Combivir 150mg/300mg

As COMBIVIR contains lamivudine and zidovudine, any interactions that have been identified with these agents individually may occur with COMBIVIR.

Zidovudine plasma levels are not significantly altered when coadministered with lamivudine. Zidovudine had no effect on the pharmacokinetics of lamivudine (see Action and Clinical Pharmacology).

The possibility of interactions with other drugs administered concurrently should be considered, particularly when the main route of elimination is renal.

It is recommended that separate doses of lamivudine (as 3TC) and zidovudine [as RETROVIR (AZT)] be administered to patients with reduced renal function (see Warnings and Precautions), pediatric patients below 12 years of age, patients with low body weights (less than 50 kg) or patients requiring dosing adjustments due to adverse events. See complete prescribing information for 3TC and RETROVIR (AZT) for dosage adjustments.

The recommended oral dose of COMBIVIR (lamivudine and zidovudine) for adults and adolescents who are at least 12 years old is one tablet (containing 150 mg of lamivudine and 300 mg zidovudine) twice daily.

If you forget to take your medicine, take it as soon as you remember. Then continue as before.

abdominal distention, ascites, bleeding gums, constipation, diarrhea, discolouration of tongue, dyspepsia, dysphagia, edema of the tongue, esophagitis, esophageal ulcer, flatulence, gastritis, gastrointestinal hemorrhage, mouth ulcer, nausea and vomiting, oral mucosa pigmentation, peptic ulcer, rectal hemorrhage, rises in serum amylase, sialoadenitis, stomatitis.

The following events have been identified during post-approval use of 3TC and/or RETROVIR (AZT) alone or in combination with other antiretroviral therapy in clinical practice. 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 either their seriousness, frequency of reporting, causal connection to 3TC and/or RETROVIR (AZT), or a combination of these factors.

conjunctivitis, retinitis, visual field defect.

acidosis, anorexia, dehydration, gynecomastia, hypercholesterolemia, hyperglycemia, hyperlactataemia, hyperlipidemia, hyperuricemia, hypoglycemia, hyponatremia, inappropriate antidiuretic hormone secretion, increased appetite, increased CPK, increased LDH, increased serum iron, lactic acidosis and hepatic steatosis (see Warnings and Precautions), weight loss.

ageusia, amblyopia, hearing loss, photophobia, taste disturbance, speech disorder, tinnitus.

breathing disorders (2%), general signs and symptoms (1%), pain (2%), sexual function disturbances (1%), temperature regulation disturbance (1%).

redistribution/accumulation of body fat (see Warnings and Precautions, Fat Redistribution).

apnea, cough, dyspnea, epistaxis, hyperventilation, influenza, pharyngitis, pneumonia, rhinitis, sinusitis.

mood disorders (1%), sleep disorders (4%), taste disturbances (1%).

amenorrhea, decreased libido, gynaecomastia impotence, intermenstrual bleeding.

amyotrophy, arthralgia, muscle disorders including rarely rhabdomyoloysis, myositis, tremor, twitch, myalgia, hemarthrosis, leg cramps.

abdominal pain, allergic reaction, anaphylaxis, back pain, Candida infection, chills, chest pain, death, edema of face, edema of extremities, fatigue, fever, flu syndrome, hypertonia, hypotonia, malaise, pain, pallor, sepsis, weakness.

albuminuria, dysuria, hematuria, increased creatinine levels, polyuria, renal dysfunction, renal failure, urinary frequency.

acne, alopecia, changes in skin and nail pigmentation, dryness of skin, erythema multiforme, exfoliative dermatitis, hair colour change, hirsutism, hyperpigmentation, maculopapular lesions, nail disorders, photosensitivity, pruritus, rash, rubelliform rash, Stevens-Johnson syndrome, sweating, urticaria, vesciculobullous rash.

Frequencies of Selected Laboratory Abnormalities Among Adults in 4 Controlled Clinical Trials of 3TC 300 mg/day Plus RETROVIR (AZT) 600 mg/day^a

abnormalities of red cells, abnormalities of white cells, agranulocytosis, anemia, aplastic anemia, bone marrow depression, eosinophilia, hemolysis, impaired red cell maturation, leukocytosis, leukopenia, lymphadenopathy, lymphocytosis, lymphoma, methemoglobinemia, neutropenia, pancytopenia, pure red cell aplasia, sarcoma, splenomegaly, thrombocytopenia, thrombotic thrombocytopenic purpura.

cholestatic jaundice, fatty liver, hepatic impairment, hepatic failure, hepatitis, hepatomegaly, hyperbilirubinemia, increased aminotransferase levels, increased amylase, jaundice, pancreatitis.

aggressive behavior, agitation, amnesia, anxiety, ataxia, confusion, convulsions, delusions, dementia, depression, dizziness, dystonic movement(s), emotional lability, encephalitis, facial palsy, hallucinations, headache, hypoesthesia, insomnia, loss of mental acuity, meningitis, myasthenia, nervousness, mania, paresthesia, paranoia, peripheral neuritis, peripheral neuropathy, personality disorder, psychotic disorders, somnolence, tremor, vertigo.

cardiac arrest, cardiac failure, cardiomegaly, cardiomyopathy, cerebrovascular accident, hypertension, hypotension, intracranial hemorrhage, orthostatic hypotension, palpitation(s), syncope, tachycardia, vasculitis, vasodilation.

