Viramune 200mg Tablets

1. Name Of The Medicinal Product

Viramune 200 mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 200 mg of nevirapine (as anhydrous).

Excipient: each tablet contains 318 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

White, oval, biconvex tablets. One side is embossed with the code “54 193”, with a single bisect separating the “54” and “193”. The opposite side is marked with the company symbol. The tablet should not be divided.

4. Clinical Particulars

4.1 Therapeutic Indications

Viramune is indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infected adults, adolescents, and children of any age (see section 4.4.).

Most of the experience with Viramune is in combination with nucleoside reverse transcriptase inhibitors (NRTIs). The choice of a subsequent therapy after Viramune should be based on clinical experience and resistance testing (see section 5.1).

4.2 Posology And Method Of Administration

Viramune should be administered by physicians who are experienced in the treatment of HIV infection.

Posology

Patients 16 years and older

The recommended dose of Viramune is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily, in combination with at least two additional antiretroviral agents.

If a dose is recognized as missed within 8 hours of when it was due, the patient should take the missed dose as soon as possible. If a dose is missed and it is more than 8 hours later, the patient should only take the next dose at the usual time.

Dose management considerations

Patients experiencing rash during the 14-day lead-in period of 200 mg/day should not have their Viramune dose increased until the rash has resolved. The isolated rash should be closely monitored (please refer to section 4.4). The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point in time an alternative treatment should be sought due to the possible risk of underexposure and resistance.

Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing regimen using the two week lead-in period.

For toxicities that require interruption of Viramune therapy, see section 4.4.

Special populations

Renal impairment

For patients with renal dysfunction requiring dialysis an additional 200 mg dose of nevirapine following each dialysis treatment is recommended. Patients with CLcr

Hepatic impairment

Nevirapine should not be used in patients with severe hepatic impairment (Child-Pugh C, see section 4.3). No dose adjustment is necessary in patients with mild to moderate hepatic impairment (see sections 4.4 and 5.2).

Elderly

Nevirapine has not been specifically investigated in patients over the age of 65.

Paediatric population

Viramune 200 mg tablets, following the dosing schedule described above, are suitable for larger children, particularly adolescents, below the age of 16 who weigh more than 50 kg or whose body surface area is above 1.25 m² according to the Mosteller formula. An oral suspension dosage form, which can be dosed according to body weight or body surface area, is available for children in this age group weighing less than 50 kg or whose body surface area is below 1.25 m² (please refer to the Summary of Product Characteristics of Viramune oral suspension).

Method of administration

The tablets shall be taken with liquid, and should not be crushed or chewed. Viramune may be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Readministration to patients who have required permanent discontinuation for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to nevirapine.

Patients with severe hepatic impairment (Child-Pugh C) or pre-treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN.

Readministration to patients who previously had ASAT or ALAT > 5 ULN during nevirapine therapy and had recurrence of liver function abnormalities upon readministration of nevirapine (see section 4.4).

Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking Viramune due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine (see section 4.5).

4.4 Special Warnings And Precautions For Use

Viramune should only be used with at least two other antiretroviral agents (see section 5.1).

Viramune should not be used as the sole active antiretroviral, as monotherapy with any antiretroviral has shown to result in viral resistance.

The first 18 weeks of therapy with nevirapine are a critical period which requires close monitoring of patients to disclose the potential appearance of severe and life-threatening skin reactions (including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) and serious hepatitis/hepatic failure. The greatest risk of hepatic events and skin reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past this period and monitoring should continue at frequent intervals. Female gender and higher CD4 counts (>250/mm3 in adult females and >400/mm3 in adult males) at the initiation of nevirapine therapy are associated with a greater risk of hepatic adverse events if the patient has detectable plasma HIV-1 RNA - i.e. a concentration In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Nevirapine must not be restarted following severe hepatic, skin or hypersensitivity reactions (see section 4.3). The dose must be strictly adhered to, especially the 14-days lead-in period (see section 4.2).

Cutaneous reactions

Severe and life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine mainly during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterised by rash, constitutional findings and visceral involvement. Patients should be intensively monitored during the first 18 weeks of treatment. Patients should be closely monitored if an isolated rash occurs. Nevirapine must be permanently discontinued in any patient experiencing severe rash or a rash accompanied by constitutional symptoms (such as fever, blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise), including Stevens-Johnson syndrome, or toxic epidermal necrolysis. Nevirapine must be permanently discontinued in any patient experiencing hypersensitivity reaction (characterised by rash with constitutional symptoms, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction), see section 4.4.

Viramune administration above the recommended dose might increase the frequency and seriousness of skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with Viramune use.

Concomitant prednisone use (40 mg/day for the first 14 days of Viramune administration) has been shown not to decrease the incidence of nevirapine -associated rash, and may be associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy.

Some risk factors for developing serious cutaneous reactions have been identified; they include failure to follow the initial dosing of 200 mg daily during the lead-in period and a long delay between the initial symptoms and medical consultation. Women appear to be at higher risk than men of developing rash, whether receiving nevirapine or non- nevirapine containing therapy.

