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Product
Antiretroviral products (Lamivir-S)
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Antiretroviral products (Lamivir-S)
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Lamivir-S
Lamivudine and stavudine tablets
COMPOSITION
LAMIVIR-S – 30
Each tablet contains
Stavudine 30 mg
Lamivudine 150 mg
LAMIVIR-S – 40
Each tablet contains
Stavudine 40 mg
Lamivudine 150 mg
DESCRIPTION
LAMIVIR-S is a combination of two drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Both stavudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by inhibiting the reverse transcriptase of HIV, and by terminating the growth of the DNA chain. Stavudine in combination with lamivudine has been shown to have synergistic antiretroviral activity.
Each tablet of LAMIVIR-S contains half of the commonly prescribed daily doses of both stavudine and lamivudine. With the availability of this combination tablet patients may be better able to adhere to complex drug treatment regimens, thereby enhancing compliance.
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PHARMACOLOGY
Pharmacodynamics:
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5`-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is the inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian DNA polymerases alpha and beta, and mitochondrial DNA polymerase-gamma.
Stavudine: Stavudine, a nucleoside analogue of thymidine, inhibits the replication of HIV in human cells in vitro. Stavudine is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (K i =0.0083 to 0.032 µM), and by its incorporation into viral DNA causing a termination of DNA chain elongation because stavudine lacks the essential 3`-OH group. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA.
Pharmacokinetics
Lamivudine
Absorption and bioavailability: Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet. After oral administration of 2 mg/kg twice a day to 9 adults with HIV, the peak serum lamivudine concentration (C max ) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.
There was no significant difference in systemic exposure (AUC(infinity)) in the fed and fasted states; therefore, lamivudine tablets and oral solution may be administered with or without food.
Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 patients was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. Volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is low (<36%).
Metabolism : Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.
Elimination: The majority of lamivudine is eliminated unchanged in urine. In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). In most single-dose studies in HIV-infected patients, HBV-infected patients, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t 1/2 ) ranged from 5 to 7 hours. In HIV-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD).
Stavudine
Absorption : Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The oral bioavailability of stavudine is 86.4 ± 18.2%. The systemic exposure to stavudine is the same following administration as capsules or solution.
Distribution: Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/mL. Stavudine distributes equally between red blood cells and plasma. The apparent oral volume of distribution is 46 ± 21 L.
Metabolism: The metabolism fate of stavudine has not been elucidated in humans.
Elimination: Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. Elimination half-life for oral dose is 1.6 ± 0.23 h.
INDICATIONS
LAMIVIR-S tablets are indicated for the treatment of HIV infection as a component of combination antiretroviral therapy.
DOSAGE AND ADMINISTRATION
The interval between doses of Lamivir S should be 12 hours. Lamivir S may be taken with or without food.
Adults
LAMIVIR-S – 30
1 tablet twice daily for patients weighing <60 kg
LAMIVIR-S – 40
1 tablet twice daily for patients weighing ≥ 60 kg
Dose adjustment: Because it is a fixed-dose combination, LAMIVIR-S should not be prescribed for patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance ≤ 50 ml/min), or those experiencing dose-limiting adverse events.
CONTRAINDICATIONS
LAMIVIR-S is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the formulation.
WARNINGS AND PRECAUTIONS
In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur (see Undesirable Effects ).
In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin. The clinical significance of these in vitro interactions is unknown; therefore concomitant use of stavudine with either of these drugs should be undertaken with caution.
Lactic Acidosis/Severe Hepatomegaly with Steatosis/Hepatic Failure
Lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, has been reported with the use of antiretroviral nucleoside analogues alone or in combination, including stavudine, lamivudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity and prolonged nucleoside exposure may be risk factors.
Particular caution should be exercised when administering stavudine and lamivudine to any patient, and particularly to those with known risk factors for liver disease. Cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and sudden unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms (including motor weakness), might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.
Treatment should be discontinued in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked aminotransferase elevations).
Important Differences Among Lamivudine-Containing Products
LAMIVIR-S Tablets contain a higher dose of the same active ingredient (lamivudine) than in Lamivir-HBV Tablets. Lamivir-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of lamivudine in Lamivir-HBV are not appropriate for patients dually infected with HIV and HBV. Lamivudine has not been adequately studied for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. If treatment with Lamivir-HBV is prescribed for chronic hepatitis B for a patient with unrecognised or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV treatment. If a decision is made to administer lamivudine to patients dually infected with HIV and HBV, Lamivir Tablets, LAMIVIR-S Tablets, or Duovir tablets should be used as part of an appropriate combination regimen. Duovir (a fixed-dose combination tablet of lamivudine and zidovudine) should not be administered concomitantly with Lamivir, Lamivir-HBV or Zidovir .
Post treatment Exacerbations of Hepatitis
In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from post-marketing experience after changes from lamivudine-containing HIV treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.
Use With Interferon- and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was co-administered with lamivudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).
Patients with HIV and Hepatitis B virus Co-infection
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see Lamivir-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Post treatment exacerbations of hepatitis have also been reported.
Hepatic Impairment and Toxicity:
The safety and efficacy of stavudine have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, 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.
Use with Didanosine and Hydroxyurea-Based Regimens
An increased risk of hepatotoxicity may occur in patients treated with stavudine in combination with didanosine and hydroxyurea compared to when stavudine is used alone. Deaths attributed to hepatotoxicity have occurred in patients receiving this combination. This combination should be avoided.
