INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo SONKE-LAMIVUDINE + ZIDOVUDINE tablets
SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

SONKE-LAMIVUDINE + ZIDOVUDINE tablets

COMPOSITION:
Each film-coated tablet contains:
Lamivudine         150 mg
Zidovudine        300 mg
Sugar free.

PHARMACOLOGICAL CLASSIFICATION
A 20.2.8 Antiviral agents.

PHARMACOLOGICAL ACTION
Lamivudine
Lamivudine is a selective inhibitor of HIV-1 and HIV-2 replication in in vitro, including zidovudine-resistant clinical isolates of the human immunodeficiency virus (HIV). Lamivudine is metabolised intracellularly to the active 5’-triphosphate which inhibits the RNA- and DNA-dependent activities of HIV reverse transcriptase by termination of the viral DNA chain. Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondraial DNA content. In vitro, lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines and to a variety of bone marrow progenitor cells. In vitro, lamivudine, therefore, has a high therapeutic index. Reduced in vitro sensitivity to lamivudine has been reported for HIV isolated from patients who have received lamivudine therapy before. Lamivudine has been shown to act additively or synergistically with other anti-HIV agents, particularly zidovudine, inhibiting replication of HIV in cell culture.In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine-sensitive when they acquire resistance to lamivudine.
Zidovudine
Zidovudine, a thymidine nucleoside analogue, is an antiviral medicine with in vitro activity against retroviruses such as the Human Immunodeficiency Virus (HIV) and the Human T Lymphotropic Virus (HTLV)-1. Following diffusion into both infected and uninfected host cells, zidovudine is phosphorylated to the monophosphate derivative by cellular thymidine kinase. The phosphorylation of zidovudine-monophosphate to the diphosphate derivative and to zidovudine-triphosphate which is in turn catalysed by cellular thymidylate kinase and unspecific kinases, respectively.
Zidovudine-triphosphate is a competitive inhibitor of, and a substrate for, reverse transcriptase with respect to the thymidine triphosphate (TTP) nucleotide. The incorporation of zidovudine-triphosphate into the proviral DNA chain blocks further chain formation and results in chain termination. Zidovudine-triphosphate has a greater affinity (approximately 100-fold) for reverse transcriptase than for human DNA polymerase alpha.
Combination therapy with lamivudine
Zidovudine monotherapy leads to development of in vitro and in vivo resistance to zidovudine. Zidovudine has been shown to act additively or synergistically with other anti-HIV agents, inhibiting the replication of HIV in cell culture. Additive or synergistic activity in cell culture has been demonstrated in medicine combination studies of zidovudine with indinavir, zalcitabine, didanosine, delaviridine, lamivudine, saquinavir, ritonavir, nevirapine and interferon-alpha. In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine-sensitive when they acquire resistance to lamivudine.
Pharmacokinetics
Lamivudine
Pharmacokinetics in Adults
Following oral administration, lamivudine is well absorbed with bioavailability of approximately 80%. The mean time (Tmax) to maximum serum concentration (Cmax) is about an hour. At therapeutic dose levels of 4 mg/kg/day (as two 12-hourly doses), Cmax is in the order of 1-1,5 micrograms/mL. The mean volume of distribution from intravenous studies has been reported as 1,3 L/kg and the mean terminal half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0,32 L/kg/hr, with predominantly renal clearance of more than 70% via active tubular secretion, but little hepatic metabolism at less than 10%. The intracellular half-life of the lamivudine triphosphate active metabolite is prolonged, averaging over 10 hours in peripheral blood lymphocytes. A delay in Tmax and reduction in Cmax have been observed when co-administered with food, but no dose adjustment is needed, as lamivudine bioavailability is not altered. Lamivudine displays limited binding to albumin and exhibits linear pharmacokinetics over the therapeutic dose range. Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. No dosage adjustments are necessary as this is not considered to be of significance to patient safety. Limited data show that lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The true extent of penetration or relationship with any clinical efficacy is unknown.
Pharmacokinetics in Children
In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability is reduced to approximately 65% in paediatric patients, with an increased clearance of 0,52 L/kg/hr.
Zidovudine
Zidovudine is well absorbed from the gut and oral bioavailability is approximately 60 to 70%. Absorption varies in HIV-infected patients and is retarded after food intake. Cerebrospinal fluid concentrations vary, but average approximately 53% of those in plasma in adults and 24% of those in children. The plasma elimination half-life is approximately 0,9 to 1,5 hours. Zidovudine undergoes first-pass hepatic metabolism and is converted to its 5’-O-glucoronide metabolite which has a similar plasma elimination half-life, but lacks anti-HIV activity. The recovery of zidovudine and its glucoronide metabolite in urine after oral administration averages 14% and 75%, respectively. Renal clearance involves both glomerular filtration and tubular secretion. Two- to three-fold increases in plasma levels and plasma elimination half-life occur in liver cirrhosis. There are no clinically significant pharmacokinetic interactions when zidovudine is given concomitantly with the following antiretroviral medicines:
Nucleoside reverse transcriptase inhibitors (NRTIs) –zalcitabine, didanosine and abacavir.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) –nevirapine and efavirenz.
Protease inhibitors –indinavir sulphate, saquinavir mesylate, ritonavir, amprenavir and nelfinavir.