Patients should be instructed that a major toxicity of nevirapine is rash. They should be advised to promptly notify their physician of any rash and avoid delay between the initial symptoms and medical consultation. The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Therefore, patients should be monitored carefully for the appearance of rash during this period. Patients should be instructed that dose escalation is not to occur if any rash occurs during the two-week lead-in dosing period, until the rash resolves. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point in time an alternative treatment should be sought due to the possible risk of underexposure and resistance.

Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise should discontinue the medicinal product and immediately seek medical evaluation. In these patients nevirapine must not be restarted. If patients present with a suspected nevirapine -associated rash, liver function tests should be performed. Patients with moderate to severe elevations (ASAT or ALAT > 5 ULN) should be permanently discontinued from nevirapine. If a hypersensitivity reaction occurs, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, nevirapine must be permanently stopped and not be re-introduced (see section 4.3).

Hepatic reactions

Severe and life-threatening hepatoxicity, including fatal fulminant hepatitis, has occurred in patients treated with nevirapine. The first 18 weeks of treatment is a critical period which requires close monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk continues past this period and monitoring should continue at frequent intervals throughout treatment.

Rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with nevirapine use.

Increased ASAT or ALAT levels > 2.5 ULN and/or co-infection with hepatitis B and/or C at the start of antiretroviral therapy is associated with greater risk of hepatic adverse reactions during antiretroviral therapy in general, including nevirapine containing regimens.

Female gender and higher CD4 counts at the initiation of nevirapine therapy in treatment-naïve patients is associated with increased risk of hepatic adverse events.Women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and treatment-naïve patients of either gender with detectable HIV-1 RNA in plasma with higher CD4 counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review of predominantly patients with a plasma HIV-1 viral load of 50 copies/ml or higher, women with CD4 counts >250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts <250 cells/mm3 (11.0% versus 0.9%). An increased risk was observed in men with detectable HIV-1 RNA in plasma and CD4 counts > 400 cells/mm3 (6.3% versus 1.2% for men with CD4 counts <400 cells/mm3). This increased risk for toxicity based on CD4 count thresholds has not been detected in patients with undetectable (i.e. < 50 copies/ml) plasma viral load.

Patients should be informed that hepatic reactions are a major toxicity of nevirapine requiring close monitoring during the first 18 weeks. They should be informed that occurrence of symptoms suggestive of hepatitis should lead them to discontinue nevirapine and immediately seek medical evaluation, which should include liver function tests.

Liver monitoring

Clinical chemistry tests, which include liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.

Abnormal liver function tests have been reported with nevirapine, some in the first few weeks of therapy.

Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a contraindication to use nevirapine. Asymptomatic GGT elevations are not a contraindication to continue therapy.

Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, at the 3rd month and then regularly thereafter. Liver test monitoring should be performed if the patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity.

If ASAT or ALAT > 2.5 ULN before or during treatment, then liver tests should be monitored more frequently during regular clinic visits. nevirapine must not be administered to patients with pre-treatment ASAT or ALAT > 5 ULN until baseline ASAT/ALAT are stabilised < 5 ULN (see section 4.3).

Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as anorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patients should be instructed to seek medical attention promptly if these occur. If ASAT or ALAT increase to > 5 ULN during treatment, nevirapine should be immediately stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or symptoms of hepatitis, rash, constitutional symptoms or other findings suggestive of organ dysfunction, it may be possible to reintroduce nevirapine, on a case by case basis, at the starting dose regimen of 200 mg/day for 14 days followed by 400 mg/day. In these cases, more frequent liver monitoring is required. If liver function abnormalities recur, nevirapine should be permanently discontinued. If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus AND laboratory findings (such as moderate or severe liver function test abnormalities (excluding GGT)), nevirapine must be permanently stopped. Viramune must not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.

Liver disease

The safety and efficacy of Viramune has not been established in patients with significant underlying liver disorders. Viramune is contraindicated in patients with severe hepatic impairment (Child-Pugh C, see section 4.3). Pharmacokinetic results suggest caution should be exercised when nevirapine is administered to patients with moderate hepatic dysfunction (Child-Pugh B). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In the case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Other warnings

Post-Exposure-Prophylaxis: Serious hepatotoxicity, including liver failure requiring transplantation, has been reported in HIV-uninfected individuals receiving multiple doses of Viramune in the setting of post-exposure-prophylaxis (PEP), an unapproved use. The use of Viramune has not been evaluated within a specific study on PEP, especially in term of treatment duration and therefore, is strongly discouraged.

Combination therapy with nevirapine is not a curative treatment of patients infected with HIV-1; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections.

Combination therapy with nevirapine has not been shown to eliminate the risk of transmission of HIV-1 to others through sexual contact or contaminated blood.

Hormonal methods of birth control other than Depo-medroxyprogesterone acetate (DMPA) should not be used as the sole method of contraception in women taking Viramune, since nevirapine might lower the plasma concentrations of these medicinal products. For this reason, and to reduce the risk of HIV transmission, barrier contraception (e.g., condoms) is recommended. Additionally, when postmenopausal hormone therapy is used during administration of nevirapine, its therapeutic effect should be monitored.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicinal product related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

In clinical studies, Viramune has been associated with an increase in HDL- cholesterol and an overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies with nevirapine on modifying the cardiovascular risk in HIV infected patients, the clinical impact of these findings is not known. The selection of antiretroviral medicinal products must be guided primarily by their antiviral efficacy.

