public assessment report · bachupally, quthubullapur, mandal, hyderabad, andhra pradesh, 500 072,...

FDA Tentative Approval November 8, 2005 Lamivudine Oral Solution (10 mg/mL) Aurobindo Pharma, Ltd.

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PUBLIC ASSESSMENT REPORT

Lamivudine Oral Solution (10 mg/mL)

International Nonproprietary Name (INN): Lamivudine

Abstract Lamivudine Oral Solution, supplied by Aurobindo Pharma, Ltd., Unit III, Survey No. 313, Bachupally, Quthubullapur, Mandal, Hyderabad, Andhra Pradesh, 500 072, India, was the subject of an Abbreviated New Drug Application (ANDA) submitted to the U. S. Food and Drug Administration (USFDA) pursuant to section 505(j) of the U. S. Federal Food, Drug, and Cosmetic Act. This ANDA was reviewed under the President’s Emergency Plan for AIDS Relief (PEPFAR). Based upon the information presented to date the USFDA concluded that Lamivudine Oral Solution is safe and effective for use as recommended in the submitted labeling. The USFDA was unable to grant final approval to this ANDA at the time of review due to existing patent protection. Therefore, the ANDA was tentatively approved on November 8, 2005. This determination was based upon information available to the agency (i.e., information in the ANDA and the status of current good manufacturing practices (cGMPs) of the facilities used in the manufacturing and testing of the drug product). Lamivudine Oral Solution, on the basis of USFDA tentative approval, was placed on the WHO Prequalification Programme list of manufacturers and suppliers whose HIV-related products have been found acceptable, in principle, for procurement by UN Agencies (Prequalification Programme: Priority Essential Medicines, 63rd Edition, February 1, 2008). Products listed on the WHO Prequalification list with the note “USFDA” have been added to the list based on the scientific assessment and inspections conducted by the USFDA. A product listed as USFDA tentatively approved indicates that although existing patents and/or other marketing exclusivity prevent marketing of the product in the USA, the product meets all of USFDA’s safety, efficacy, and manufacturing quality standards required for marketing in the USA, and is eligible for purchase with PEPFAR funds. Lamivudine Oral Solution is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. Detailed conditions for the use of this product are described in the Summary of Product Characteristics (SPC) and Scientific Discussion, which are Parts 4 and 6 of this Public Assessment Report. The active pharmaceutical ingredient (API) of Lamivudine Oral Solution is the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine, a well established and documented product for the treatment of HIV/AIDS in combination with other products. Lamivudine has been investigated in combination therapy in several clinical trials in both treatment-naïve and treatment-experienced patients. These studies have demonstrated significant decreases in HIV-1 viral load and increases in CD4 cell count. Clinical end-point data indicate


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that therapy with lamivudine in combination with other antiretroviral agents results in a significant reduction in the risk of disease progression and mortality. The most frequent adverse events observed during treatment were headache, insomnia, nausea, abdominal pain, diarrhea, hair loss, and fatigue. The most important safety problem with lamivudine is related to administration to patients with chronic Hepatitis B infection as hepatic deterioration and hepatitis flare may develop on discontinuation of lamivudine. The risk/benefit profile of Lamivudine Oral Solution showed an acceptable safety profile and adequate antiretroviral activity.


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All Accepted Presentations Status USFDA Tentative Approval INN Lamivudine Strength 10 mg/mL Form Oral solution Route of administration

Oral

Packaging Bottle Package size 240 mL


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PACKAGE LEAFLET


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PACKAGE LEAFLET: INFORMATION FOR THE USER

Lamivudine Oral Solution Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor, health care porovider or pharmacist. • This medicine has been prescribed for you. Do not pass it on to others. It may harm them,

even if their symptoms are the same as yours. In this leaflet: 1. What Lamivudine Oral Solution is and what it is used for 2. Before you take Lamivudine Oral Solution 3. How to take Lamivudine Oral Solution 4. Possible side effects 5. How to store Lamivudine Oral Solution 6. Further information 1. WHAT LAMIVUDINE ORAL SOLUTION IS AND WHAT IT IS USED FOR Lamivudine belongs to a group of Anti-HIV medicines, also known as antiretrovirals or antiviral medicines, in the category known as nucleoside reverse transcriptase inhibitors (NRTIs). Lamivudine Oral Solution is used to treat Human Immunodeficiency Virus (HIV) infection as part of combination treatment with other medicines. Lamivudine reduces the amount of HIV virus in your body and keeps it at a low level. It also increases CD4 cell counts. (CD4 cells are a type of white blood cell that plays an important role in maintaining a healthy immune system to help fight infection.) Response to treatment with Lamivudine Oral Solution varies between patients. Your doctor or health care provider will monitor the effectiveness of your treatment. Lamivudine Oral Solution may improve your condition but is not a cure for HIV infection. HIV infection is a disease spread by contact with blood or sexual contact with an infected individual. Treatment with Lamivudine Oral Solution has not been shown to reduce the risk of passing HIV infection on to others by sexual contact or by blood transfer. Therefore, you must continue to take appropriate precautions to avoid giving the virus to others. During your treatment, other infections linked to your weakened immunity (opportunistic infections) may arise. These will require specific and sometimes preventive treatment. 2. BEFORE YOU TAKE LAMIVUDINE ORAL SOLUTION Do not take Lamivudine Oral Solution if you are allergic (hypersensitive) to Lamivudine Oral Solution or any of the other ingredients of Lamivudine Oral Solution (see section 6, “What Lamivudine Oral Solution Contains”).