Pharmacokinetics in children
In children over the age of five months, the pharmacokinetic profile of zidovudine is similar to that in adults.

INDICATIONS
SONKE-LAMIVUDINE + ZIDOVUDINE is indicated for the treatment of HIV infection when a combination therapy with zidovudine and lamivudine is required.

CONTRA-INDICATIONS
Hypersensitivity to any of the ingredients.
Zidovudine
Abnormally low neutrophil cell counts (less than 0,75 x 109/litre).
Abnormally low haemoglobin levels (less than 7,5 g/decilitre).
Co-administration with stavudine (d4T) and ribavirin (See Interactions).
Breast feeding
The safety of zidovudine for the mother and foetus during the first trimester of pregnancy has not been established.

WARNINGS
Lamivudine
Patients receiving SONKE-LAMIVUDINE + ZIDOVUDINE and another antiretroviral agent may continue to develop opportunistic infections and other complications of HIV infection. Patients should therefore remain under close supervision by medical practitioners experienced in the treatment of patients with HIV-associated diseases.
Current antiretroviral therapy including SONKE-LAMIVUDINE + ZIDOVUDINE has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of lamivudine alone or in combination, in the treatment of HIV infection.
Zidovudine
Patients should be warned about the concomitant use of self-administered medicines (see Interactions).
PATIENTS SHOULD BE ADVISED THAT SONKE-LAMIVUDINE + ZIDOVUDINE THERAPY HAS NOT BEEN SHOWN TO REDUCE THE RISK OF TRANSMISSION OF HIV TO OTHERS THROUGH SEXUAL CONTACT OR BLOOD CONTAMINATION.
Pregnant women considering the use of SONKE-LAMIVUDINE + ZIDOVUDINEduring pregnancy for prevention of HIV transmission to their infants should be advised that transmission to their infants might still occur despite therapy.
SONKE-LAMIVUDINE + ZIDOVUDINE is not a cure for HIV infection and patients remain at risk of developing illnesses associated with immune suppression, including opportunistic infections and neoplasms.
In patients with early HIV disease on long-term treatment, the risk of lymphoma development is unknown as data on the development of neoplasms, including lymphomas, are limited.
Patients receiving combination therapy may also continue to develop opportunistic infections and other complications of HIV infection and, therefore, should remain under close observation by medical practitioners experienced in the treatment of patients with HIV-associated diseases.

