Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Abacavir and lamivudine tablets, USP contain 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP. The tablets are orange colored, capsule-shaped, biconvex film coated tablets, debossed with “LT” on one side and plain on other side. They are packaged as follows: Bottles of 30 tablets NDC 42385-962-30 Bottles of 90 tablets NDC 42385-962-90 Bottles of 180 tablets NDC 42385-962-18 Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature.]; PRINCIPAL DISPLAY PANEL - Container Label (30's count) NDC 42385-962-30 Abacavir and Lamivudine Tablets, USP 600 mg/300 mg Notice to Authorized Dispenser. Each time Abacavir and Lamivudine Tablets are dispensed. give the patient a Medication Guide and Warning Card. 30 Tablets RX Only LAURUS Labs figure1
- 16 HOW SUPPLIED/STORAGE AND HANDLING Abacavir and lamivudine tablets, USP contain 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP. The tablets are orange colored, capsule-shaped, biconvex film coated tablets, debossed with “LT” on one side and plain on other side. They are packaged as follows: Bottles of 30 tablets NDC 42385-962-30 Bottles of 90 tablets NDC 42385-962-90 Bottles of 180 tablets NDC 42385-962-18 Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° to 30°C (59° to 86°F). [see USP Controlled Room Temperature.]
- PRINCIPAL DISPLAY PANEL - Container Label (30's count) NDC 42385-962-30 Abacavir and Lamivudine Tablets, USP 600 mg/300 mg Notice to Authorized Dispenser. Each time Abacavir and Lamivudine Tablets are dispensed. give the patient a Medication Guide and Warning Card. 30 Tablets RX Only LAURUS Labs figure1
Overview
Abacavir and Lamivudine Abacavir and lamivudine tablets, USP contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1. Abacavir and lamivudine tablets, USP are for oral administration. Each orange colored, capsule-shaped, biconvex film coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate USP and 300 mg of lamivudine USP, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY orange YS-1-13065-A) that is made of FD&C Yellow No.6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide. Abacavir Sulfate, USP The chemical name of abacavir sulfate, USP is ( 1 S, 4R)- 4-[2-amino-6-(cyclopropylamino)-9 H -purin-9yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S , 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C 14 H 18 N 6 O) 2 •H 2 SO 4 and a molecular weight of 670.74 g per mol. It has the following structural formula: Abacavir sulfate, USP is a white to almost white powder and is soluble in water. In vivo , abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir. Lamivudine, USP The chemical name of lamivudine, USP is (2(1 H )-Pyrimidinone,4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-, (2 R - cis )-. Lamivudine, USP is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine, USP has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.26 g per mol. It has the following structural formula: Lamivudine, USP is a white to almost white solid and is soluble in water, sparingly soluble in methanol, slightly soluble to practically insoluble in 96% ethanol and practically insoluble in acetone. FDA approved dissolution test specifications differ from USP. abacavir structure lamivudine structure
Indications & Usage
Abacavir and lamivudine tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Abacavir and lamivudine tablets, are combination of abacavir and lamivudine, both nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1)
Dosage & Administration
Before initiating abacavir and lamivudine tablets, screen for the HLA-B*5701 allele because abacavir and lamivudine tablets contain abacavir. (2.1) Adults: One tablet orally once daily. (2.2) Pediatric patients weighing at least 25 kg: One tablet daily. (2.3) Because abacavir and lamivudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets are not recommended in patients with creatinine clearance less than 30 mL per minute or patients with hepatic impairment. (2.4, 4) 2.1 Screening for HLA-B*5701 Allele Prior to Starting Abacavir and Lamivudine Tablets Screen for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine tablets [see Boxed Warning, Warnings and Precautions (5.1) ] . 2.2 Recommended Dosage for Adult Patients The recommended dosage of abacavir and lamivudine tablets for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food. 2.3 Recommended Dosage for Pediatric Patients The recommended oral dose of abacavir and lamivudine tablets for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see Clinical Studies (14.2) ] . Before prescribing abacavir and lamivudine tablets, pediatric patients should be assessed for the ability to swallow tablets. 2.4 Not Recommended Due to Lack of Dosage Adjustment Because abacavir and lamivudine tablet is a fixed-dose tablet and cannot be dose adjusted, abacavir and lamivudine tablets are not recommended for: patients with creatinine clearance less than 30 mL per minute [see Use in Specific Populations (8.6) ] . patients with mild hepatic impairment. Abacavir and lamivudine tablets are contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4) , Use in Specific Populations (8.7) ] . Use of EPIVIR (lamivudine) oral solution or tablets and ZIAGEN (abacavir) oral solution may be considered.