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Take special care with Lamivudine Oral Solution Discuss the use of Lamivudine Oral Solution with your doctor or health care provider if you have kidney disease. The standard recommended dose may have to be reduced. Tell your doctor or health care provider if you have a history of liver disease. Patients with chronic hepatitis B or C who are treated with antiretroviral agents are at increased risk for severe and potentially fatal liver adverse events and may require blood tests to monitor liver function.

If you have chronic hepatitis B infection, you should not stop your treatment without instructions from your doctor or health care provider, as you may have a recurrence of your hepatitis. This recurrence may be more severe if you have serious liver disease. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, tell your doctor or health care provider immediately.

Lamivudine Oral Solution contains sucrose, a form of sugar. If you have Diabetes Mellitus (sugar diabetes), discuss the use of this medicine with your doctor or health care provider. Take Lamivudine Oral Solution every day as prescribed by your doctor or health care provider. Keep in regular contact with your doctor or health care provider. Do not stop taking your medicine without first talking to your doctor or health care provider. Taking Lamuvudine Oral Solution with food and drink Lamivudine Oral Solution may be taken with or without food. Pregnancy If you become pregnant or are planning to become pregnant, talk to your doctor or health care provider to discuss the benefits and risks of your anti-HIV therapy for you and your child. If you have taken Lamivudine Oral Solution during your pregnancy, your doctor or health care provider may request regular visits to monitor the development of your child. Such visits may include blood tests and other diagnostic tests. In children whose mother took anti-HIV medications during pregnancy, the benefit from the reduced chance of being infected with HIV is greater than the risk of suffering from side effects. Breast-feeding Since both lamivudine and the HIV virus pass into breast milk it is recommended that HIV infected women taking lamivudine do not breast-feed their infants under any circumstances in order to avoid transmission of HIV. Driving and using machines No studies on the effects of lamivudine on the ability to drive and use machines have been performed.


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Taking other medicines Tell your doctor about all medicines you are taking including those you have purchased yourself (“over the counter” medicines). These may affect the action of Lamivudine Oral Solution, or Lamivudine Oral Solution may affect their action. Make sure your doctor knows about all medicines you take. 3. HOW TO TAKE LAMIVUDINE ORAL SOLUTION Always take Lamivudine Oral Solution exactly as your doctor or health care provider instructs you. You should check with your doctor, health care provider or pharmacist if you are not sure about how to take Lamivudine Oral Solution. The recommended oral dose of Lamivudine Oral Solution in HIV-1-infected adults and adolescents 16 years of age or older is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily, taken in combination with other antiretroviral agents. Some older children are able to swallow tablets, and lamivudine is available in tablet form. This oral solution formulation is available for infants, younger children, or children who have difficulty swallowing tablets. The required daily dose of Lamivudine Oral Solution for newborns, infants, and children aged 3 months to 16 years of age is calculated according to body weight. Be sure that your doctor or health care provider clearly informs you what the correct dosage for your child should be. The exact dosage should be measured using a calibrated dropper, calibrated spoon, oral syringe, or dosage cup. If none of these are supplied with your medication, ask your doctor or pharmacist to provide you with one of these devices and instruct you in its use and how to measure your child’s correct dose. Lamivudine may be administered with or without food. For individuals with kidney problems, the dose of Lamivudine Oral Solution may need to be altered. Follow the instructions of your doctor or health care provider. Lamivudine Oral Solution will always be taken in combination with other antiretroviral medication. Make sure to follow the instructions within the supplied package leaflet(s). If you take more Lamivudine Oral Solution than you should Taking too much Lamivudine Oral Solution, or if someone other than you accidentally swallows some, poses no immediate danger. However, you should contact your doctor, health care provider, or the nearest clinic, hospital, or hospital emergency department for further advice as soon as you can after any accidental overdose. If you forget to take Lamivudine Oral Solution If you accidentally miss a dose, then simply take your normal dose when the next one is due. Do not take a double dose to make up for forgotten doses. If you have any further questions on the use of this product, ask your doctor, health care provider, or pharmacist.