Patients with impaired renal function may be at a greater risk of toxicity from COMBIVIR due to decreased renal clearance of the drug. Therefore a dosage adjustment of lamivudine and zidovudine may be necessary. It is recommended that COMBIVIR not be used in patients with reduced renal function (creatinine clearance ≤50 mL/min). For these patients, it is recommended that 3TC (lamivudine) and RETROVIR (AZT) (zidovudine) be administered. The individual Product Monographs for 3TC (lamivudine) and RETROVIR (AZT) (zidovudine) should be consulted for appropriate dosage adjustments.

COMBIVIR should be used with extreme caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm³ or haemoglobin <9.5 g/dL. In patients with advanced symptomatic disease, anemia and granulocytopenia were the most significant adverse events observed (see Adverse Reactions). There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuation of the drug.

Additionally dosage adjustment of zidovudine may be required if severe anemia or myelosuppression occurs during treatment with COMBIVIR, or in patients with pre-existing bone marrow compromise for example haemoglobin less than 9 g/dL (5.59 mmol/l) or neutrophil count less than 1.0×10⁹/L. As dosage adjustment of COMBIVIR is not possible separate preparations of zidovudine and lamivudine should be used (see Contraindications).

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including lamivudine and zidovudine. A majority of these cases have been in women.

Clinical features which may be indicative of the development of lactic acidosis include generalized weakness, anorexia and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnea and tachypnea).

Caution should be exercised when administering COMBIVIR to any patient, and particularly to those with known risk factors for liver disease. Treatment with COMBIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Cases of pancreatitis have occurred rarely in patients treated with lamivudine and zidovudine. However it is not clear whether these cases were due to treatment with the medicinal products or to the underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of COMBIVIR until diagnosis of pancreatitis is excluded.

Coadministration of zidovudine with other drugs metabolized by glucuronidation should be avoided because the toxicity of either drug may be potentiated (see Drug Interactions).

There are no data on the use of COMBIVIR in pediatric patients.

COMBIVIR is not recommended in children less than 12 years of age, as appropriate dose reduction for the weight of the child cannot be made (see Dosage and Administration).

To monitor maternal-fetal outcomes of pregnant women exposed to COMBIVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling GlaxoSmithKline's Drug Surveillance Department (1-800-387-7374).

There are no adequate and well-controlled studies of COMBIVIR in pregnant women.

Consistent with passive transmission of the drug across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum.

A randomized, double-blind, placebo-controlled trial was conducted in HIV-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-transmission. Congenital abnormalities occurred with similar frequency between infants born to mothers who received zidovudine and infants born to mothers who received placebo. Abnormalities were either problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.

The long-term consequences of in utero and infant exposure to zidovudine are unknown. The long-term effects of early or short-term use of zidovudine in pregnant women are also unknown.

There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peripartum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Reproductive studies with lamivudine in animals have not shown evidence of teratogenicity, and showed no effect on male or female fertility. Lamivudine induced early embryolethality when lamivudine was administered to pregnant rabbits at exposure levels comparable to those achieved in man.

Because animal reproduction studies are not always predictive of the human response, COMBIVIR should be used during pregnancy only if the potential benefit outweighs any possible risk. Administration of COMBIVIR during the first three months of pregnancy is not recommended unless the benefit outweighs the risk.

Myopathy and myositis with pathological changes similar to those produced by HIV disease have been associated with prolonged use of zidovudine and may occur with COMBIVIR therapy.

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Very rare occurrences of pure red cell aplasia have been reported with lamivudine or zidovudine use. Discontinuation of lamivudine and/or zidovudine has resulted in normalization of hematologic parameters in patients with suspected lamivudine or zidovudine-induced pure red cell aplasia.

Anemia, neutropenia and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine. These occurred more frequently at higher zidovudine dosages (1200 to 1500 mg/day), in patients with advanced HIV disease and in those who had poor marrow reserve prior to treatment (see Adverse Reactions). Hematological parameters should therefore be carefully monitored (see Contraindications) in patients receiving COMBIVIR.

These hematological effects are not usually observed before four to six weeks therapy. For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter. In patients with early HIV disease hematological adverse reactions are infrequent. Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months.