INTERACTIONS
Lamivudine
Zidovudine plasma levels are not significantly altered when co-administered with lamivudine (See Pharmacokinetics).
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40% increase in lamivudine plasma concentrations at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with SONKE-LAMIVUDINE + ZIDOVUDINE in patients with renal impairment should be carefully assessed. SONKE-LAMIVUDINE + ZIDOVUDINE may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. SONKE-LAMIVUDINE + ZIDOVUDINE is, therefore, not recommended to be used in combination with zalcitabine.
Zidovudine
As zidovudine is primarily eliminated by hepatic conjugation to its inactive glucuronidated metabolite, medicines that are primarily eliminated by hepatic metabolism, especially by glucuronidation, may have the potential to inhibit the metabolism of SONKE-LAMIVUDINE + ZIDOVUDINE. The interactions listed below, though not exhaustive, are representative of the classes of medicines where caution should be exercised:
• Caution must be exercised in the concomitant use of self-administered medicines.
• Phenytoin levels should be carefully monitored in patients receiving both medicines. There is a risk of either sub-therapeutic or toxic levels of phenytoin resulting from co-administration of these medicines.
• Aspirin, codeine, morphine, indomethacin, ketoprofen, naproxen, oxazepam, lorazepam, cimetidine, clofibrate, dapsone and isoprinosine may alter the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting hepatic microsomal metabolism especially in chronic combination therapy.
• Concomitant therapy with potentially nephrotoxic or myelosuppressive medicines such as dapsone, systemic pentamidine, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin may also increase risk of toxicity with SONKE-LAMIVUDINE + ZIDOVUDINE. If concomitant therapy with any of these medicines is necessary, then extra care should be employed in monitoring renal function and haematological parameters and, if required, the dosage of one or both medicines should be reduced.
• There is an in vitro antagonistic interaction between zidovudine and either ribavirin or stavudine. The concomitant use of either of these medicines with zidovudine should be avoided.
• Some patients receiving zidovudine may continue to experience opportunistic infections and concomitant use of prophylactic antimicrobial therapy may have to be considered. There are limited data that indicate no increased risk of toxicity with co-trimoxazole, aerolised pentamidine, pyrimethamine and aciclovir.
• There are limited data suggesting that probenecid increases the mean half-life and the area under the time-concentration curve (AUC) of zidovudine by reducing glucuronidation. Renal excretion of the inactive glucuronide metabolite, and of possibly zidovudine itself, is reduced in the presence of probenecid.
• There are limited data suggesting that co-administration of zidovudine and rifampicin decreases the AUC of zidovudine. The clinical significance of this is not known.
• There is a modest increase in the Cmax of zidovudine when administered with lamivudine, however, overall exposure to zidovudine (AUC) is not altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.
• See under Pharmacokinetics for information on the effect on the pharmacokinetics of zidovudine when administered with other antiretroviral medications.

PREGNANCY AND LACTATION
Safety in pregnancy and lactation has not been established. (See Contra-indications). The long-term consequences of in utero and infant exposure to SONKE-LAMIVUDINE + ZIDOVUDINE are unknown (See Special Precautions).

DOSAGE AND DIRECTIONS FOR USE
Adults
The recommended oral dose of SONKE-LAMIVUDINE + ZIDOVUDINE for adults and adolescents (at least 12 years of age) is 1 tablet (containing lamivudine 150 mg and zidovudine 300 mg) twice daily.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
The following side-effects have been reported during therapy of HIV disease with SONKE-LAMIVUDINE + ZIDOVUDINE alone and in combination with other antiretrovirals.
Very common (>1/10); common (>1/100 <?1/10); uncommon (>1/1 000 <?1/100);
rare (> 1/10 000 <1/1 000); very rare (<1/10 000); 

Lamivudine
Blood and lymphatic system disorders
Rare: Neutropenia and anaemia.
Frequency unknown: Thrombocytopenia.
Nervous system disorders
More frequently: Peripheral neuropathy and headache.
Rare: Paraesthesia.
Gastro-intestinal disorders
More frequently: Pancreatitis, upper abdominal pain, nausea, vomiting and diarrhoea.
Skin and subcutaneous tissue disorders
More frequently: Skin rash (hypersensitivity reaction).
Frequency unknown: Alopecia.
Musculoskeletal, connective tissue and bone disorders
More frequently: Arthralgia and muscle disorders.
Less frequently: Rhabdomyolysis.
General
More frequently: Malaise and fatigue.
Rare: Fever.
Investigations
Frequency unknown: Transient rises in serum liver enzymes (AST, ALT) and rises in serum amylase have been reported.