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4. POSSIBLE SIDE EFFECTS Like all medicines, Lamivudine Oral Solution can have side effects, although not every individual taking Lamivudine Oral Solution will have side effects. When treating HIV infection, it is not always possible to differentiate between unwanted effects caused by Lamivudine Oral Solution, effects caused by other medicines you may be taking, or by HIV disease. For this reason, it is important that you tell your doctor or health care provider of any changes in your health. Short-term adverse reactions to combination antiretroviral therapy are common. After you start taking Lamivudine Oral Solution the following side effects may occur: headache, nausea and vomiting, abdominal pain, diarrhea, and fatigue. These reactions are usually mild and disappear within a few weeks. Treatment does not have to be discontinued. The most commonly reported side effects (more than 1 in every 100 patients treated) are abdominal pain, nausea, vomiting , diarrhea, headache, joint pain, muscle disorders, cough, nasal symptoms (irritation, running nose), fever, tiredness, general feeling of being unwell, skin rash, hair loss, and difficulty sleeping. Uncommon side effects (between 1 in 1,000 and 1 in 100 patients treated) include anemia (low red blood cell count), neutropenia (low white blood cell count), and reductions in platelets (blood cells important for blood clotting). If the number of red blood cells is reduced you may have symptoms of tiredness or breathlessness. A reduction in your white blood cell count can make you more prone to infection. If you have a low platelet count you may notice that you bruise more easily. Increases in some liver enzymes have also been noted in the blood samples from patients being treated with lamivudine. There are very rare reports (between 1 in 10,000 to 1 in 1,000 patients treated) of numbness, tingling sensations, or weakness of the limbs, severe anemia (reduced number of red blood cells), and severe neutropenia (reduced number of white blood cells). Combination antiretroviral therapy may cause a condition called lactic acidosis, which is a build-up of lactic acid in the body. Lactic acidosis can cause dehydration and coma, and has been reported on rare occasions in patients taking NRTIs. Deep, rapid breathing, drowsiness, and symptoms such as stomach pain, nausea, and vomiting may indicate the development of lactic acidosis. In some individuals, combination antiretroviral therapy can cause changes in body fat distribution. These changes may include loss of fat from legs, arms, and face, increased fat in the neck, abdomen (belly), and other internal organs, breast enlargement, and fatty lumps on the back of the neck (“buffalo hump”). The cause and long term health effects of these conditions are not known at this time. Combination antiretroviral therapy may also cause increased levels of lactic acid and sugar in the blood, hyperlipidemia (increased fats in the blood), and an increased resistance to insulin. Always tell your doctor or pharmacist about any side effects that occur while taking Lamivudine Oral Solution, even those that are not mentioned in this leaflet.


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5. STORING LAMIVUDINE ORAL SOLUTION Store at 20° to 25°C (68° to 77°F) Keep out of sight and reach of children. Do not use Lamivudine Oral Solution after the expiration date which is stated on both the carton and the bottle. Do not use Lamivudine Oral Solution if you notice visible signs of deterioration (discoloration, thickening, caking, etc.). Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Lamivudine Oral Solution contains The active ingredient is lamivudine. There are 10 mg (milligrams) of lamivudine in each mL (milliliter) of Lamivudine Oral Solution. The other ingredients of the solution are sucrose, propylene glycol, methylparaben, propylparaben, citric acid, sodium citrate, purified water, editate disodium, and alcohol. What Lamivudine Oral Solution looks like and contents of the packaging Lamivudine Oral Solution is a clear, colorless to pale yellow liquid packaged in 250 mL bottles. For further information about this product, contact the supplier: Aurobindo Pharma, Ltd., Unit III, Survey No. 313, Bachupally, Quthubullapur, Mandal, Hyderabad, Andhra Pradesh, India 500 072


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SUMMARY OF PRODUCT CHARACTERISTICS


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SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT Lamivudine Oral Solution (10 mg/mL) 2. QUALITATIVE AND QUANTITAVE COMPOSITION Oral solution containing Lamivudine 10 mg/mL. For excipients see section 6.1 3. PHARMACEUTICAL FORM Colorless to pale yellow liquid packaged in 250 mL bottle containing 240 mL oral solution 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications Lamivudine is indicated for the treatment of Human Immunodeficiency Virus Infection in combination with other antiretroviral agents. 4.2 Posology and method of administration Adults and adolescents over 12 years of age: The recommended dose of lamivudine is 300 mg daily. This may be administered as either 150 mg twice daily or 300 mg once daily in combination with other antiretroviral agants. Children: 3 months-16 years: 4mg/kg twice daily (maximum daily dose 300 mg). Lamivudine may be administered with or without food. Renal impairment Lamivudine concentrations are increased in patients with moderate to severe renal impairment due to decreased clearance. Therefore a dose reduction is recommended for patients with impaired renal function. The dose adjustment of lamivudine in accordance with renal function is presented in the table below. Adjustment of lamivudine dose in adults and adolescents based on creatinine clearance Creatinine Clearance (ml/min) First dose Maintenance dose ≥ 50 300 mg (or 150 mg if BID dosing 300 mg daily (or 150 mg BID) 30-49 150 mg 150 mg daily 15-29 150 mg 100 mg daily 5-14 150 mg 50 mg daily ≤ 5 50 mg 25 mg daily


