TUDOFOVIR
(Tenofovir Disoproxil Fumarate Tablets IP)
COMPOSITION
Each film coated tablet contains:
Tenofovir Disoproxil Fumarate IP 300 mg
Colours : Indigo Carmine & Titanium Dioxide.
PHARMACOLOGY
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5`-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha and beta, and mitochondrial DNA polymerase gamma.
PHARMACOKINETICS
The pharmacokinetics of tenofovir disoproxil fumarate has been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics is similar between these populations.
Absorption:Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients is approximately 25%. Following oral administration of a single dose of tenofovir disoproxil fumarate 300 mg to HIV-1 infected patients in the fasted state, maximum serum concentrations (Cmax ) are
achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 296 ± 90 ng/mL and 2287 ± 685 ng·hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a tenofovir disoproxil fumarate dose range of 75 to 600 mg and are not affected by repeated dosing.
Effects of Food on Oral Absorption:Administration of tenofovir disoproxil fumarate following a high-fat meal (~700 to 1000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC of approximately 40% and an increase in Cmax of approximately 14%. However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour.
Distribution:In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination:In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes.
Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion.
INDICATIONS: TUDOFOVIRis indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
DOSAGE AND ADMINISTRATION:
The dose of TUDOFOVIR is 300 mg once daily taken orally, without regard to food. Therapy should be initiated by a physician experienced in the management of HIV infection and/or treatment of chronic hepatitis B.
Adults: The recommended dose for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.
Chronic hepatitis B: The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:
- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy.
Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse. Paediatric patients: Tenofovir Disoproxil Fumarate Tablets is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy.
Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years.
Renal insufficiency: Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long term safety data has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min).
Dose interval adjustments are recommended for patients with creatinine clearance < 50 ml/min.
Mild renal impairment (creatinine clearance 50-80 ml/min): Limited data from clinical studies support once daily dosing of tenofovir disoproxil fumarate in patients with mild renal impairment.
Moderate renal impairment (creatinine clearance 30-49 ml/min): Administration of 245 mg tenofovir disoproxil (as fumarate) every 48 hours is recommended based on modelling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies.
Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients: Adequate dose adjustments cannot be applied due to lack of alternative tablet strengths; therefore use in this group of patients is not recommended. If no alternative treatment is available, prolonged dose intervals may be used as follows:
Severe renal impairment: 245 mg tenofovir disoproxil (as fumarate) may be administered every 72-96 hours (dosing twice a week). Haemodialysis patients: 245 mg tenofovir disoproxil (as fumarate) may be administered every 7 days following completion of a haemodialysis session*.
These dose adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Therefore clinical response to treatment and renal function should be closely monitored.
*Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.
No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance < 10 ml/min.
Hepatic impairment: No dose adjustment is required in patients with hepatic impairment.
If it is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis.
CONTRAINDICATIONS:
TUDOFOVIRis contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.
PRECAUTIONS AND WARNING:
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors.
Patients Co-infected with HIV and Hepatitis B Virus
It is recommended that all patients with HIV be tested for the presence of chronic Hepatitis B virus (HBV) before initiating antiretroviral therapy. It is not indicated for the treatment of chronic HBV infection and the safety and efficacy of tenofovir disoproxil fumarate have not been established in patients co-infected with HBV and HIV.
Renal Impairment Tenofovir is principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with creatinine clearance <50 mL/min. No safety data are available in patients with renal dysfunction who received tenofovir disoproxil fumarate using these dosing guidelines. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported in association with the use of tenofovir disoproxil fumarate.
Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and
phosphorus. It should not be used in combination with the fixed-dose combination product containing tenofovir disoproxil fumarate as one of its components.
Bone Effects
In both arms of the study 903 through 144 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir disoproxil fumarate group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through Week 144.
SIDE EFFECTS:
HIV-1: Assessment of adverse reactions from clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-natïve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
See also Post-marketing experience below. Metabolism and nutrition disorders:
Very common: hypophosphataemia Nervous system disorders:
Very common: dizziness Gastrointestinal disorders:
Very common: diarrhoea, vomiting, nausea
Common: flatulence
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
Hepatitis B: Assessment of adverse reactions from clinical study data is based on experience in two double-blind comparative controlled studies in which 641 patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.
The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Frequencies are defined as common (≥ 1/100, < 1/10).
See also Post-marketing experience below. Nervous system disorders:
Common: headache Gastrointestinal disorders:
Common: diarrhoea, vomiting, abdominal pain, nausea, abdominal distension, flatulence
Hepatobiliary disorders: Common: ALT increase
General disorders and administration site conditions: Common: fatigue
Exacerbations during treatment: In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients versus 1.9% of adefovir dipivoxil-treated patients.
Post-marketing experience: In addition to adverse reaction reports from clinical studies the following possible adverse reactions have also been identified during post-marketing safety surveillance of tenofovir disoproxil fumarate. Frequencies are defined as rare (≥
1/10,000, < 1/1,000) or very rare (< 1/10,000) including isolated reports. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot always be made.
Metabolism and nutrition disorders: Rare: lactic acidosis
Not known: hypokalaemia
Respiratory, thoracic and mediastinal disorders: Very rare: dyspnoea
Gastrointestinal disorders: Rare: pancreatitis Hepatobiliary disorders: Rare: increased transaminases Very rare: hepatitis
Not known: hepatic steatosis
Skin and subcutaneous tissue disorders:
Rare: rash
Musculoskeletal and connective tissue disorders:
Not known: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), muscular weakness, myopathy
Renal and urinary disorders:
Rare: acute renal failure, renal failure, proximal renal tubulopathy (including Fanconi syndrome), increased creatinine
Very rare: acute tubular necrosis
Not known: nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus
General disorders and administration site conditions: Very rare: asthenia
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to fractures), hypokalaemia, muscular weakness, myopathy and hypophosphataemia.
DRUG INTERACTIONS
Interaction studies have only been performed in adults.
Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.
Concomitant use not recommended: Didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended Renally eliminated medicinal products: Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, h OAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.
Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2
Other interactions:
Interactions between tenofovir disoproxil fumarate and protease inhibitors and antiretroviral agents other than protease inhibitors Atazanavir/Ritonavir , Lopinavir/Ritonavir & Darunavir/Ritonavir Studies conducted with other medicinal products: There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.
OVERDOSAGE
Limited clinical experience at doses higher than the therapeutic dose of tenofovir disoproxil fumarate 300 mg is available. In Study 901, 600 mg tenofovir disoproxil fumarate was administered to 8 patients orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known.
If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
PACKING:
HDPE Bottle pack of 30 tablets and packed in a unit carton along with package insert.
SHELF LIFE:24 months from the date of manufacturing
STORAGE INSTRUCTIONS:
Store below 30ºC. Protect from light.
Keep this medicine out of the sight and reach of children. Do not store above 30°C. Store in the original container.
Do not use this medicine after the expiry date which is stated on the bottle.
The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
MARKETED BY:
Aprazer Healthcare Pvt. Ltd.
B-256, 2nd Floor Naraina Phase 1,
New Delhi India 1100028
MANUFACTURER:
Mcneil & Argus Pharmaceuticals Ltd.
100, Rampur Sarsehri Road,
Ambala Cantt – 133001, Haryana (INDIA)
