Drug Intercation

Cholecalciferol 3775 UNT / folate 1 MG Oral Capsule

DESCRIPTION

Zolate is an orally-administered (capsule) prescription folate product specifically formulated for the dietary management of patients with unique nutritional needs due to medical conditions and disease states requiring increased folate levels and specific Vitamin D supplementation levels.

HOW SUPPLIED

Zolate are clear gelatin capsules, and are supplied in bottles of 30 capsules.

INDICATIONS AND USAGE

Zolate is indicated for the distinct nutritional requirements of patients in need of folate and Vitamin D supplementation as determined by a licensed medical practitioner.

Zolate should be administered under the supervision of a licensed medical practitioner.

WARNING AND CAUTIONS

WARNINGS AND PRECAUTIONS Caution is recommended in patients with a history of bipolar illness, as mood elevation is possible in this population.

Patients taking anticonvulsant medications should also exercise caution before taking this product, as folate may (i) interfere with anticonvulsant medication, and/or (ii) lower seizure threshold.

Conversely, anticonvulsant medications may interfere with folate metabolism, although the exact mechanism of action is not clear or well understood.

Patients undergoing cancer treatment should consult their licensed medical practitioner for advice.

Folate alone is improper therapy in the treatment of pernicious anemia and other megaloblastic anemias where vitamin B12 is deficient.

Folate in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission may occur while neurological manifestations progress.

DOSAGE AND ADMINISTRATION

One (1) capsule daily or as directed by a licensed medical practitioner.

Ritonavir 100 MG Oral Capsule

DRUG INTERACTIONS

7 When co-administering NORVIR with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.

Co-administration of NORVIR can alter the concentrations of other drugs.

The potential for drug-drug interactions must be considered prior to and during therapy.

(4, 5.1, 7, 12.3) 7.1 Potential for NORVIR to Affect Other Drugs Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A.

Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir.

Thus, co-administration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.

Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 3 .

Ritonavir also inhibits CYP2D6 to a lesser extent.

Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction.

Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.

These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir.

The healthcare provider should consult appropriate references for comprehensive information.

7.2 Established and Other Potentially Significant Drug Interactions Table 3 provides a list of established or potentially clinically significant drug interactions.

Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )] for magnitude of interaction.

Table 3.

Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comments HIV-Antiviral Agents HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir ↑ amprenavir ↑ atazanavir ↑ darunavir See the complete prescribing information for fosamprenavir, atazanavir, darunavir, for details on co-administration with ritonavir.

HIV-1 Protease Inhibitor: indinavir ↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established.

HIV-1 Protease Inhibitor: saquinavir ↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.

Saquinavir/ritonavir in combination with rifampin is not recommended, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

HIV-1 Protease Inhibitor: tipranavir ↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.

Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine ↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established.

HIV-1 CCR5 – antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.

Integrase Inhibitor: raltegravir ↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.

Other Agents Alpha 1- Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Contraindicated due to potential hypotension [see Contraindications (4) ] .

Antianginal: ranolazine ↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ] .

Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl ↑ analgesics ↓ methadone ↑ fentanyl A dose decrease may be needed for these drugs when co-administered with ritonavir.

Dosage increase of methadone may be considered.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.

Anesthetic: meperidine ↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).

Antialcoholics: disulfiram/metronidazole Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine ↑ antiarrhythmics Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ].

Antiarrhythmics: disopyramide, lidocaine, mexiletine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.

Anticancer Agents: abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib, neratinib, nilotinib, venetoclax, vinblastine, vincristine ↑ anticancer agents ↓ ritonavir # Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications (4) ] .

Avoid co-administration of encorafenib or ivosidenib with NORVIR due to potential risk of serious adverse events such as QT interval prolongation.

If co-administration of encorafenib with NORVIR cannot be avoided, modify dose as recommended in encorafenib USPI.

If co-administration of ivosidenib with NORVIR cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with NORVIR.

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine.

Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR.

Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulant: warfarin ↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.

Anticoagulant: rivaroxaban ↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir.

Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.

Anticonvulsants: carbamazepine, clonazepam, ethosuximide ↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Anticonvulsants: divalproex, lamotrigine, phenytoin ↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.

Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g.

fluoxetine, paroxetine, tricyclics: e.g.

amitriptyline, nortriptyline ↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.

Antidepressant: bupropion ↓ bupropion ↓ active metabolite, hydroxybupropion Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant: desipramine ↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.

Antidepressant: trazodone ↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR.

A lower dose of trazodone should be considered.

Antiemetic: dronabinol ↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.

Antifungal: ketoconazole itraconazole voriconazole ↑ ketoconazole ↑ itraconazole ↓ voriconazole High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated due to the potential for loss of antifungal response [see Contraindications (4) ] .

Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Anti-gout: colchicine ↑ colchicine Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4) ] .

For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later.

Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients with CL CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.

For patients with CL CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.

Antimycobacterial: bedaquiline ↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.

Antimycobacterial: rifabutin ↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week).

Further dosage reduction may be necessary.

Antimycobacterial: rifampin ↓ ritonavir May lead to loss of virologic response.

Alternate antimycobacterial agents such as rifabutin should be considered.

Antiparasitic: atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.

Antiparasitic: quinine ↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.

Antipsychotics: lurasidone pimozide ↑ lurasidone ↑ pimozide Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4) ] .

Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] .

Antipsychotics: perphenazine, risperidone, thioridazine ↑ antipsychotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Antipsychotics: quetiapine ↑ quetiapine Initiation of NORVIR in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures.

If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.

Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking NORVIR: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

β-Blockers: metoprolol, timolol ↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended.

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Bronchodilator: theophylline ↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.

Calcium channel blockers: diltiazem, nifedipine, verapamil ↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.

A dose decrease may be needed for these drugs when co-administered with ritonavir.

Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels.

Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.

Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

GnRH Receptor Antagonists: elagolix ↑ elagolix ↓ ritonavir Concomitant use of elagolix 200 mg twice daily and NORVIR for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations.

Limit concomitant use of elagolix 150 mg once daily and NORVIR to 6 months.

Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4) ] .

GI Motility Agent: cisapride ↑ cisapride Contraindicated due to potential for cardiac arrhythmias [see Contraindications (4) ] .

Hepatitis C direct acting antiviral: glecaprevir/pibrentasvir simeprevir ↑ glecaprevir ↑ pibrentasvir ↑simeprevir It is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir.

Herbal Products: St.

John’s Wort (hypericum perforatum) ↓ ritonavir Contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications (4) ] .

Lipid-modifying agents HMG-CoA Reductase Inhibitor: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ↑ lovastatin ↑ simvastatin ↑ atorvastatin ↑ rosuvastatin ↑ lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4) ] .

Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.

If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.

Lomitapide is a sensitive substrate for CYP3A4 metabolism.

CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold.

Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications (4) ] .

Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.

Kinase Inhibitors: fostamatinib (also see anticancer agents above) ↑ fostamatinib metabolite R406 Monitor for toxicities of R406 such as hepatotoxicity and neutropenia.

Fostamatinib dose reduction may be required.

Long-acting beta- adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended.

The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Oral Contraceptives or Patch Contraceptives: ethinyl estradiol ↓ ethinyl estradiol Alternate methods of contraception should be considered.

PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil ↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio ® ) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications (4) ] .

Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir.

Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ® ) is contraindicated [see Contraindications (4) ] .

The following dose adjustments are recommended for use of tadalafil (Adcirca ® ) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir.

Stop ADCIRCA at least 24 hours prior to starting ritonavir.

After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily.

Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4) ] .

Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Stimulant: methamphetamine ↑ methamphetamine Use with caution.

A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone ↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

# refers to interaction with apalutamide.

OVERDOSAGE

10 Acute Overdosage – Human Overdose Experience Human experience of acute overdose with NORVIR is limited.

One patient in clinical trials took NORVIR 1500 mg per day for two days.

The patient reported paresthesias which resolved after the dose was decreased.

A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

Management of Overdosage Treatment of overdose with NORVIR consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

There is no specific antidote for overdose with NORVIR.

If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.

Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.

Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.

A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR.

DESCRIPTION

11 NORVIR (ritonavir) is an inhibitor of HIV-1 protease with activity against the Human Immunodeficiency Virus (HIV) type 1.

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)].

Its molecular formula is C 37 H 48 N 6 O 5 S 2 , and its molecular weight is 720.95.

Ritonavir has the following structural formula: Ritonavir is a white-to-light-tan powder.

Ritonavir has a bitter metallic taste.

It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

NORVIR soft gelatin capsules are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: Butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide.

Chemical structure for ritonavir.

CLINICAL STUDIES

14 The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.

14.1 Advanced Patients with Prior Antiretroviral Therapy Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-1 infected patients with at least nine months of prior antiretroviral therapy and baseline CD 4 cell counts less than or equal to 100 cells per µL.

NORVIR 600 mg twice-daily or placebo was added to each patient’s baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents.

The study accrued 1090 patients, with mean baseline CD 4 cell count at study entry of 32 cells per µL.

After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period.

Median duration of double-blind therapy with NORVIR and placebo was 6 months.

The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% (140/543) for patients initially randomized to NORVIR compared to 42% (229/547) for patients initially randomized to placebo.