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

The available pharmacokinetic data suggest that the concomitant use of rifampicin and nevirapine is not recommended (please also refer to section 4.5).

Lactose: Viramune tablets contain 636 mg of lactose per maximum recommended daily dose.

Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring within 2-4 weeks of initiating multiple-dose therapy.

Compounds using this metabolic pathway may have decreased plasma concentrations when co-administered with nevirapine. Careful monitoring of the therapeutic effectiveness of P450 metabolised medicinal products is recommended when taken in combination with nevirapine.

The absorption of nevirapine is not affected by food, antacids or medicinal products which are formulated with an alkaline buffering agent.

The interaction data is presented as geometric mean value with 90% confidence interval (90% CI) whenever these data were available. ND = Not Determined, ↑ = Increased,

Medicinal products by therapeutic areas	Interaction	Recommendations concerning co-administration
ANTI-INFECTIVES
ANTIRETROVIRALS
NRTIs
Didanosine 100-150 mg BID	Didanosine AUC ↔ 1.08 (0.92-1.27) Didanosine Cmin ND Didanosine Cmax↔ 0.98 (0.79-1.21)	Didanosine and Viramune can be co-administered without dose adjustments.
Lamivudine 150 mg BID	No changes to lamivudine apparent clearance and volume of distribution, suggesting no induction effect of nevirapine on lamivudine clearance.	Lamivudine and Viramune can be co-administered without dose adjustments.
Stavudine: 30/40 mg BID	Stavudine AUC ↔ 0.96 (0.89-1.03) Stavudine Cmin ND Stavudine Cmax ↔ 0.94 (0.86-1.03) Nevirapine: compared to historical controls, levels appeared to be unchanged.	Stavudine and Viramune can be co-administered without dose adjustments.
Tenofovir 300 mg QD	Tenofovir plasma levels remain unchanged when co-administered with Nevirapine. Nevirapine plasma levels were not altered by co-administration of tenofovir.	Tenofovir and Viramune can be co-administered without dose adjustments.
Zidovudine 100-200 mg TID	Zidovudine AUC Zidovudine Cmin ND Zidovudine Cmax Nevirapine: Zidovudine had no effect its pharmacokinetics.	Zidovudine and Viramune can be co-administered without dose adjustments
NNRTIs
Efavirenz 600 mg QD	Efavirenz AUC Efavirenz Cmin Efavirenz Cmax	It is not recommended to co-administer efavirenz and Viramune, because of additive toxicity and no benefit in terms of efficacy over either NNRTI alone.
PIs
Atazanavir/ritonavir 300/100 mg QD 400/100 mg QD	Atazanavir/r 300/100mg: Atazanavir/r AUC Atazanavir/r Cmin Atazanavir/r Cmax Atazanavir/r 400/100mg: Atazanavir/r AUC Atazanavir/r Cmin Atazanavir/r Cmax↔ 1.02 (0.85-1.24) (compared to 300/100mg without nevirapine) Nevirapine AUC ↑ 1.25 (1.17-1.34) Nevirapine Cmin↑ 1.32 (1.22-1.43) Nevirapine Cmax↑ 1.17 (1.09-1.25)	It is not recommended to co-administer atazanavir/ritonavir and Viramune.
Darunavir/ritonavir 400/100 mg BID	Darunavir AUC ↑ 1.24 (0.97-1.57) Darunavir Cmin ↔ 1.02 (0.79-1.32) Darunavir Cmax ↑ 1.40 (1.14-1.73) Nevirapine AUC ↑ 1.27 (1.12-1.44) Nevirapine Cmin↑ 1.47 (1.20-1.82) Nevirapine Cmax ↑ 1.18 (1.02-1.37)	Darunavir and Viramune can be co-administered without dose adjustments.
Fosamprenavir 1400 mg BID,	Amprenavir AUC Amprenavir Cmin Amprenavir Cmax Nevirapine AUC ↑ 1.29 (1.19-1.40) Nevirapine Cmin↑ 1.34 (1.21-1.49) Nevirapine Cmax↑ 1.25 (1.14-1.37)	It is not recommended to co-administer fosamprenavir and Viramune if fosamprenavir is not co-administered with ritonavir.
Fosamprenavir/ritonavir 700/100 mg BID	Amprenavir AUC ↔ 0.89 (0.77-1.03) Amprenavir Cmin Amprenavir Cmax↔ 0.97 (0.85-1.10) Nevirapine AUC ↑ 1.14 (1.05-1.24) Nevirapine Cmin↑ 1.22 (1.10-1.35) Nevirapine Cmax↑ 1.13 (1.03-1.24)	Fosamprenavir/ritonavir and Viramune can be co-administered without dose adjustments
Lopinavir/ritonavir (capsules) 400/100 mg BID	patients: Lopinavir AUC Lopinavir Cmin Lopinavir Cmax	An increase in the dose of lopinavir/ritonavir to 533/133 mg (4 capsules) or 500/125 mg (5 tablets with 100/25 mg each) twice daily with food is recommended in combination with Viramune. Dose adjustment of Viramune is not required when co-administered with lopinavir.
Lopinavir/ritonavir (oral solution) 300/75 mg/m2 BID	Paediatric patients: Lopinavir AUC Lopinavir Cmin Lopinavir Cmax	For children, increase of the dose of lopinavir/ritonavir to 300/75 mg/m2 twice daily with food should be considered when used in combination with Viramune, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Nelfinavir 750 mg TID	Nelfinavir AUC ↔ 1.06 (0.78-1.14) Cmin↔ 0.68 (0.50-1.5) Cmax↔ 1.06 (0.92-1.22) Nelfinavir metabolite M8: AUC Cmin Cmax Nevirapine: compared to historical controls, levels appeared to be unchanged.	Nelfinavir and Viramune can be co-administered without dose adjustments.
Ritonavir 600 mg BID	Ritonavir AUC↔ 0.92 (0.79-1.07) Ritonavir Cmin↔ 0.93 (0.76-1.14) Ritonavir Cmax↔ 0.93 (0.78-1.07) Nevirapine: Co-administration of ritonavir does not lead to any clinically relevant change in nevirapine plasma levels.	Ritonavir and Viramune can be co-administered without dose adjustments.
Saquinavir/ritonavir	The limited data available with saquinavir soft gel capsule boosted with ritonavir do not suggest any clinically relevant interaction between saquinavir boosted with ritonavir and Nevirapine	Saquinavir/ritonavir and Viramune can be co-administered without dose adjustments.