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No additional dosing of lamivudine is required after routine (4 hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of lamivudine in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered. Hepatic impairment The safety of lamivudine in patients with decompensated liver disease has not been established. Data obtained in patients with moderate to severe hepatic impairment shows that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction. Based on these data, no dose adjustment is necessary in patients with moderate or severe hepatic impairment unless accompanied by renal impairment. 4.3 Contraindications Hypersensitivity to lamivudine or to any of the excipients in Lamivudine Oral Solution. 4.4 Special warnings and special precautions for use 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. Pancreatitis Cases of pancreatitis have occurred rarely in patients treated with lamivudine. It is not clear if these cases were due to antiretroviral treatment or to underlying HIV disease. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur. Pancreatitis in Pediatric Patients In pediatric patients with a history of both prior NRTI exposure and pancreatitis, or significant risk factors for the development of pancreatitis, lamivudine should be used with caution. Lamivudine therapy should be discontinued immediately if clinical signs, symptoms, or laboratory data suggest pancreatitis. Lactic acidosis Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been reported with the use of nucleoside analogues. Early symptoms (symptomatic hyperlactatemia) include non-specific digestive symptoms (nausea, vomiting, and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including motor weakness). Lactic acidosis carries a high mortality and may be associated with pancreatitis, liver failure, or renal failure. When it occurs, lactic acidosis generally emerges after a few to several months of treatment.


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Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including use of certain medicinal products and alcoholism). Patients co-infected with Hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. Body Fat Changes Combination antiretroviral therapy has been associated with changes in body fat distribution (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown, and knowledge about the mechanism is incomplete. Higher risk of lipodystrophy has been associated with older age, with longer duration of antiretroviral treatment, and associated metabolic changes. Clinical assessment should evaluate patients for history of or physical signs of body fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders discovered coincidentally should be managed as clinically appropriate. Post-treatment exacerbation of hepatitis In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B (HBV), 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 following 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 reinitiation of lamivudine alters the course of post-treatment exacerbations of hepatitis. If lamivudine is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication should be considered. The safety and efficacy of lamivudine have not been established for treatment of chronic HBV in patients dually infected with HIV and HBV. In non–HIV-infected patients treated with lamivudine for chronic HBV, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response. Emergence of HBV 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 HBV. Impaired renal function Reduction of the dosage of lamivudine is recommended for patients with impaired renal function; see Table below.


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Adjustment of Dosage of Lamivudine Oral Solution in Adults and Adolescents (≥ 30 kg) in

Accordance With Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of Lamivudine Oral Solution ≥ 50 150 mg twice daily or 300 mg once daily 30 - 49 150 mg twice daily 15 - 29 150 mg first dose, then 100 mg once daily 5 - 14 150 mg first dose, then 50 mg once daily < 5 50 mg first dose, then 25 mg once daily Immune Reconstitution Syndrome Immune reconstitution syndrome (also known as immune reactivation syndrome) has been reported in some patients treated with combination antiretroviral therapy, including lamivudine. During the initial treatment phase using a combination antretroviral strategy, some patients whose immune systems respond to therapy may develop an acute inflammatory response to residual or subclinical opportunistic infections, such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (also known as pneumocystis carinii or PCP), herpes zoster, and tuberculosis. Patients may be more susceptible to immune reconstitution syndrome if starting combination antiretroviral therapy for the first time. Appropriate clinical monitoring is recommended. Diabetes Mellitus Diabetic patients should be advised that Lamivudine Oral Solution contains sucrose. 4.5 Interaction with other medicinal products and other forms of interaction Lamivudine should not be administered concurrently with other products also containing lamivudine. Since lamivudine has complete renal clearance, the possibility of interaction with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is active renal secretion via organic cationic transport system (e.g., trimethoprim). Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (TMP/SMX, also known as co-trimoxazole) results in a 44% increase in lamivudine exposure due to the trimethoprim component (both lamivudine and trimethoprim are cleared by the kidneys). However, unless a patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. When concurrent administration is indicated, patients should be monitored clinically. Co-administration of lamivudine with high doses of TMP/SMX for the treatment of common AIDS-related opportunistic diseases as such as Pneumocystis carinii pneumonia (PCP) and toxoplasmosis should be done with caution. Lamivudine does not inhibit cytochrome P450 isoform CYP3A, thereby making interactions with medicinal products metabolized by this system unlikely. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.


