1l 1996. 1999, Glaxo Wellcome Inc. All rights resumed.
`November 1999
`RL~774
`
`Sandoz
`
`Exhibit1010
`
`Page2
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`Sandoz Exhibit 1010 Page 2
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`