Zidovudine
The adverse event profile appears similar for adults and children.
Blood and lymphatic system: The most serious adverse reactions include anaemia, usually occurring after six weeks of therapy, but occasionally earlier and often requiring transfusions; neutropenia, usually occurring at any time after 4 weeks of therapy, but sometimes earlier; and leucopenia which is usually secondary to neutropenia. Thrombocytopenia, pancytopenia with marrow hypoplasia have also been reported. Anaemia, neutropenia and leucopenia occur more frequently at higher dosages, 1 200 to 1 500 mg/day, and in patients with advanced HIV disease, especially when there is poor bone marrow reserve prior to treatment and particularly in patients with low T4 (T-helper) cell counts (less than 100/mm3). Dosage reduction or cessation of therapy may become necessary (See Dosage and Directions for Use). The incidence of neutropenia was also increased in patients with pre-existing neutropenia or anaemia, those with low vitamin B12 levels and those taking paracetamol concomitantly (See Interactions).
The following events have also been reported in patients treated with SONKE-LAMIVUDINE + ZIDOVUDINE. The relationship between these events and the use of SONKE-LAMIVUDINE + ZIDOVUDINE may be difficult to evaluate, particularly in medically complicated situations that characterise advanced HIV disease. A reduction in dose or suspension of SONKE-LAMIVUDINE + ZIDOVUDINE therapy may be warranted in the management of these conditions.
Metabolic/endocrine disorders
Rare: Lactic acidosis in the absence of hypoxia (See Special Precautions).
Psychiatric disorders
Frequency unknown: Anxiety and depression.
Nervous system disorders
More frequent: Headache and insomnia.
Rare: Loss of mental acuity and convulsions.
Frequency unknown: Dizziness, paraesthesia and somnolence.
Respiratory, thoracic and mediastinal disorders
Frequency unknown: Dyspnoea, cough and chest pain.
Gastro-intestinal disorders
More frequently: Nausea, vomiting and anorexia.
Frequency unknown: Abdominal pain, dyspepsia, diarrhoea and flatulence.
Hepatobiliary disorders
Frequency unknown: Liver disorders such as severe hepatomegaly with steatosis, raised blood levels of liver enzymes and bilirubin, pancreatitis.
Skin and subcutaneous tissue disorders
Less frequent: Nail and skin pigmentation.
Frequency unknown: Rash, urticaria, pruritus, sweating and pigmentation of the oral mucosa.
Musculoskeletal, connective tissue and bone disorders
More frequently: Myalgia and asthenia.
Rare: Myopathy
Renal and urinary disorders
Frequency unknown: Urinary frequency.
Reproductive system and breast disorders
Frequency unknown: Gynaecomastia.
General
More frequently: Malaise.
Frequency unknown: Fever, generalised pain, chills, influenza-like syndrome and taste perversion.

Special Precautions
Lamivudine
SONKE-LAMIVUDINE + ZIDOVUDINE should be used with caution in patients with advanced cirrhotic liver disease due to chronic Hepatitis B infection as there is a small risk of rebound hepatitis post treatment.
Pancreatitis
Pancreatitis has been observed in some patients receiving lamivudine. However, it is unclear whether this is due to SONKE-LAMIVUDINE + ZIDOVUDINE or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of SONKE-LAMIVUDINE + ZIDOVUDINE until diagnosis of pancreatitis is excluded.
Lactic acidosis/severe hepatomegaly with steatosis
Long-term use of lamivudine can result in potentially fatal lactic acidosis. Symptomatic hyperlactacaemia and lactic acidosis are uncommon. Clinical features are non-specific and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal <2 mmol/L) and respond as follows:
Lactate 2-5 mmol/L Monitor regularly and be alert for clinical signs.
Lactate 5-10 mmol/L without symptoms Monitor closely.
Lactate 5-10 mmol/L with symptoms STOP all therapy. Exclude other causes e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, lymphoma.
Lactate >10 mmol/L STOP all therapy. (80% mortality)
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a raised lactate level.
Blood for lactate assays should be heparinised and stored on ice.
After recovery, NRTI’s should be avoided. Seek expert advice on medicine selection.
The above lactate values may not be applicable to paediatric patients.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of lamivudine alone or in combination, in the treatment of HIV infection. Most cases were women.
Caution should be exercised when administering SONKE-LAMIVUDINE + ZIDOVUDINE to patients with known risk factors for liver disease (See Warnings). Treatment with SONKE-LAMIVUDINE + ZIDOVUDINE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.
Opportunistic infections
Patients receiving SONKE-LAMIVUDINE + ZIDOVUDINE may continue to develop opportunistic infections and other complications of HIV infection and, therefore, they should remain under close observation by medical practitioners experienced in the treatment of patients with associated HIV disease (See Warnings).
The risk of HIV transmission to others
Patients should be advised that current antiretroviral therapy, including SONKE-LAMIVUDINE + ZIDOVUDINE, 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 employed.
Patients with moderate to severe renal impairment
In patients with moderate to severe renal impairment, the terminal half-life of lamivudine is increased due to decreased clearance. The dose should, therefore, be adjusted (See Dosage and Directions for Use).