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There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a study of 19 healthy male subjects. No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). 4.6 Pregnancy and lactation Pregnancy Lamivudine is classified as USFDA Pregnancy Category C (animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. Lamivudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lamivudine pharmacokinetics were studied in pregnant women during two clinical studies conducted in South Africa. The study assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These studies were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in the pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients. Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus. Placental and breast milk transmission Lamivudine crosses the placenta in humans, achieving comparable cord blood and maternal concentrations. Lamivudine is excreted into human breast milk. Lactation Lamivudine is excreted into human breast milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily + 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. The US Centers for Disease Control and Prevention (CDC) recommends that HIV-1-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.


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Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine. 4.7 Effects on ability to drive and use machines No studies on the effects of lamivudine on the ability to drive and use machines have been performed. 4.8 Undesirable effects The following adverse events have been reported during treatment with lamivudine. With many of these it is unclear whether they are related to lamivudine, other medications taken concurrently, or are a result of the underlying disease process. Adverse events considered at least possibly related to the treatment are listed below by body system, organ class, and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000). Blood and lymphatic systems

• Uncommon: neutropenia and anemia (both occasionally severe), thrombocytopenia • Very rare: pure red cell aplasia

Nervous system

• Common: headache, insomnia • Very rare: peripheral neuropathy and paresthesias

Respiratory

• Common: cough, nasal congestion Gastrointestinal

• Common: nausea, vomiting, abdominal pain or cramps, diarrhea • Rare: elavations in serum amylase, pancreatitis

Hepatobiliary

• Uncommon: transient elevations of AST, ALT • Rare: hepatitis

Skin and subcutaneous tissue

• Common: rash, alopecia Musculoskeletal and connective tissue

• Common: arthralgia, muscle disorders • Rare: rhabdomyolysis

General

• Common: fatigue, malaise, fever


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Combination antiretroviral therapy has been associated with metabolic abnormalities such as elevated cholesterol and/or triglyceride levels, insulin resistance, hyperglycemia and lactic acidosis. 4.9 Overdose There is no known antidote for lamivudine. One case of an adult ingesting 6 g of lamivudine was reported, but no clinical signs or symptoms were noted and hematological tests remained normal. Two cases of pediatric overdose have been reported without clinical signs or symptoms noted in either case. Although lamivudine can be removed by hemodialysis, a negligible amount of lamivudine is removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis. Therefore, 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. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: nucleoside analogue, ATC code: J05A F05 Lamivudine is a synthetic nucleoside analogue, a dideoxynucleoside analogue which has activity against human immunodeficiency virus and hepatitis B virus. It is metabolized intracellularly to its active 5’-triphosphate metabolite, lamivudine triphosphate (L-TP). The principal mode of action of L-TP is the selective inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue into viral DNA. Clinical efficacy and drug resistance Lamivudine has been investigated in several randomized, prospective clinical trials combined with other antiretroviral drugs. These studies have demonstrated significant decreases in plasma HIV RNA and increases in CD4 cell counts when used in combination with another nucleoside analogues and either a NNRTI or a PI. In recent studies by intention-to-treat analysis > 75% of subjects have achieved plasma HIV RNA < 50 copies/ml after 48 weeks of combination antiretroviral treatment. Lamivudine-resistant variants of HIV-1 have been selected in vitro. Genotypic analysis showed that resistance was due to a specific amino acid substitution in the HIV-1 reverse transcriptase at codon 184 changing the methionine residue to either isoleucine or valine. HIV-1 strains resistant to both lamivudine and zidovudine have been isolated from patients. Susceptibility of clinical isolates to lamivudine and zidovudine was monitored in controlled clinical trials. In patients receiving lamivudine monotherapy or combination therapy with lamivudine plus zidovudine, HIV-1 isolates from most patients became phenotypically and genotypically resistant to lamivudine within 12 weeks. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of mutations conferring resistance to zidovudine.


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Cross Resistance Lamivudine-resistant HIV-1 mutants were cross resistant to didanosine and zalcitabine. In some patients treated with zidovudine plus didanosine or zalcitabine, isolates resistant to multiple reverse transcriptase inhibitors, including lamivudine, have emerged. Lamivudine should not be used as part of a triple combination consisting of NRTIs in combination with the following other NRTIs: didanosine and stavudine, tenofovir and abacavir, or tenofovir and didanosine. These combinations have inferior efficacy compared to other combination regimens. Lamivudine should only be used in a combination with zidovudine and abacavir in treatment-naïve patients when a regimen is based on a PI, or an NNRTI cannot be used. 5.2 Pharmacokinetic properties Absorption and Bioavailability Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in a study involving 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, peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg. An investigational 25 mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-infected patients on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC.) in the fed and fasted states; therefore, lamivudine 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. The volume of distribution was independent of dose and did not correlate with body weight. Binding of lamivudine to human plasma proteins is low (<36%). In vitro studies showed that over a concentration range of 0.1 to 100 mcg/mL the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration. Metabolism / Elimination Metabolism of lamivudine is a minor route of elimination. The only known metabolite of lamivudine in humans 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. The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 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 20 HIV-infected patients given a single IV dose, renal clearance