Tipranavir/ritonavir 500/200 mg BID	No specific drug-drug interaction study has been performed. The limited data available from a phase IIa study in HIV-infected patients have shown a clinically non significant 20% decrease of TPV Cmin.	Tipranavir and Viramune can be co-administered without dose adjustments.
ENTRY INHIBITORS
Enfuvirtide	Due to the metabolic pathway no clinically significant pharmacokinetic interactions are expected between enfuvirtide and nevirapine.	Enfuvirtide and Viramune can be co-administered without dose adjustments.
Maraviroc 300 mg QD	Maraviroc AUC ↔ 1.01 (0.6 -1.55) Maraviroc Cmin ND Maraviroc Cmax↔ 1.54 (0.94-2.52) compared to historical controls Nevirapine concentrations not measured, no effect is expected.	Maraviroc and Viramune can be co-administered without dose adjustments.
INTEGRASE INHIBITORS
Raltegravir 400 mg BID	No clinical data available. Due to the metabolic pathway of raltegravir no interaction is expected.	Raltegravir and Viramune can be co-administered without dose adjustments.
ANTIBIOTICS
Clarithromycin 500 mg BID	Clarithromycin AUC Clarithromycin Cmin Clarithromycin Cmax Metabolite 14-OH clarithromycin AUC ↑ 1.42 (1.16-1.73) Metabolite 14-OH clarithromycin Cmin↔ 0 (0.68-1.49) Metabolite 14-OH clarithromycin Cmax↑ 1.47 (1.21-1.80) Nevirapine AUC ↑ 1.26 Nevirapine Cmin↑ 1.28 Nevirapine Cmax↑ 1.24 compared to historical controls.	Clarithromycin exposure was significantly decreased, 14-OH metabolite exposure increased. Because the clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex overall activity against the pathogen may be altered. Alternatives to clarithromycin, such as azithromycin should be considered. Close monitoring for hepatic abnormalities is recommended
Rifabutin 150 or 300 mg QD	Rifabutin AUC ↑ 1.17 (0.98-1.40) Rifabutin Cmin↔ 1.07 (0.84-1.37) Rifabutin Cmax↑ 1.28 (1.09-1.51) Metabolite 25-O-desacetylrifabutin AUC ↑ 1.24 (0.84-1.84) Metabolite 25-O-desacetylrifabutin Cmin↑ 1.22 (0.86-1.74) Metabolite 25-O-desacetylrifabutin Cmax↑ 1.29 (0.98-1.68) A clinically not relevant increase in the apparent clearance of nevirapine (by 9%) compared to historical data was reported.	No significant effect on rifabutin and Viramune mean PK parameters is seen. Rifabutin and Viramune can be co-administered without dose adjustments. However, due to the high interpatient variability some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampicin 600 mg QD	Rifampicin AUC ↔ 1.11 (0.96-1.28) Rifampicin Cmin ND Rifampicin Cmax↔ 1.06 (0.91-1.22) Nevirapine AUC Nevirapine Cmin Nevirapine Cmax compared to historical controls.	It is not recommended to co-administer rifampicin and Viramune (see section 4.4). Physicians needing to treat patients co-infected with tuberculosis and using a Viramune containing regimen may consider co-administration of rifabutin instead.
ANTIFUNGALS
Fluconazole 200 mg QD	Fluconazole AUC ↔ 0.94 (0.88-1.01) Fluconazole Cmin↔ 0.93 (0.86-1.01) Fluconazole Cmax↔ 0.92 (0.85-0.99) Nevirapine: exposure: ↑100% compared with historical data where nevirapine was administered alone.	Because of the risk of increased exposure to Viramune, caution should be exercised if the medicinal products are given concomitantly and patients should be monitored closely.
Itraconazole 200 mg QD	Itraconazole AUC Itraconazole Cmin Itraconazole Cmax Nevirapine: there was no significant difference in Nevirapine pharmacokinetic parameters.	A dose increase for itraconazole should be considered when these two agents are administered concomitantly.
Ketoconazole 400 mg QD	Ketoconazole AUC Ketoconazole Cmin ND Ketoconazole Cmax Nevirapine: plasma levels: ↑ 1.15-1.28 compared to historical controls.	It is not recommended to co-administer ketoconazole and Viramune.
ANTACIDS
Cimetidine	Cimetidine: no significant effect on cimetidine PK parameters is seen. Nevirapine Cmin↑ 1.07	Cimetidine and Viramune can be co-administered without dose adjustments.
ANTITHROMBOTICS
Warfarin	The interaction between Nevirapine and the antithrombotic agent warfarin is complex, with the potential for both increases and decreases in coagulation time when used concomitantly.	Close monitoring of anticoagulation levels is warranted.
CONTRACEPTIVES
Depo-medroxyprogesterone acetate (DMPA) 150 mg every 3 months	DMPA AUC ↔ DMPA Cmin↔ DMPA Cmax↔ Nevirapine AUC ↑ 1.20 Nevirapine Cmax↑ 1.20	Viramune co-administration did not alter the ovulation suppression effects of DMPA. DMPA and Viramune can be co-administered without dose adjustments.
Ethinyl estradiol (EE) 0.035 mg	EE AUC EE Cmin ND EE Cmax↔ 0.94 (0.79 - 1.12)	Oral hormonal contraceptives should not be used as the sole method of contraception in women taking Viramune (see section 4.4). Appropriate doses for hormonal contraceptives (oral or other forms of application) other than DMPA in combination with Viramune have not been established with respect to safety and efficacy.
Norethindrone (NET) 1.0 mg QD	NET AUC NET Cmin ND NET Cmax
DRUG ABUSE
Methadone Individual Patient Dosing	Methadone AUC Methadone Cmin ND Methadone Cmax	Methadone-maintained patients beginning Viramune therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
HERBAL PRODUCTS
St. John's Wort	Serum levels of Nevirapine can be reduced by concomitant use of the herbal preparation St. John's Wort (Hypericum perforatum). This is due to induction of medicinal product metabolism enzymes and/or transport proteins by St. John's Wort.	Herbal preparations containing St. John's Wort and Viramune must not be co-administered (see section 4.3). If a patient is already taking St. John's Wort check nevirapine and if possible viral levels and stop St John's Wort. Nevirap