Zidovudine
Haematological toxicity
Haematological parameters should be carefully monitored. It is recommended that blood tests be performed at least every two weeks for the first three months of therapy and at least once a month for patients with advanced symptomatic HIV disease. Haematological toxicity is less frequent in patients with early HIV disease where bone marrow reserve is generally good. Depending on the overall condition of the patient, blood tests may be performed less often,for example every one to three months. If heamoglobin level falls to between 7,5 g/dL (4,65 mmol/L) and 9 g/dL (5,59 mml/L), or the neutrophil count falls to between 0,75 x 109/L and 1,0x109/L, the daily dosage may be reduced until there is evidence of marrow recovery. Alternatively, recovery may be enhanced by a brief 2 to 4 week interruption of SONKE-LAMIVUDINE + ZIDOVUDINE therapy. Marrow recovery is usually observed within 2 weeks after which time SONKE-LAMIVUDINE + ZIDOVUDINE therapy may be restarted at a reduced dose. Dosage adjustments do not necessarily eliminate the need for transfusions in patients with significant anaemia (See Side-effects).
Lactic acidosis/severe hepatomegaly with steatosis
See above as for lamivudine under “Special Precautions”.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS T REATMENT
Lamivudine
Treatment is symptomatic and supportive.
Zidovudine
Symptoms or signs such as fatigue, headache, vomiting and reports of heamatological disturbances have been identified following acute overdosage with zidovudine. Reported blood levels of zidovudine over 16 times the normal therapeutic level did not present with any short-term clinical, biochemical or haematological sequelae in the patient. Haemodialysis appears to have a limited effect on the elimination of zidovudine, but enhances the elimination of the inactive glucuronide metabolite.

Prevention of mother-to-foetus transmission
The long-term consequences of in utero and infant exposure to SONKE-LAMIVUDINE + ZIDOVUDINE are unknown. Low haemoglobin concentrations have been reported in infants exposed to zidovudine for this indication, but transfusion was not required. Anaemia resolved within 6 weeks after completion of zidovudine therapy.
Lactation
To avoid the transmission of HIV to their infants, women infected with HIV should not breast-feed.

IDENTIFICATION
White to off-white, film-coated capsule shaped tablets debossed with “RX923”on one side and plain on other side.

PRESENTATION
10 Tablets are packed in blister strips of clear, transparent, PVC film with an aluminium foil backing. Cartons contain 10, 30, 60 or 100 tablets.
60 Tablets packed in white opaque HDPE bottles.

STORAGE INSTRUCTIONS
Store below 25 °C in original container, protected from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
A40/20.2.8/0254

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House
1006 Lenchen Avenue North
Centurion

DATE OF PUBLICATION OF THE PACKAGE INSERT
April 2006

Marketed by Sonke Pharmaceuticals (Pty) Ltd

This product is for use only in South Africa, is not for resale and any other use is not authorised.

New addition to this site: March 2007
Source: Pharmaceutical Industry

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