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was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. 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 (t½) ranged from 5 to 7 hours. In HIV-infected patients, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range from 0.25 to 10 mg/kg. 5.3 Preclinical safety data Administration of lamivudine in animal toxicity studies at high doses was not associated with major organ toxicity. Lamivudine was not mutagenic in bacterial tests, but showed activity in an in vitro cytogenetic assay and the mouse lymphoma assay. Lamivudine was not genotoxic in vitro at doses that gave plasma concentrations around 40-50 times higher than the anticipated clinical plasma levels. As the in vitro mutagenic activity of lamivudine could not be confirmed in vivo tests, it is concluded that lamivudine should not represent a genotoxic hazard to patients undergoing treatment. The results of long-term carcinogenicity studies in rats and mice did not show any carcinogenic potential relevant for humans. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sucrose, propylene glycol, methylparaben, propylparaben, citric acid, sodium citrate, purified water, editate disodium, and alcohol 6.2 Incompatibilities Not applicable 6.3 Shelf life 18 months 6.4 Special precautions for storage Store at 20° to 25°C (68° to 77°F) 6.5 Nature and contents of container Lamivudine Oral Solution is a clear, colorless to pale yellow, strawberry-banana flavored liquid that contains 10 mg of lamivudine in each 1 mL packaged in HDPE bottles of 240 mL with child-resistant closures and tamper evident seals (shrink wrap).


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6.6 Instructions for use and handling This product does not require reconstitution. No special requirements for handling. 7. SUPPLIER Aurobindo Pharma, Ltd., Unit III, Survey No. 313, Bachupally, Quthubullapur, Mandal Hyderabad, Andhra Pradesh, India 500 072 8. DATE OF USFDA TENTATIVE APPROVAL November 8, 2005


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LABELING


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING OR, WHERE THERE IS NO OUTER PACKAGING, ON THE IMMEDIATE PACKAGING Lamivudine Oral Solution 1. NAME OF THE MEDICINAL PRODUCT Lamivudine Oral Solution 2. STATEMENT OF ACTIVE SUBSTANCES Each milliliter (mL) of Lamivudine Oral Solution contains 10 mg of lamivudine 3. LIST OF EXCIPIENTS Sucrose, propylene glycol, methylparaben, propylparaben, citric acid, sodium citrate, purified water, editate disodium, alcohol 4. PHARMACEUTICAL FORM AND CONTENTS Oral solution 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Read the package leaflet before use. 8. EXPIRATION DATE EXP [MM/YYYY] 9. SPECIAL STORAGE CONDITIONS Store at 20° to 25°C (68° to 77°F)


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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF SUPPLIER Aurobindo Pharma, Ltd., Unit III, Survey No. 313, Bachupally, Quthubullapur, Mandal Hyderabad, Andhra Pradesh, 500 072 India 12. MARKETING AUTHORIZATION NUMBERS 13. MANUFACTURER’S BATCH NUMBER <Batch> <Lot> <number> 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription 15. INSTRUCTIONS FOR USE


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SCIENTIFIC DISCUSSION


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DISCUSSION Name of the Finished Pharmaceutical Product:

Lamivudine Oral Solution

Supplier:

Aurobindo Pharma, Ltd.

Active Pharmaceutical Ingredient (API): Lamivudine

International Non-proprietary Name: Lamivudine

Pharmaco-therapeutic group (ATC Code):

Lamivudine J05A F05

Therapeutic indication: Indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents


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1. Introduction Human Immunodeficiency Virus (HIV) is a retrovirus which replicates by transcribing its viral RNA to DNA utilizing the enzyme reverse transcriptase (RT), damaging the immune system in the human body by destroying the CD4 T-lymphocyte cells. Agents of the family 2’,-3’-dideoxynucleoside analogues, which include lamivudine, suppress viral replication through competitive inhibition with the naturally occurring nucleoside analogues for the binding site of RT and, after incorporation, prevent further elongation of viral DNA (chain termination). Lamivudine is a synthetic nucleoside analogue with activity against HIV. Lamivudine is a (-) enantiomer of dideoxy analogue of cytidine. Lamivudine is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. Lamivudine is not indicated for use in patients with clinically significant hypersensitivity to lamivudine or to any of the components contained in the formulation. 2. Assessment of Quality Introduction This assessment was conducted by the USFDA as an abbreviated new drug application (ANDA), and was reviewed under the U. S. President’s Emergency Plan for AIDS Relief (PEPFAR). Composition Each milliliter of Lamivudine Oral Solution contains 10 mg of lamuvidine. Other inactive ingredients include sucrose, propylene glycol, methylparaben, propylparaben, citric acid, sodium citrate, purified water, editate disodium, and alcohol. Control of active pharmaceutical ingredient (API) Lamivudine Oral Solution controls are consistent with cGMP and USP requirements and take into account product- and process-specific needs and information. Control testing of the finished medicinal product The release and shelf-life specifications are in line with the requirements of major internationally used pharmacopoeias and guidelines for oral solutions. The test methods have been adequately validated. Stability Stability studies have been conducted and results show that the product conforms with the proposed end of shelf life specification including description, disintegration time, dissolution, assay, and degradation products. Stability data for this product in the proposed marketing containers conforms to specifications. Based on the stability data provided the proposed expiration dating is acceptable. Conclusions It is concluded that the data submitted ensure acceptable quality of the finished pharmaceutical product when stored under the conditions specified on the label.


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3. Assessment of Bioequivalence Aurobindo Pharma Ltd. referenced innovator product Epivir® Oral Solution (10 mg/mL) to obtain a waiver of in vivo bioequivalence testing for Lamivudine Oral Solution. Biowaiver was granted by the USFDA Office of Generic Drugs Division of Bioequvalence. 4. Summary of Product Safety and Efficacy 4.1 Introduction. Background Lamivudine, the negative enantiomer of 2'-deoxy-3'-thiacytidine, is a dideoxynucleoside analogue which has activity against human immunodeficiency virus and hepatitis B virus. See the introductory discussion above as well as the Summary of Product Characteristics, Part 4 of this Public Assessment Report (Section 5.1), for further discussion. Product Design The development strategy for Lamivudine Oral Solution was concentrated on compatibility of the active ingredient with the excipients identified to match the dissolution profile of the innovator, thus producing a robust formulation. Clinical Safety The clinical safety of this product is considered to be acceptable when the guidances and restrictions presented in the Summary of Product Characteristics (SPC), Part 4 of this Public Assessment Report, are taken into consideration. See the SPC, Section 4 (“Clinical Particulars”) for extensive discussion of contraindications, special precautions, interactions, use in pregnancy, patient exposure (including overdosage), adverse events, and serious adverse events. Approved Indication Lamivudine is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. Clinical Pharmacology Pharmacodynamics Lamivudine is a nucleoside analogue of thymidine. It possesses virustatic activity against human immunodeficiency virus type I (HIV–1) and type 2 (HIV–2). It inhibits the replication of HIV in human cells in vitro. Lamivudine is phosphorylated by cellular kinase to the active metabolite lamivudine triphosphate, which exerts antiviral activity. Because phosphorylation of lamivudine depends on cellular rather than viral enzymes, conversion of the drug to the active triphosphate derivative occurs in both virus-infected and uninfected cells. Lamivudine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate, and by its incorporation into viral DNA causing a termination of DNA chain elongation. See the Summary of Product Characteristics, Part 4 of this Public Assessment Report, Section 5.2 (“Pharmokinetic properties”) for further and related discussion of lamivudine pharmocodynamics and pharmacokinetics.


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Pharmacokinetics Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of lamivudine with repeated administration every 6, 8, or 12 hours. Absorption and Bioavailability Lamivudine is rapidly absorbed following oral administration. Bioavailability is between 80 and 85%. Peak plasma concentrations occur within 1 hour after dosing. In healthy volunteers, at a therapeutic dose of 150 mg twice daily, mean steady-state Cmax and Cmin of lamivudine in plasma were 1.2 µg/ml and 0.09 µg/ml, respectively. The mean area under the curve (AUC) over a dosing interval of 12 hours is 4.7 µg.h/ml. At a therapeutic dose of 300 mg once daily, mean steady-state Cmax, Cmin and 24h AUC are 2.0 µg/ml, 0.04 µg/ml and 8.8 µg.h/ml, respectively. Distribution The estimated volume of distribution is 1.3 L/kg. The observed half-life is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, with predominantly renal clearance (> 70 %) via the organic cationic transport system. Protein binding is limited. Metabolism/Elimination The active moiety, intracellular lamivudine triphosphate, has a prolonged half-life in the cell (16 to 19 hours) compared to the plasma half-life. Lamivudine is predominantly cleared unchanged by renal excretion. Drug interactions, related side effects, and contraindications Lamivudine should not be administered concurrently with other products also containing lamivudine. Because of overlapping resistance and lack of additive antiretroviral effects, lamivudine or combination products containing lamivudine should not be coadministered with emtricitabine. Lamivudine and zalcitabine may inhibit intracellular metabolism of one another. Therefore, concurrent use of lamivudine or lamivudine-containing products and zalcitabine is not recommended. Co-administration with trimethoprim/sulfamethoxazole (TMP/SMX) results in a 40% increase in lamivudine area under the concentration curve. (Both trimethoprim and lamivudine are cleared via the kidneys). Unless a patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. Lamivudine does not inhibit cytochrome P450 isoform CYP3A, thereby making interactions with other medicinal products metabolized by this system unlikely. Also see the Summary of Product Characteristics, Section 4.5 (“Interaction with other medicinal products and other forms of interaction”) in this Public Assessment Report for further and related discussion of interactions with lamivudine.