ambenonium

Generic Name: ambenonium (am ben OH nee um)

Brand Names: Mytelase Chloride

What is ambenonium?

Ambenonium affects chemicals in the body that are involved in the communication between nerve impulses and muscle movement.

Ambenonium is used to treat the symptoms of myasthenia gravis.

Ambenonium may also be used for purposes not listed in this medication guide.

What is the most important information I should know about ambenonium?

You should not use this medication if you are allergic to ambenonium, or if you are using certain medications.

Be sure your doctor knows if you use: mecamylamine, (Inversine), atropine (Atreza, Donnatal, Sal-Tropine, Lomotil, Lomocot, and others), blood pressure medications, or a diuretic (water pill).

Before using ambenonium, tell your doctor if you have asthma, Parkinson's disease, or a bladder or bowel obstruction.

Your doctor may occasionally change your dose to make sure you get the best results. You may be asked to keep a daily record of when you took each dose and how long the effects lasted. This will help your doctor determine if your dose needs to be adjusted.

What should I discuss with my health care provider before taking ambenonium?

You should not use this medication if you are allergic to ambenonium, or if you are using certain medications. Be sure your doctor knows if you use:

• 
  

  mecamylamine, (Inversine);

  
  


• 
  

  atropine (Atreza, Donnatal, Sal-Tropine, Lomotil, Lomocot, and others);

  
  


• 
  

  blood pressure medications; or

  
  


• 
  

  a diuretic (water pill).

  
  

To make sure you can safely take ambenonium, tell your doctor if you have any of these other conditions:

• 
  

  asthma;

  
  


• 
  

  Parkinson's disease; or

  
  


• 
  

  a bladder or bowel obstruction.

  
  

It is not known whether ambenonium will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether ambenonium passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using ambenonium.

How should I take ambenonium?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Ambenonium is usually taken every 3 to 4 hours during the day. Follow your doctor's instructions.

Your doctor may occasionally change your dose to make sure you get the best results. You may be asked to keep a daily record of when you took each dose and how long the effects lasted. This will help your doctor determine if your dose needs to be adjusted.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe diarrhea, muscle twitching, anxiety, sweating, and cough or breathing problems.

What should I avoid while taking ambenonium?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Ambenonium side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

• 
  

  severe diarrhea;

  
  


• 
  

  muscle twitching; or

  
  


• 
  

  cough with sputum (mucus).

  
  

Less serious side effects may include:

• 
  

  sweating or urinating more than usual;

  
  


• 
  

  drooling, watery eyes;

  
  


• 
  

  warmth or tingly feeling;

  
  


• 
  

  nausea, vomiting, stomach pain;

  
  


• 
  

  blurred vision;

  
  


• 
  

  anxiety;

  
  


• 
  

  dizziness, spinning feeling; or

  
  


• 
  

  muscle cramps.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect ambenonium?