The incidence of adverse reactions appears to increase with disease progression and patients should be monitored carefully, especially as disease progression occurs.

The complete prescribing information for all agents being considered for use with COMBIVIR (lamivudine and zidovudine) should be consulted before combination therapy with COMBIVIR is initiated.

Patients should be cautioned about the concomitant use of self-administered medications.

Several serious adverse events have been reported with use of zidovudine in clinical practice. Reports of pancreatitis, sensitization reactions (including anaphylaxis in one patient), vasculitis, and seizures have been rare. These adverse events, except for sensitization, have also been associated with HIV disease. Changes in skin and nail pigmentation have been associated with the use of zidovudine.

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine 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 COMBIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of COMBIVIR 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., Child Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Several serious adverse events have been reported with use of lamivudine in clinical practice. Reports of anaphylaxis, rhabdomyolysis and peripheral neuropathy have been rare (<1 in 1000) (see Drug Interactions).

Patients receiving COMBIVIR or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close observation by physicians experienced in the treatment of patients with HIV-associated diseases.

Patients should be advised that current antiretroviral therapy, including COMBIVIR, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

It is recommended that the dose of lamivudine be reduced for adults with body weight below 50 kg therefore; a patient may be on a reduced dose of lamivudine and a standard dose of zidovudine and would not be a candidate for the use of COMBIVIR tablets. See complete prescribing information for 3TC and RETROVIR (AZT) for dosage adjustment.

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.

Clinical trials and marketed use of lamivudine, have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If COMBIVIR is discontinued in a patient with HIV and HBV coinfection, periodic monitoring of both liver function tests and markers of HBV replication should be considered.

It is recommended that HIV infected women do not breastfeed their infants in order to avoid transmission of HIV. Both lamivudine and zidovudine are excreted in human milk at similar concentrations to those found in serum. Since lamivudine, zidovudine and HIV virus pass into breast milk it is recommended that mothers taking COMBIVIR do not breastfeed their infants.

Following oral administration, lamivudine was excreted in breast milk at similar concentrations to those found in serum. It is recommended that mothers taking lamivudine do not breastfeed to avoid risking postnatal transmission of HIV infection and potential adverse effects from lamivudine in nursing infants.

Zidovudine is excreted in human milk. After administration of a single dose of 200 mg zidovudine to 13 HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. Mothers should be instructed to discontinue nursing if they are receiving COMBIVIR.

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co-administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anemia.

Lamivudine and zidovudine are potent, selective inhibitors of HIV-1 and HIV-2 replication in vitro. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Zidovudine is a thymidine analogue in which the 3'-hydroxy (-OH) group is replaced by an azido (-N3) group. Intracellularly, lamivudine and zidovudine are phosphorylated to their active 5'́-triphosphate metabolites, lamivudine triphosphate ( L-TP) and zidovudine triphosphate (ZDV-TP). In vitro L-TP has an intracellular half-life of approximately 10.5 to 15.5 hours. The principal mode of action of L-TP and ZDV-TP is inhibition of HIV reverse transcription (RT) via viral DNA chain termination. L-TP is a weak inhibitor of mammalian α, β, and γ-DNA polymerases. ZDV-TP is a weak inhibitor of the cellular DNA polymerase-α and mitochondrial polymerase-γ and has been reported to be incorporated into the DNA of cells in culture.

The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-infected adult patients after administration of single oral, multiple oral and intravenous (IV) doses ranging from 0.25 to 10 mg/kg. After oral administration of 2 mg/kg, the peak plasma lamivudine concentration (C_max) was 1.5±0.5 µg/mL (mean±S.D.) and half-life was 2.6±0.5 hours. There were no significant differences in half-life across the range of single doses (0.25 to 8 mg/kg). The area under the plasma concentration versus time curve (AUC) and C_max increased in proportion to dose over the range from 0.25 to 10 mg/kg.

Lamivudine is well absorbed from the gut, and the bioavailability of oral lamivudine in adults is normally between 80 and 85%. Following oral administration, the mean time (t_max) to maximal serum concentrations (C_max) is about an hour.

Pharmacokinetic studies of RETROVIR (AZT) following intravenous dosing in adults indicate dose-independent kinetics over the range of 1 to 5 mg/kg with a mean zidovudine half-life of 1.1 hours. Zidovudine is rapidly metabolized in the liver to 3'-azido-3'-deoxy-5'-O-β-D- glucopyranuronosylthymidine (GZDV, formerly called GAZT), and both are rapidly eliminated by the kidney. A second metabolite, 3'-amino-3'-deoxythymidine (AMT) has been identified in the plasma following single dose intravenous administration of zidovudine.

After oral dosing in adults, zidovudine is rapidly absorbed from the gastrointestinal tract with peak serum concentrations occurring within 0.5 to 1.5 hours, with an average oral bioavailability of 65%.