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Clinical efficacy Lamivudine has been investigated in several randomized, prospective clinical trials combined with other antiretroviral drugs. These studies demonstrated significant decreases in plasma HIV RNA and increases in CD4 cell counts when used in combination with another nucleoside analogues and either a NNRTI or a PI. In recent studies by intention-to-treat analysis > 75% of subjects have achieved plasma HIV RNA < 50 copies/ml after 48 weeks of combination antiretroviral treatment. HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase (www.iasusa.org). M184V mutants display reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro. Cross-resistance conferred by the M184V mutation is limited within the nucleoside/nucleotide inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harboring only the M184V mutation. The M184V mutants shows a < 4-fold decrease in susceptibility to didanosine; the clinical significance of this is unknown. Continuation of lamivudine therapy in those with lamivudine-resistant HIV is associated with slightly lower plasma viral load and more stable CD4+ lymphocyte counts. Clinical studies in special populations Renal Impairment (Adults) It is recommended that lamivudine dosing be modified in patients with reduced creatinine clearance according to the table below. Creatinine clearance (mL/min)

Lamivudine dose

≥ 50 300 mg daily 30-49 150 mg daily 15-29 100 mg daily 5-14 50 mg daily < 5 25 mg daily Renal Impairment (Children) There is no data available on the use of lamivudine in children with renal impairrment. Based on the assumption that creatinine clearance and lamivudine are correlated similarly in children as in adults it is recommended that the dose in children with renal impairment be reduced according to their creatinine clearance by the same proportion as in adults (see Table below).

Lamivudine dosing in children and adolescents with renal impairment Creatinine clearance (mL/min)

Lamivudine dose

≥ 50 8 mg/kg daily 30-49 8 mg/kg daily 15-29 5.2 mg/kg daily 5-14 2.6 mg/kg daily < 5 1.4 mg/kg daily

http://www.iasusa.org/


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Impaired Hepatic Function (Adults) No dose adjustment necessary. Clinical Safety Short-term adverse reactions are common. At the beginning of therapy, headache, nausea, vomiting, abdominal pain, diarrhea and fatigue may occur. These reactions are usually mild and disappear within a few weeks even if treatment is continued. The following adverse events have been reported in controlled clinical trials and case series during treatment of HIV-1 infection with lamivudine. The adverse events considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000). Blood and lymphatic systems Uncommon: neutropenia Central nervous system Common: headache and insomnia Gastrointestinal Common: nausea, abdominal pain, diarrhea Skin and subcutaneous tissue Common: hair loss General Common: fatigue Overdose Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred and the patients recovered. Lamivudine can be removed by hemodialysis. 5. Benefit Risk assessment and overall conclusion Quality The quality of this product is considered to be acceptable when used in accordance with the conditions defined in the Summary of Product Characteristics, Part 4 of this Public Assessment Report. Physicochemical and biological aspects relevant to the uniform clinical performance of the product have been investigated and are controlled in a satisfactory way. Bioequivalence Lamivudine Oral Solution has been shown to be bioequivalent to Epivir® Oral Solution.


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Efficacy and Safety Lamivudine Oral Solution is considered safe and effective when the guidances and restrictions presented in the Summary of Product Characteristics (Part 4 of this Public Assessment Report) are taken into consideration. Benefit Risk Assessment Based on USFDA assessment of data on quality, bioequivalence, safety, and efficacy, the benefit risk profile of Lamivudine Oral Solution was considered acceptable for the following indication: HIV infection in combination with other antiretroviral agents. Products added to the WHO prequalification list on the basis of USFDA tentative approval rely on scientific assessment and inspections conducted by the USFDA. A product listed as USFDA tentatively approved indicates that although existing patents and/or other marketing exclusivity prevent marketing of this product in the USA, the product meets all of USFDA’s safety, efficacy, and manufacturing quality standards required for marketing in the USA, and is eligible for purchase with PEPFAR funds. For further information about this medicinal product, please contact: Justina A. Molzon, M.S. Pharm, J.D. Associate Director for International Programs U. S. Food and Drug Administration Center for Drug Evaluation and Research Building 51, Room 6118 10903 New Hampshire Ave. Silver Spring, MD 20993 USA [email protected]

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