Viramune

Viramune Special Precautions

nevirapine

Manufacturer:

Boehringer Ingelheim

Distributor:

DKSH
Full Prescribing Info
Special Precautions
The first 18 weeks of therapy with VIRAMUNE 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 and toxic epidermal necrolysis) 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 VIRAMUNE therapy are associated with a greater risk of hepatic adverse events if the patient has detectable plasma HIV-1 RNA- i.e. a concentration ≥50 copies/mL at the initiation of VIRAMUNE.
As serious and life-threatening hepatotoxicity has been observed in controlled and uncontrolled studies predominantly in patients with a plasma HIV-1 viral load of 50 copies/mL or higher, VIRAMUNE should not be initiated in adult females with CD4+ cell counts greater than 250 cells/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 who have a detectable plasmatic HIV-1 RNA unless the benefit outweighs the risk.
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 VIRAMUNE and seek medical evaluation immediately.
VIRAMUNE should not be restarted following severe hepatic, skin or hypersensitivity reactions.
The dosage must be strictly adhered to, especially the 14-days lead-in period (see Dosage & Administration).
Skin Reactions: Severe and life threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE mainly during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and hypersensitivity syndrome characterised by rash, constitutional findings, and visceral involvement. Patients should be carefully monitored during the first 18 weeks of treatment. Patients should be closely monitored if an isolated rash occurs.
VIRAMUNE 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. VIRAMUNE must be permanently discontinued in any patient experiencing hypersensitivity reactions, characterised by rash with constitutional symptoms, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction or signs of other visceral involvement (see Side Effects).
Patients should be advised that a major toxicity of VIRAMUNE is rash. The lead-in period should be used because it has been found to lessen the frequency of rash (see Dosage & Administration).
The majority of rashes associated with VIRAMUNE occur within the first six weeks of therapy therefore patients should be monitored carefully for the appearance of rash during this period.
For VIRAMUNE immediate-release, patients should be instructed that the dose escalation to twice-daily dosing is not to occur if any rash occurs during the lead-in period until the rash has resolved. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point an alternative antiretroviral regimen should be sought.
In rare instances 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 immediate-release administration) has been shown not to decrease the incidence of VIRAMUNE-associated rash, and may be associated with an increase in rash during the first 6 weeks of VIRAMUNE therapy.
Risk factors for developing serious cutaneous reactions include failure to follow the initial dosing of 200 mg daily during the lead-in period. A long delay between the initial symptoms and medical consultation may increase the risk of a more serious outcome of cutaneous reactions. Women appear to be at higher risk than men of developing rash, whether receiving VIRAMUNEor non-VIRAMUNE containing therapy.
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 medication and immediately seek medical evaluation. In these patients VIRAMUNE must not be restarted.
If patients present with a suspected VIRAMUNE-associated rash, liver function tests should be performed. Patients with moderate to severe elevations (ASAT or ALAT >5 X ULN) should be permanently discontinued from VIRAMUNE.
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 should be permanently stopped and not be re-introduced.
Viramune XR: For VIRAMUNE XR extended-release, patients should be instructed that they should not begin VIRAMUNE XR extended-release until any rash that has occurred during the 14 day lead-in period of VIRAMUNE immediate-release has resolved. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point an alternative antiretroviral regimen should be sought.
Hepatic Reactions: Severe or life threatening hepatotoxicity, including fatal fulminant hepatitis has occurred in patients treated with VIRAMUNE. The first 18 weeks of treatment are a critical period which require 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. Patients should be informed that hepatic reactions are a major toxicity of VIRAMUNE.
Patients with signs or symptoms of hepatitis must be advised to discontinue VIRAMUNE and immediately seek medical evaluation, which should include liver function tests.
In rare instances rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with VIRAMUNE use.
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 indication and therefore is strongly discouraged.
Increased ASAT or ALAT levels >2.5 X 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 events during antiretroviral therapy in general, including VIRAMUNE-containing regimens.
Female gender and higher CD4+ counts at the initiation of VIRAMUNE therapy in treatment naïve patients are associated with increased risk of hepatic adverse events.
In a retrospective analysis of pooled clinical studies with VIRAMUNE immediate-release tablets, women had a three-fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4+ counts at initiation of VIRAMUNE therapy were at higher risk for symptomatic hepatic events with VIRAMUNE. 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 CD4+ counts >400 cells/mm3 (6.3% versus 1.2 % for men with CD4+ counts <400 cells/mm3).
Viramune: 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 woman with CD4+ counts <250 cells/mm3 (11.0% versus 0.9%).
This increased risk for toxicity based on CD4+ count threshold has not been detected in patients with undetectable (i.e. <50 copies/ml) plasma viral load.
Liver Monitoring: Abnormal liver function tests have been reported with VIRAMUNE, some in the first few weeks of therapy. Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a contraindication to use VIRAMUNE. Asymptomatic GGT elevations are not a contraindication to continuing therapy.
Monitoring of liver function tests is strongly recommended at frequent intervals, appropriate to the patient's clinical needs, especially during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout VIRAMUNE treatment. Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as anorexia, nausea, jaundice, bilirubinuria, alcholic stools, hepatomegaly or liver tenderness. Patients should be instructed to seek medical attention if these occur.
With ASAT or ALAT values >2.5 X ULN before or during treatment, liver tests should be monitored more frequently during regular clinic visits. VIRAMUNE should not be administered to patients with pre-treatment ASAT or ALAT >5X ULN until baseline ASAT or ALAT are stabilized at values <5X ULN.