This difference in rates was statistically significant.

Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo.

This difference in rates was statistically significant.

However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.

During the double-blind phase of Study 247, CD 4 cell counts increases from baseline for patients randomized to NORVIR at Week 2 and Week 4 were observed.

From Week 4 and through Week 24, mean CD 4 cell counts for patients randomized to NORVIR appeared to plateau.

In contrast, there was no apparent change in mean CD 4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.

14.2 Patients without Prior Antiretroviral Therapy In Study 245, 356 antiretroviral-naive HIV-1 infected patients (mean baseline CD 4 = 364 cells/µL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs.

During the double-blind phase of study 245, greater mean CD 4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms.

Mean CD 4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD 4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms.

Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the NORVIR-containing arms compared to the zidovudine arm.

After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.

HOW SUPPLIED

16 /STORAGE AND HANDLING The package sizes, strengths, and storage and handling recommendations for NORVIR (ritonavir) soft gelatin capsules are shown in the table below.

NORVIR Capsules, Soft Gelatin, 100 mg Ritonavir Presentation White capsules imprinted with the “a” logo, 100 and the code DS Packaging Size Bottles containing 120 capsules Bottles containing 30 capsules NDC Number 0074-3333-30 0074-6633-30 Recommended Storage Store NORVIR soft gelatin capsules in the refrigerator between 2°-8°C (36°-46°F) until dispensed.

Refrigeration of NORVIR soft gelatin capsules by the patient is recommended, but not required if used within 30 days and stored below 25°C (77°F).

Protect from light.

Avoid exposure to excessive heat.

Product should be stored and dispensed in the original container.

Keep cap tightly closed.

RECENT MAJOR CHANGES

Contraindications ( 4 ) 12/2019

GERIATRIC USE

8.5 Geriatric Use Clinical studies of NORVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 NORVIR (ritonavir) capsules, soft gelatin White soft gelatin capsules imprinted with the “a” logo, 100 and the code DS, providing 100 mg of ritonavir.

Capsule, Soft Gelatin: 100 mg.

(3)

MECHANISM OF ACTION

12.1 Mechanism of Action Ritonavir is an antiretroviral drug [see Microbiology (12.4) ] .

INDICATIONS AND USAGE

1 NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

NORVIR is an HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

(1)

PEDIATRIC USE

8.4 Pediatric Use In HIV-1 infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NORVIR during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.

Risk Summary Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage.

Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S.

reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data ].

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits.

During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose.

In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor [see Data].

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Human Data Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S.

reference population of the MACDP.

The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens.

While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.

Animal Data Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day), and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively).

No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose.

Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose.

A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose.

Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic dosage equivalent to 1.8 times higher than the recommended daily dose, based on a body surface area conversion factor.

In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day 6 through postnatal day 20.

At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on a body surface area conversion factor.

NUSRING MOTHERS

8.3 Females and Males of Reproductive Potential Contraception Use of NORVIR may reduce the efficacy of combined hormonal contraceptives.

Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2) ] .

BOXED WARNING

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs.

Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR [see Contraindications (4) , Warnings and Precautions (5.1) .

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS See full prescribing information for complete boxed warning Co-administration of NORVIR with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs.

Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR (4 , 5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS The following have been observed in patients receiving NORVIR: The concomitant use of NORVIR and certain other drugs may result in known or potentially significant drug interactions.

Consult the full prescribing information prior to and during treatment for potential drug interactions.

(5.1, 7.2) Hepatotoxicity: Fatalities have occurred.

Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations.

(5.2, 8.6) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate.

(5.3) Allergic Reactions/Hypersensitivity: Allergic reactions have been reported and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm and angioedema.

Discontinue treatment if severe reactions develop.

(5.4, 6.2) PR interval prolongation may occur in some patients.

Cases of second and third degree heart block have been reported.

Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval.

(5.5, 12.3) Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter.

(5.6) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia.

(5.7) Patients may develop immune reconstitution syndrome.

(5.8) Patients may develop redistribution/accumulation of body fat.

(5.9) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.

(5.10) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A.

Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively.

These interactions may lead to: Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.

Clinically significant adverse reactions from greater exposures of NORVIR.

Loss of therapeutic effect of NORVIR and possible development of resistance.

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] .

Consider the potential for drug interactions prior to and during NORVIR therapy; review concomitant medications during NORVIR therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ] .

5.2 Hepatotoxicity Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs (see Table 2).

There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C.

Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use In Specific Populations (8.6) ] .

There have been postmarketing reports of hepatic dysfunction, including some fatalities.