Tell your doctor about all other medicines you use, especially:

• 
  

  atropine (Atreza, Sal-Tropine), belladonna (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm Scop);

  
  


• 
  

  bronchodilators such as ipratropium (Atrovent) or tiotropium (Spiriva);

  
  


• 
  

  bladder or urinary medicines such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);

  
  


• 
  

  irritable bowel medicines such as dicyclomine (Bentyl), hyoscyamine (Hyomax), or propantheline (Pro Banthine); or

  
  


• 
  

  ulcer medications such as glycopyrrolate (Robinul) or mepenzolate (Cantil).

  
  

This list is not complete and other drugs may interact with ambenonium. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More ambenonium resources

• Ambenonium Side Effects (in more detail)
• Ambenonium Use in Pregnancy & Breastfeeding
• Ambenonium Drug Interactions
• Ambenonium Support Group
• 0 Reviews for Ambenonium - Add your own review/rating

• Ambenonium MedFacts Consumer Leaflet (Wolters Kluwer)

Compare ambenonium with other medications

• Myasthenia Gravis

Where can I get more information?

• Your pharmacist can provide more information about ambenonium.

See also: ambenonium side effects (in more detail)

Phenytoin Infatabs

Dosage Form: tablet, chewable
INFATABS®

Phenytoin

(Phenytoin Tablets, USP)

NOT FOR ONCE-A-DAY DOSING

Phenytoin Infatabs Description

Phenytoin Infatabs is an antiepileptic drug.

Phenytoin is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4-imidazolidinedione, having the following structural formula:

Each Phenytoin Infatabs, for oral administration, contains 50 mg phenytoin, USP. Also contains: D&C yellow No. 10, Al lake; FD&C yellow No. 6, Al lake; flavor; saccharin sodium, USP; sucrose, NF; talc, USP; and other ingredients.

Phenytoin Infatabs - Clinical Pharmacology

Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.

Clinical studies using Phenytoin Infatabs have shown an average plasma half-life of 14 hours with a range of 7 to 29 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day.

When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Phenytoin Infatabs, peak levels occur 1½ –3 hours after administration.

Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.

In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

Clinical studies show that chewed and unchewed Phenytoin Infatabs are bioequivalent, yield approximately equivalent plasma levels, and are more rapidly absorbed than 100-mg Dilantin Capsules .

Indications and Usage for Phenytoin Infatabs

Phenytoin Infatabs (Phenytoin Tablets, USP) are indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery. Phenytoin serum level determinations may be necessary for optimal dosage adjustments (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY sections).

Contraindications

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin or its inactive ingredients or other hydantoins.

Warnings

Effects of Abrupt Withdrawal

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Phenytoin Infatabs, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5–100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1 Risk by indication for antiepileptic drugs in the pooled analysis

Indication	Placebo Patients with Events Per 1000 Patients	Drug Patients with Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Phenytoin Infatabs or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Lymphadenopathy

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, e.g., fever, rash, and liver involvement. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Effects of Alcohol Use on Phenytoin Serum Levels

Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels.

Exacerbation of Porphyria

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Usage in Pregnancy

Clinical

A.

Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated.

 

B.

Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.


Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.


Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.

 

C.

Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Preclinical

Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

Skin reactions

Phenytoin can cause rare, serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears (see WARNINGS section regarding drug discontinuation). If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using another anticonvulsive drug. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including Phenytoin Infatabs, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

Anticonvulsant Hypersensitivity Syndrome

Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication. It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2–4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. Although up to 1 in 5 patients on phenytoin may develop cutaneous eruptions, only a small proportion will progress to AHS.

Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the phenytoin and provide appropriate supportive measures.

Precautions

General

The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.

A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined.

Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, hepatotoxicity, and Anticonvulsant Hypersensitivity Syndrome in black patients. (See WARNINGS section).

Phenytoin should be discontinued if a skin rash appears (see WARNINGS section regarding drug discontinuation). If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome, or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered. (See ADVERSE REACTIONS.) If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated.

Phenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, caution should be exercised if using structurally similar (e.g., barbiturates, succinimides, oxazolidinediones, and other related compounds) in these same patients.

Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.

Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to Vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.

Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed.

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS section.)

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking Phenytoin Infatabs. Instruct patients to take Phenytoin Infatabs only as prescribed.

Patients taking phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.

Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician's advice.

Patients should be instructed to call their physician if skin rash develops.

The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.

Patients, their caregivers, and families should be counseled that AEDs, including Phenytoin Infatabs, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 (see PRECAUTIONS: Pregnancy section).

Laboratory Tests

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.

Drug Interactions

There are many drugs which may increase or decrease phenytoin levels or which phenytoin may affect. Serum level determinations for phenytoin are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed below:

1. Drugs which may increase phenytoin serum levels include: acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, dicumarol, disulfiram, estrogens, ethosuximide, fluoxetine, fluorouracil, fluvoxamine, H2-antagonists, halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, phenylbutazone, salicylates, sertraline, succinimides, sulfonamides, ticlopidine, tolbutamide, trazodone.