If ASAT or ALAT increase to >5X ULN during treatment, VIRAMUNE should be immediately stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or symptoms of hepatitis or constitutional symptoms or other findings suggestive of organ dysfunction, it may be possible to reintroduce VIRAMUNE, based on clinical needs and judgment, on a case by case basis.
VIRAMUNE should be restarted with heightened clinical and laboratory vigilance at the starting dosage regimen of one immediate-release 200 mg tablet daily for 14 days followed by one 200mg VIRAMUNE immediate-release twice daily or one 400mg VIRAMUNE XR extended-release tablet once daily. If liver function abnormalities recur, VIRAMUNE 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)), VIRAMUNE must be permanently stopped. VIRAMUNE should not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to VIRAMUNE.
If ASAT or ALAT increase to >5X ULN during treatment, VIRAMUNE should be immediately stopped. If ASAT and ALAT return to baseline values and if the patient had no clinical signs or symptoms of hepatitis or constitutional symptoms or other findings suggestive of organ dysfunction, it may be possible to reintroduce VIRAMUNE, based on clinical needs and judgment, on a case by case basis.
VIRAMUNE should be restarted with heightened clinical and laboratory vigilance at the starting dosage regimen of one immediate-release 200 mg tablet daily for 14 days followed by one 200mg VIRAMUNE immediate-release twice daily or one 400mg VIRAMUNE XR extended-release tablet once daily. If liver function abnormalities recur, VIRAMUNE 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)], VIRAMUNE must be permanently stopped. VIRAMUNE should not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to VIRAMUNE.
Viramune XR: For patients already on a regimen of VIRAMUNE immediate-release twice daily, who switch to VIRAMUNE XR extended-release once daily, there is no need for a change in their monitoring schedule.
Other Warnings: The following events have also been reported when VIRAMUNE has been used in combination with other anti-retroviral agents: pancreatitis, peripheral neuropathy and thrombocytopenia. These events are commonly associated with other anti-retroviral agents and may be expected to occur when VIRAMUNE is used in combination with other agents; however it is unlikely that these events are due to nevirapine treatment.
Patients receiving VIRAMUNE or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. The long-term effects of VIRAMUNE are unknown at this time. VIRAMUNE therapy has not been shown to reduce the risk of horizontal transmission of HIV-1 to others.
VIRAMUNE is extensively metabolised by the liver and nevirapine metabolites are eliminated largely by the kidney. Pharmacokinetic results suggest caution should be exercised when VIRAMUNE is administered to patients with moderate hepatic dysfunction (Child-Pugh Class B). VIRAMUNE should not be administered to patients with severe hepatic dysfunction (Child-Pugh Class C). VIRAMUNE XR extended-release has not been evaluated in subjects with hepatic impairment.
In adult patients with renal dysfunction who are undergoing dialysis pharmacokinetic results suggest that supplementing VIRAMUNE therapy with an additional 200 mg dose of VIRAMUNE immediate-release tablets following each dialysis treatment would help offset the effects of dialysis on VIRAMUNE clearance. Otherwise patients with CLcr ≥20 ml/min do not require an adjustment in VIRAMUNE dosing (see Pharmacology: Pharmacokinetics under Actions).
In paediatric patients with renal dysfunction who are undergoing dialysis it is recommended that following each dialysis treatment patients receive an additional dose of VIRAMUNE oral suspension or immediate-release tablets representing 50% of the recommended daily dose of VIRAMUNE oral suspension or immediate-release tablets which would help offset the effects of dialysis on VIRAMUNE clearance. VIRAMUNE XR extended-release tablets have not been studied in patients with renal dysfunction.
Hormonal methods of birth control other than DMPA should not be used as the sole method of contraception in women taking VIRAMUNE. Nevirapine may lower the plasma concentrations of these medications (see Interactions). Therefore, when postmenopausal hormone therapy is used during administration of VIRAMUNE, its therapeutic effect should be monitored.
Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, should not take this medicine.
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 drug 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.
Viramune: VIRAMUNE immediate-release tablets contain 636 mg of lactose per maximum recommended daily dose.
Viramune XR:
VIRAMUNE XR extended-release tablets contain 400 mg of lactose per maximum recommended daily dose.
Occasionally, the inactive ingredients of VIRAMUNE XR extended-release tablets will be eliminated in the faeces as soft, hydrated remnants which may resemble intact tablets. These occurrences have not been shown to affect drug levels or response.
Oral susp: VIRAMUNE suspension contains 6 g of sucrose per maximum recommended daily dose.
Patients with the rare hereditary conditions of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
VIRAMUNE suspension contains 6.5 g of sorbitol per maximum recommended daily dose.
Patients with the rare hereditary condition of fructose intolerance should not take this medicine.
VIRAMUNE suspension contains the excipients methyl parahydroxy benzoate and propyl parahydroxy benzoate, which may cause allergic reactions (possibly delayed).
Immune Reactivation Syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy, 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 combination antiretroviral therapy. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis pneumonia. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Warning on Concomitant Use with Other Drugs (for detailed description see Interactions): VIRAMUNE can alter plasma exposure of other drugs, and other drugs can alter plasma exposure of VIRAMUNE.
Combining the following compounds with VIRAMUNE is not recommended: Efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (in combination with cobicistat), boceprevir; if not co-administered with low dose ritonavir: fosamprenavir, saquinavir, atazanavir.
Effects on Ability to Drive and Use Machines: There are no specific studies about the ability to drive vehicles and use machinery.
However, patients should be advised that they may experience undesirable effects such as fatigue during treatment with VIRAMUNE. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue they should avoid potentially hazardous tasks such as driving or operating machinery.
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