These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

5.3 Pancreatitis Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia.

In some cases fatalities have been observed.

Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis [see Warnings and Precautions (5.8) ] .

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur.

Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

5.4 Allergic Reactions/Hypersensitivity Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported.

Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported.

Discontinue treatment if severe reactions develop.

5.5 PR Interval Prolongation Ritonavir prolongs the PR interval in some patients.

Post marketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated.

As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A.

Clinical monitoring is recommended [see Drug Interactions (7) , and Clinical Pharmacology (12.3) ] .

5.6 Lipid Disorders Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1) ] .

Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy.

Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see Contraindications (4) , and Drug Interactions (7) ] .

5.7 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy.

Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events.

In some cases, diabetic ketoacidosis has occurred.

In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases.

Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with NORVIR.

5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including NORVIR.

During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.9 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

The mechanism and long-term consequences of these events are currently unknown.

A causal relationship has not been established.

5.10 Patients with Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors.

In some patients additional factor VIII was given.

In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced.

A causal relationship between protease inhibitor therapy and these events has not been established.

5.11 Resistance/Cross-resistance Varying degrees of cross-resistance among protease inhibitors have been observed.

Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4) ] .

5.12 Laboratory Tests Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid.

Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient information).

General Administration Information [see Dosage and Administration ( 2 )] : Advise patients and caregivers to pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.

Advise caregivers to inform their healthcare provider if their child’s weight changes in order to make sure that the child’s NORVIR dose is adjusted as needed.

Advise patients to take NORVIR with meals.

For adult patients taking NORVIR capsules, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.

Advise patients to remain under the care of a physician while using NORVIR and to take NORVIR and other concomitant antiretroviral therapy every day as prescribed.

NORVIR must always be used in combination with other antiretroviral drugs.

Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider.

If a dose of NORVIR is missed patients should take the dose as soon as possible and then return to their normal schedule.

However, if a dose is skipped the patient should not double the next dose.

Continued NORVIR therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

NORVIR is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.

Patients should remain under the care of a physician when using NORVIR.

Drug Interactions NORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St.

John’s Wort.

Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with NORVIR because hormonal levels may decrease [see Drug Interactions (7.2) , Use in Specific Populations (8.3) ].

Hepatotoxicity Pre-existing liver disease including Hepatitis B or C can worsen with use of NORVIR.

This can be seen as worsening of transaminase elevations or hepatic decompensation.

Advise patients that their liver function tests will need to be monitored closely especially during the first several months of NORVIR treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin [see Warnings and Precautions (5.3) ] .

Pancreatitis Pancreatitis, including some fatalities, has been observed in patients receiving NORVIR therapy.

Advise patients to notify their healthcare provider of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis [see Warnings and Precautions (5.4) ] .

Allergic Reactions/Hypersensitivity Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving NORVIR.

Advise patients to contact their healthcare provider if they develop a rash while taking NORVIR [see Warnings and Precautions (5.5) ] .

PR Interval Prolongation NORVIR may produce changes in the electrocardiogram (e.g., PR prolongation).

Advise patients to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness [see Warnings and Precautions (5.6) ] .

Lipid Disorders Advise patients that treatment with NORVIR therapy can result in substantial increases in the concentration of total cholesterol and triglycerides [see Warnings and Precautions (5.7) ] .

Diabetes Mellitus/Hyperglycemia Advise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported and to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on NORVIR as they may require a change in their diabetes treatment or new treatment [see Warnings and Precautions (5.7) ] .

Immune Reconstitution Syndrome Advise patients that immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including NORVIR [see Warnings and Precautions (5.9) ] .

Fat Redistribution Advise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time [see Warnings and Precautions (5.10) ] .

Patients with Hemophilia Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as NORVIR [see Warnings and Precautions (5.11) ] .

Pregnancy Exposure Registry Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to NORVIR [see Use in Specific Populations (8.1) ] .

Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2) ] .

NORVIR 100 mg soft gelatin capsules are manufactured for: AbbVie Inc.

DOSAGE AND ADMINISTRATION

2 Dose modification for NORVIR is necessary when used with other protease inhibitors.

(2) Adult patients: 600 mg twice-daily with meals if possible.

(2.2) Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals.

(2.3) 2.1 General Administration Recommendations NORVIR must be used in combination with other antiretroviral agents.

NORVIR is administered orally in combination with other antiretroviral agents.

It is recommended that NORVIR be taken with meals.

General Dosing Guidelines Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued.

2.2 Dosage Recommendations in Adults Recommended Dosage for treatment of HIV-1 The recommended dosage of NORVIR is 600 mg twice daily by mouth.

Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels.

NORVIR should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.