2. Drugs which may decrease phenytoin serum levels include: carbamazepine, chronic alcohol abuse, reserpine, and sucralfate. Moban® brand of Molindone Hydrochloride contains calcium ions which interfere with the absorption of phenytoin. Ingestion times of phenytoin and antacid preparations containing calcium should be staggered in patients with low serum phenytoin levels to prevent absorption problems.


3. Drugs which may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, teniposide, valproic acid, and sodium valproate serum levels is unpredictable.


4. Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.


5. Drugs whose efficacy is impaired by phenytoin include: azoles, corticosteroids, coumarin anticoagulants, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, vitamin D.

Drug Enteral Feeding/Nutritional Preparations Interaction

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation. More frequent serum phenytoin levels monitoring may be necessary in these patients.

Drug/Laboratory Test Interactions

Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).

Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations.

Carcinogenesis

See WARNINGS section for information on carcinogenesis.

Pregnancy

Pregnancy Category D: See WARNINGS section.

To provide information regarding the effects of in utero exposure to Phenytoin Infatabs, physicians are advised to recommend that pregnant patients taking Phenytoin Infatabs enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Nursing Mothers

Infant breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk.

Pediatric Use

See DOSAGE AND ADMINISTRATION section.

Adverse Reactions

Body as a whole

Anaphylactoid reaction and anaphylaxis.

Central Nervous System

The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, paresthesias, somnolence and headache have also been observed. There have also been rare reports of phenytoin-induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Gastrointestinal System

Nausea, vomiting, constipation, toxic hepatitis and liver damage.

Integumentary System

Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis (see PRECAUTIONS and WARNINGS section).

Hemopoietic System

Hemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported (see WARNINGS section).

Connective Tissue System

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hypertrichosis, and Peyronie's disease.

Immunologic

Anticonvulsant Hypersensitivity Syndrome (AHS) (which may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy, or rash), systemic lupus erythematosus, periarteritis nodosa and immunoglobulin abnormalities (See WARNINGS section).

Musculoskeletal System

Bone fractures and osteomalacia have been associated with long-term (> 10 years) use of phenytoin by patients with chronic epilepsy. Osteoporosis and other disorders of bone metabolism such as hypocalcemia, hypophosphatemia and decreased levels of Vitamin D metabolites have also been reported.

Special Senses

Taste perversion

Overdosage

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia, and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.

Treatment

Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed.

Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Phenytoin Infatabs Dosage and Administration

When given in equal doses, Phenytoin Infatabs yield higher plasma levels than Dilantin Kapseals®. For this reason serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form.

Dilantin capsules is formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspensions and Phenytoin Infatabs. Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

General

Not for once-a-day dosing.

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum level is usually 10–20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

Phenytoin Infatabs can be either chewed thoroughly before being swallowed or swallowed whole.

Adult Dosage

Patients who have received no previous treatment may be started on two Phenytoin Infatabs three times daily, and the dose is then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be six to eight Phenytoin Infatabs daily; an increase to twelve Phenytoin Infatabs daily may be made, if necessary.

Pediatric Dosage

Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years old and adolescents may require the minimum adult dose (300 mg/day). If the daily dosage cannot be divided equally, the larger dose should be given before retiring.

How is Phenytoin Infatabs Supplied

Phenytoin Infatabs are supplied as:

NDC 59762-5210-1— 50 mg Bottle of 100.

Store at controlled room temperature 20°–25°C (68°–77°F).

Protect from moisture.

Each tablet contains 50 mg phenytoin in a yellow triangular scored chewable tablet.

LAB-0523-1.0

July 2011

MEDICATION GUIDE

Phenytoin Infatabs

(Phenytoin Tablets, USP)

Read this Medication Guide before you start taking Phenytoin Infatabs and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about Phenytoin Infatabs, ask your healthcare provider or pharmacist.

What is the most important information I should know about Phenytoin Infatabs?

Do not stop taking Phenytoin Infatabs without first talking to your healthcare provider.

Stopping Phenytoin Infatabs suddenly can cause serious problems.

Phenytoin Infatabs can cause serious side effects including:

1.

Like other antiepileptic drugs, Phenytoin Infatabs may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying


• attempts to commit suicide


• new or worse depression


• new or worse anxiety


• feeling agitated or restless


• panic attacks


• trouble sleeping (insomnia)


• new or worse irritability


• acting aggressive, being angry, or violent


• acting on dangerous impulses


• an extreme increase activity and talking (mania)


• other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.


• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop taking Phenytoin Infatabs without first talking to a healthcare provider.

• 
  

  Stopping Phenytoin Infatabs suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

  
  

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

2.

Phenytoin Infatabs may harm your unborn baby.

• If you take Phenytoin Infatabs during pregnancy, your baby is at risk for serious birth defects.


• Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors


• If you take Phenytoin Infatabs during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.


• All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of Phenytoin Infatabs. If the decision is made to use Phenytoin Infatabs, you should use effective birth control (contraception) unless you are planning to become pregnant.


• Tell your healthcare provider right away if you become pregnant while taking Phenytoin Infatabs. You and your healthcare provider should decide if you will take Phenytoin Infatabs while you are pregnant.


