Rarudine 50 mg/300 mg Tablets

RARUDINE is a triple combination therapy indicated for the treatment of human immunodeficiency virus (HIV) infection in adults aged 18 years and older.

Posology
RARUDINE should be prescribed by a health care provider experienced in the management of HIV infection.
Adults: The dose of RARUDINE is one tablet taken orally, once daily, without regard to food.
Special populations
Renal impairment: Significantly increased exposure occurred when tenofovir, as in RARUDINE, was administered to patients with moderate to severe renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in RARUDINE, have not been evaluated in non-haemodialysis patients with creatinine clearance u02c2 80 mL/min); therefore, no dosing recommendations is available for these patients. For treatment-nau00efve and treatment experienced patients the recommended dose of RARUDINE is one tablet once daily. RARUDINE is contraindicated in patients with renal impairment with creatinine clearance less than 80 mL/min (see section 4.3).
Hepatic impairment
RARUDINE is contraindicated in patients with moderate or severe hepatic impairment (see section 4.3).
Concomitant use with rifampicin
Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given in patients taking RARUDINE (see section 4.5).
Paediatric population
RARUDINE is not recommended for use in patients younger than 18 years of age.
Method of administration
Oral use. It is recommended that RARUDINE be swallowed whole with water. RARUDINE can usually be taken with food or between meals.

• Hypersensitivity to dolutegravir, lamivudine, tenofovir disoproxil fumarate or to any of the ingredients of RARUDINE
• Impairment of renal function < 80 mL/min
• Pregnancy and lactation (see section 4.6)
• Women of child-bearing age unless they are using highly effective contraception
• Co-administration with adefovir dipivoxil
• Co-administration with dofetilide and pilsicainide.
• Co-administration with didanosine
• Co-administration with metformin
• Patients younger than 18 years of age
• Moderate and severe hepatic impairment

Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as those contained in RARUDINE have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-medicine combination, as in RARUDINE, for the treatment of HIV has not been established.
WARNING
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. RARUDINE is not indicated for the treatment of chronic hepatitis B virus (HBV) infection. The safety and efficacy of RARUDINE has not been established in patients with HBV and HIV. Severe acute exacerbations of Hepatitis B have been reported in patients who are co-infected with HBV and HIV and have discontinued the combination tablet. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue RARUDINE and are co-infected with HBV and HIV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
General: HBV antibody testing should be offered to all individuals before initiating lamivudine and tenofovir disoproxil-containing therapies (see below Patients with HIV and hepatitis B (HBV) or C virus (HCV) co-infections).
Metabolic abnormalities
Combination antiretroviral therapy, including RARUDINE, has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia. Lipodystrophy: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, elevated serum lipid and glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine-related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution.
Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should also have a thorough cardiovascular risk assessment.
Immune Reconstitution Inflammatory Syndrome: Immune Reconstitution Inflammatory Syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reactions present by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of antiretroviral therapy (ART) and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, atypical mycobacterial infections, cytomegalovirus retinitis, Pneumocystis jirovecii, and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS. Autoimmune disorders (such as Gravesu2019 disease, Guillain-Barre Syndrome, Polymyositis) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Raised liver enzymes, consistent with IRIS, occurred in some patients who also had hepatitis B or C infection at the start of dolutegravir therapy. Monitoring of liver function is recommended in patients with hepatitis B or C infection. Particular care should be taken in initiating or maintaining effective hepatitis B therapy when starting dolutegravir-based therapy in patients with hepatitis B.
Osteonecrosis: Osteonecrosis has been reported particularly in patients with advanced HIV disease or following long-term combination cART. Their aetiology can be multifactorial and include corticosteroid use, excessive alcohol consumption, severe immunosuppression, and being overweight. Patients should be advised to speak to their health care provider if they have joint aches and pain, joint stiffness or difficulty in movement.
Opportunistic infections
Patients receiving RARUDINE or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by health care providers experienced in the treatment of HIV associated diseases.
Transmission of HIV: Patients should be advised that treatment with RARUDINE, 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.

The likelihood of interactions is low due to the limited metabolism as plasma protein binding and almost complete renal clearance. Zidovudine plasma levels are not significantly altered when co-administered with lamivudine (as in RARUDINE). Zidovudine has no effect on the pharmacokinetics of lamivudine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine. Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in lamivudine plasma levels. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine has no effect on the pharmacokinetics of co-trimoxazole. The possibility of interactions with other medicines administered concurrently should be considered, particularly when the main route is renal. No medicine interaction studies have been conducted using RARUDINE. As RARUDINE contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with RARUDINE. Important medicine interaction information for RARUDINE is summarised in Tables 1, 2 and 3. The medicine interactions described are based on studies conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines or are potential medicine interactions. While the tables include potentially significant interactions, they are not all inclusive. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other medicines is low. An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposure at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine, as contained in RARUDINE in patients with renal impairment should be carefully assessed.

Women of childbearing potential / Contraception in males and females
RARUDINE should not be prescribed in women who plan to become pregnant. Women of childbearing age should not use RARUDINE unless they are using highly effective contraception. Treatment with RARUDINE should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with RARUDINE and especially in the event that pregnancy is suspected.
Pregnancy
RARUDINE is contraindicated in pregnancy. Neural tube defects have been noted in an observational study in humans, where DTG-bases regimens were used at the time of conception and early pregnancy (see section 4.3). Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity studies in animals. Late onset neurological disorders, including seizures, have been observed in children who have been exposed to nucleoside analogues in utero such as tenofovir and lamivudine, (see Mitochondrial Dysfunction under section 4.4)
Lactation
RARUDINE is contraindicated in lactation. Mothers breastfeeding their infants should not use RARUDINE. Lamivudine is excreted in human milk at similar concentrations to those found in serum; tenofovir is excreted in breast milk and it is not known whether dolutegravir is excreted in human milk.

RARUDINE may affect the ability to drive and use machines as RARUDINE can cause dizziness. Patients should ensure that they do not engage in driving or using machines until they know how RARUDINE affects them.

Summary of the safety profile
Studies revealed the most severe adverse reactions linked to dolutegravir treatment are hypersensitivity reactions that include rash and severe liver effects. The most common adverse reactions of dolutegravir are nausea (13 %), diarrhoea (18 %) and headache (13 %).
Renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported rarely in patients receiving tenofovir disoproxil. Monitoring of renal function is recommended for patients receiving RARUDINE (see section 4.4).
Tabulated list of adverse effects

Signs and symptoms:
If overdose occurs the patient must be monitored for evidence of toxicity (see sections 4.8 and 5.3), and standard supportive treatment applied as necessary. Tenofovir disoproxil fumarate: If overdose occurs the patient must be monitored for evidence of toxicity and palliative supportive treatment be applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 mL/min. The elimination of tenofovir by peritoneal dialysis has not been studied. Lamivudine: Limited data are available on the consequences of ingestion of acute overdose in humans. If overdosage occurs the patient should be monitored, and palliative supportive treatment applied are required. Dolutegravir: Management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of RARUDINE. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As RARUDINE is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.