The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

2.3 Dosage Recommendations in Pediatric Patients NORVIR must be used in combination with other antiretroviral agents [see Dosage and Administration (2) ] .

The recommended dosage of NORVIR in pediatric patients older than 1 month is 350 to 400 mg per m 2 twice daily by mouth and should not exceed 600 mg twice daily.

NORVIR should be started at 250 mg per m 2 twice daily and increased at 2 to 3 day intervals by 50 mg per m 2 twice daily.

If patients do not tolerate 400 mg per m 2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered.

The use of NORVIR oral solution is recommended for children greater than 1 month who cannot swallow capsules.

Please refer to the NORVIR oral solution full prescribing information for pediatric dosage and administration.

5-5-fluorouracil 50 MG/ML Injectable Solution

WARNINGS

THE DAILY DOSE OF FLUOROURACIL IS NOT TO EXCEED 800 MG.

IT IS RECOMMENDED THAT PATIENTS BE HOSPITALIZED DURING THEIR FIRST COURSE OF TREATMENT.

Fluorouracil should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function.

Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity.

1 A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity.

Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil.

Pregnancy Teratogenic Effects – Pregnancy Category D Fluorouracil may cause fetal harm when administered to a pregnant woman.

Fluorouracil has been shown to be teratogenic in laboratory animals.

Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on day 10 or 12 of gestation.

Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg given to hamsters between days 8 and 11 of gestation were teratogenic.

Malformations included cleft palates, skeletal defects and deformed appendages, paws and tails.

The dosages which were teratogenic in animals are 1 to 3 times the maximum recommended human therapeutic dose.

In monkeys, divided doses of 40 mg/kg given between days 20 and 24 of gestation were not teratogenic.

There are no adequate and well-controlled studies with fluorouracil in pregnant women.

While there is no evidence of teratogenicity in humans due to fluorouracil, it should be kept in mind that other drugs which inhibit DNA synthesis ( e.g.

, methotrexate and aminopterin) have been reported to be teratogenic in humans.

Women of childbearing potential should be advised to avoid becoming pregnant.

If the drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be told of the potential hazard to the fetus.

Fluorouracil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Combination Therapy Any form of therapy which adds to the stress of the patient, interferes with nutrition or depresses bone marrow function will increase the toxicity of Fluorouracil.

DRUG INTERACTIONS

Drug Interactions Leucovorin calcium may enhance the toxicity of fluorouracil.

Also see WARNINGS section.

OVERDOSAGE

The possibility of overdosage with fluorouracil is unlikely in view of the mode of administration.

Nevertheless, the anticipated manifestations would be nausea, vomiting, diarrhea, gastrointestinal ulceration and bleeding, bone marrow depression (including thrombocytopenia, leukopenia and agranulocytosis).

No specific antidotal therapy exists.

Patients who have been exposed to an overdose of Fluorouracil should be monitored hematologically for at least four weeks.

Should abnormalities appear, appropriate therapy should be utilized.

The acute intravenous toxicity of fluorouracil is as follows: Species LD 50 (mg/kg ±S.E.) Mouse 340 ± 17 Rat 165 ± 26 Rabbit 27 ± 5.1 Dog 31.5 ± 3.8

DESCRIPTION

Fluorouracil Injection, USP an antineoplastic antimetabolite, is a colorless to yellow aqueous sterile, nonpyrogenic injectable solution for intravenous administration.

Each mL contains: 50 mg of fluorouracil; pH is adjusted to approximately 9.2 with sodium hydroxide.

Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1 H ,3 H )-pyrimidinedione.

It is a white to practically white crystalline powder which is sparingly soluble in water.

The molecular weight is 130.08 and the structural formula is: C 4 H 3 FN 2 O 2 .

A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses.

The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion or the filling of empty sterile syringes for patients with individualized dosing requirements.

Chemical Structure

HOW SUPPLIED

NDC 66758-054-01: 50 mg/mL in a 50 mL flip-top Pharmacy Bulk Package vial, individually packaged.

NDC 66758-054-02: 50 mg/mL in a 100 mL flip-top Pharmacy Bulk Package vial, individually packaged.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

DO NOT FREEZE.

PROTECT FROM LIGHT .

Vial stoppers do not contain natural rubber latex.

For Sandoz Inc.

Customer Service, call 1-800-525-8747.

Manufactured for: SANDOZ Princeton, NJ 08540 Manufactured by: Ebewe PHARMA A-4866 Unterach, AUSTRIA April 2011

INDICATIONS AND USAGE

Fluorouracil is effective in the palliative management of carcinoma of the colon, rectum, breast, stomach and pancreas.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in children have not been established.