• Pregnancy Registry: If you become pregnant while taking Phenytoin Infatabs, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

3.

Swollen glands (lymph nodes)

4.

Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms include:

• swelling of your face, eyes, lips, or tongue


• trouble swallowing or breathing


• a skin rash


• hives


• fever, swollen glands, or sore throat that do not go away or come and go


• painful sores in the mouth or around your eyes


• yellowing of your skin or eyes


• unusual bruising or bleeding


• severe fatigue or weakness


• severe muscle pain


• frequent infections or an infection that does not go away

Call your healthcare provider right away if you have any of the symptoms listed above.

What is Phenytoin Infatabs?

Phenytoin Infatabs is a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery.

Who should not take Phenytoin Infatabs?

Do not take Phenytoin Infatabs if you:

• are allergic to Phenytoin Infatabs or any of the ingredients in Phenytoin Infatabs. See the end of this leaflet for a complete list of ingredients in Phenytoin Infatabs.


• have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).

What should I tell my healthcare provider before taking Phenytoin Infatabs?

Before you take Phenytoin Infatabs, tell your healthcare provider if you:

• Have or had liver disease


• Have or had porphyria


• Have or had diabetes


• Have or have had depression, mood problems, or suicidal thoughts or behavior


• Are pregnant or plan to become pregnant.
  
  • If you become pregnant while taking Phenytoin Infatabs, the level of Phenytoin Infatabs in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of Phenytoin Infatabs.
  
  


• Are breast feeding or plan to breastfeed. Phenytoin Infatabs can pass into breast milk. You and your healthcare provider should decide if you will take Phenytoin Infatabs or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Taking Phenytoin Infatabs with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Phenytoin Infatabs?

• Take Phenytoin Infatabs exactly as prescribed. Your healthcare provider will tell you how much Phenytoin Infatabs to take.


• Your healthcare provider may change your dose. Do not change your dose of Phenytoin Infatabs without talking to your healthcare provider.


• Phenytoin Infatabs can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking Phenytoin Infatabs can help prevent this.


• If you take too much Phenytoin Infatabs, call your healthcare provider or local Poison Control Center right away.


• Do not stop taking Phenytoin Infatabs without first talking to your healthcare provider. Stopping Phenytoin Infatabs suddenly can cause serious problems.

What should I avoid while taking Phenytoin Infatabs?

Do not drink alcohol while you take Phenytoin Infatabs without first talking to your healthcare provider. Drinking alcohol while taking Phenytoin Infatabs may change your blood levels of Phenytoin Infatabs which can cause serious problems.

Do not drive, operate heavy machinery, or do other dangerous activities until you know how Phenytoin Infatabs affects you. Phenytoin Infatabs can slow your thinking and motor skills.

What are the possible side effects of Phenytoin Infatabs?

See "What is the most important information I should know about Phenytoin Infatabs?"

Phenytoin Infatabs may cause other serious side effects including:

• Softening of your bones (osteomalacia). This can cause broken bones.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The most common side effects of Phenytoin Infatabs include:

• problems with walking and coordination


• slurred speech


• confusion


• dizziness


• trouble sleeping


• nervousness


• tremor


• headache


• nausea


• vomiting


• constipation


• rash

These are not all the possible side effects of Phenytoin Infatabs. For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Phenytoin Infatabs?

• Store Phenytoin Infatabs at room temperature between 68°F to 77°F (20°C to 25°C). Protect from moisture.

Keep Phenytoin Infatabs and all medicines out of the reach of children.

General information about Phenytoin Infatabs

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Phenytoin Infatabs for a condition for which it was not prescribed. Do not give Phenytoin Infatabs to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Phenytoin Infatabs. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Phenytoin Infatabs that was written for healthcare professionals.

For more information about Phenytoin Infatabs, call 1-800-438-1985.

What are the ingredients in Phenytoin Infatabs?

Each tablet is a yellow triangular scored chewable tablet.

Active ingredient: 50 mg phenytoin

Inactive ingredients: D & C yellow No. 10, A1 lake, FD&C yellow No. 6, flavor, saccharin sodium, sucrose, talc, and other ingredients.

LAB-0524-1.0

July 2011

PRINCIPAL DISPLAY PANEL - 50 mg Tablet Label

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 59762-5210-1

100 Tablets

GREENSTONE® BRAND

INFATABS®

Phenytoin Tablets, USP

50 mg

Rx only

Phenytoin Infatabs  phenytoin  tablet, chewable

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 59762-5210 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Phenytoin (Phenytoin) Phenytoin 50 mg

Inactive Ingredients Ingredient Name Strength D&C yellow No. 10   FD&C yellow No. 6   Aluminum Oxide   saccharin sodium   sucrose   talc

Product Characteristics Color YELLOW Score 2 pieces Shape TRIANGLE Size 12mm Flavor Imprint Code PD;007 Contains

Packaging # NDC Package Description Multilevel Packaging 1 59762-5210-1 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA084427	02/26/1979

Labeler - Greenstone LLC (825560733)

Establishment
Name	Address	ID/FEI	Operations
Pfizer Pharmaceuticals LLC		829084552	MANUFACTURE

Establishment
Name