Use with Interferon and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine. Although no evidence of a pharmacokinetic or pharmacodynamic (eg, loss of HIV/HCV virologic suppression) interaction was seen when ribavirin was co-administered with stavudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon and ribavirin . Patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (eg, Child-Pugh >6) (see the complete prescribing information for interferon and ribavirin ).
Neurological Symptoms
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy.
Peripheral neuropathy, manifested by numbness, tingling or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy including didanosine (see Undesirable Effects ).
Pancreatitis:
Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine, with or without hydroxyurea, in both treatment-naïve and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine (with or without hydroxyurea) and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring. The new regimen should contain neither didanosine nor hydroxyurea.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Drug Interactions
Zidovudine may competitively inhibit the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine is not recommended.
Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim).
Trimethoprim 160 mg/sulphamethoxazole 800 mg (TMP/SMX) once daily has been shown to increase lamivudine exposure (AUC) by 44%. No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat Pneumocystis carinii pneumonia. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.
Renal Impairment
Reduction of the dosage of both stavudine and lamivudine is required in patients with a creatinine clearance of 50 ml/min or less. Hence, LAMIVIR-S cannot be used in this patient population.
Pregnancy
Pregnancy category C. Both lamivudine and stavudine are classified under category C. There are no adequate and well-controlled studies in pregnant women. LAMIVIR-S should be used during pregnancy only if the potential benefits outweigh the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis/Hepatic Failure). The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.
Health care providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Lactation
It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV infection. It is not known whether stavudine is excreted in human milk. Lamivudine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving LAMIVIR-S.
Pediatrics
LAMIVIR-S is not intended for use in pediatric patients.
UNDESIRABLE EFFECTS
Lamivudine
Selected clinical adverse events with a ≥ 5% frequency during therapy with lamivudine 150 mg twice daily plus zidovudine 200 mg three times daily compared with zidovudine are listed below:
Body as a Whole: Headache, malaise and fatigue, fever or chills.
Digestive: Nausea, diarrhea, nausea and vomiting, anorexia and/or decreased appetite, abdominal pain, abdominal cramps, dyspepsia
Nervous System: Neuropathy, insomnia and other sleep disorders, dizziness, depressive disorders.
Respiratory: Nasal signs and symptoms, cough
Skin: Skin rashes
Musculoskeletal: Musculoskeletal pain, myalgia, arthralgia
Pancreatitis was observed in 9 of the 2,613 adult patients (0.3%) who received lamivudine in the controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and B3007.
Observed During Clinical Practice: In addition to adverse events reported from clinical trials, the following events have been identified during post-approval use of lamivudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine.
Body as a Whole: Redistribution/accumulation of body fat
Digestive: Stomatitis.
Endocrine and Metabolic: Hyperglycemia.
General: Weakness.
Haemic and Lymphatic: Anaemia (including pure red cell aplasia and severe anaemias progressing on therapy), lymphadenopathy, splenomegaly.
Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B (see WARNINGS and PRECAUTIONS).
Hypersensitivity: Anaphylaxis, urticaria.
Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.
Nervous: Paresthesia, peripheral neuropathy.
Respiratory : Abnormal breath sounds/wheezing.
Skin: Alopecia, rash, pruritus.
Stavudine
Fatal lactic acidosis has occurred in patients treated with stavudine in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with stavudine. Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis.
Stavudine therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, stavudine should be discontinued.
Stavudine therapy has also been associated with peripheral sensory neuropathy, which can be severe, is dose related, and occurs more frequently in patients being treated with neurotoxic drug therapy, including didanosine, in patients with advanced HIV infection, or in patients who have previously experienced peripheral neuropathy.
Patients should be monitored for the development of neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, patients may tolerate resumption of treatment at one-half of the dose. If neuropathy recurs after resumption, permanent discontinuation of stavudine should be considered.
When stavudine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when stavudine is used alone. Pancreatitis, peripheral neuropathy, and liver function abnormalities occur more frequently in patients treated with the combination of stavudine and didanosine, with or without hydroxyurea. Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with stavudine in combination with didanosine and hydroxyurea (see WARNINGS and PRECAUTIONS ).
Selected clinical adverse events that occurred in adult patients receiving stavudine in a controlled monotherapy study included headache, diarrhea, peripheral neurologic symptoms/neuropathy, rash, nausea and vomiting. Pancreatitis was observed in 3 of the 412 adult patients who received stavudine in a controlled monotherapy study.
Laboratory Abnormalities: Selected laboratory abnormalities reported in two controlled combination studies are provided in Table 2.
Table 2: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3-4)
Observed during clinical practice : The following events have been identified during post-approval use of stavudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors.
Body as a Whole: Abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat.
Digestive Disorders: Anorexia
Exocrine Gland Disorders: Pancreatitis (including fatal cases)
Haematologic Disorders: Anemia, leucopenia and thrombocytopenia
Liver: Symptomatic hyperlactatemia/Lactic acidosis and hepatic steatosis, hepatitis and liver failure
Musculoskeletal: Myalgia
Nervous System: Insomnia, severe motor weakness (most often reported in the setting of lactic acidosis).
OVERDOSAGE
Lamivudine
There is no known antidote for lamivudine. One case of an adult ingesting 6 g of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Because a negligible amount of lamivudine was removed via 4-hour hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.
Stavudine
Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 ml/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.
PACKAGING INFORMATION
LAMIVIR-S – 30 Container of 60 tablets
LAMIVIR-S – 40 Container of 60 tablets
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