Warnings & Precautions
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.3) Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.4) 5.1 Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1) ] . Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine or reinitiation of therapy with abacavir and lamivudine, unless patients have a previously documented HLA-B*5701 allele assessment. Abacavir and lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting abacavir and lamivudine, review medical history for prior exposure to any abacavir containing product. NEVER restart abacavir and lamivudine or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue abacavir and lamivudine immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). If a hypersensitivity reaction cannot be ruled out, do not restart abacavir and lamivudine or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. If a hypersensitivity reaction is ruled out, patients may restart abacavir and lamivudine. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of abacavir and lamivudine or any other abacavir-containing product is recommended only if medical care can be readily accessed. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. 5.2 Patients with Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine). 5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of abacavir and lamivudine). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with abacavir and lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. 5.4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir and lamivudine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.5 Myocardial Infarction Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain the potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
Boxed Warning
HYPERSENSITIVITY REACTIONS and EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of abacavir and lamivudine. Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see Warnings and Precautions (5.1) ] . Abacavir and lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see Contraindications (4) , Warnings and Precautions (5.1) ] . All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir and lamivudine or reinitiation of therapy with abacavir and lamivudine, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue abacavir and lamivudine immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4) , Warnings and Precautions (5.1) ] . Following a hypersensitivity reaction to abacavir and lamivudine, NEVER restart abacavir and lamivudine or any other abacavir-containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1) ] . Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, which is a component of abacavir and lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue abacavir and lamivudine and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2) ] . WARNING: HYPERSENSITIVITY REACTIONS and EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. Hypersensitivity Reactions ● Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. ( 5.1 ) ● Hypersensitivity to abacavir is a multi-organ clinical syndrome. ( 5.1 ) ● Patients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. ( 5.1 ) ● Abacavir and lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. ( 4 ) ● Discontinue abacavir and lamivudine as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue abacavir and lamivudine if hypersensitivity cannot be ruled out, even when other diagnoses are possible. ( 5.1 ) ● Following a hypersensitivity reaction to abacavir and lamivudine, NEVER restart abacavir and lamivudine or any other abacavir-containing product. ( 5.1 ) Exacerbations of Hepatitis B ● Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of abacavir and lamivudine. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. ( 5.2 )
Contraindications
Abacavir and lamivudine tablets are contraindicated in patients: who have the HLA-B*5701 allele [see Warnings and Precautions (5.1) ] . with prior hypersensitivity reaction to abacavir [see Warnings and Precautions (5.1) ] or lamivudine. with moderate or severe hepatic impairment [see Use in Specific Populations (8.7) ] . Presence of HLA-B*5701 allele. (4) Prior hypersensitivity reaction to abacavir or lamivudine. (4) Moderate or severe hepatic impairment. ( 4, 8.7)
Adverse Reactions
The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1) ] . Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2) ] . Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.3) ] . Immune reconstitution syndrome [see Warnings and Precautions (5.4) ] . Myocardial infarction [see Warnings and Precautions (5.5) ] . The most commonly reported adverse reactions of at least moderate intensity (incidence greater than 5%) in an adult HIV-1 clinical trial were drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious and Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Additional Adverse Reactions with Use of Abacavir and Lamivudine Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1. Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment a Subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event. b CNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group. Adverse Event ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Drug hypersensitivity a,b 9% 7% Insomnia 7% 9% Depression/Depressed mood 7% 7% Headache/Migraine 7% 6% Fatigue/Malaise 6% 8% Dizziness/Vertigo 6% 6% Nausea 5% 6% Diarrhea a 5% 6% Rash 5% 5% Pyrexia 5% 3% Abdominal pain/gastritis 4% 5% Abnormal dreams 4% 5% Anxiety 3% 5% Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. 6.2 Clinical Trials Experience in Pediatric Subjects The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as abacavir and lamivudine, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see Adverse Reactions (6.1) ] . 6.3 Postmarketing Experience The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abacavir Cardiovascular: Myocardial infarction. Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see Adverse Reactions (6.1) ] . Abacavir and Lamivudine Body as a Whole: Redistribution/accumulation of body fat. Digestive: Stomatitis. Endocrine and Metabolic: Hyperglycemia. General: Weakness. Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic: Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.3) ] , posttreatment exacerbations of hepatitis B [see Warnings and Precautions (5.2) ] . Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Muscle weakness, creatinine phosphokinase (CPK) elevation, rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.
Drug Interactions
Methadone: An increased methadone dose may be required in a small number of patients. (7.1) Sorbitol: Coadministration of lamivudine and sorbitol may decrease lamivudine concentrations; when possible, avoid chronic coadministration. (7.2) Riociguat: The riociguat dose may need to be reduced. (7.3) 7.1 Methadone In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3) ] . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. 7.2 Sorbitol Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3) ] . 7.3 Riociguat Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see Clinical Pharmacology (12.3) ] . The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).
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