TRUVADA (tenofovir disoproxil fumarate 300 mg emtricitabine 200 mg) Dailymed

TRUVADA is a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated:

• •in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg. (1.1)
• •in combination with safer sex practices for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. (1.2)

1.1Treatment of HIV-1 Infection

TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Clinical Studies (14) ] .

1.2HIV-1 Pre-Exposure Prophylaxis (PrEP)

TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in at-risk adults and adolescents weighing at least 35 kg. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP [see Dosage and Administration (2.2) ] .

• • If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) and Clinical Studies (14.3 , 14.4) ] .

When considering TRUVADA for HIV-1 PrEP, factors that help to identify individuals at risk may include:

• •has partner(s) known to be HIV-1 infected, or
• •engages in sexual activity within a high prevalence area or social network and has additional risk factors for HIV-1 acquisition, such as:
  • •inconsistent or no condom use
  • •diagnosis of sexually transmitted infections
  • •exchange of sex for commodities (such as money, food, shelter, or drugs)
  • •use of illicit drugs or alcohol dependence
  • •incarceration
  • •partner(s) of unknown HIV-1 status with any of the factors uled above

2 Dosage And Administration

• •Testing: Prior to or when initiating TRUVADA test for hepatitis B virus infection. Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (2.1)
• •HIV-1 Screening: Screen all patients for HIV-1 infection before initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA. (2.2)

Treatment of HIV-1 Infection

• •Recommended dosage in adults and pediatric patients weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. (2.3)
• •Recommended dosage in pediatric patients weighing at least 17 kg: One TRUVADA low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. (2.4)
• •Recommended dosage in renally impaired HIV-1 infected adult patients:
  • •Creatinine clearance (CrCl) 30−49 mL/min: 1 tablet every 48 hours. (2.6)
  • •CrCl below 30 mL/min or hemodialysis: TRUVADA is not recommended. (2.6)

HIV-1 Pre-Exposure Prophylaxis (PrEP)

• •Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. (2.5)
• •Recommended dosage in renally impaired HIV-uninfected individuals: TRUVADA is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. (2.6)

2.1Testing Prior to Initiation of TRUVADA for Treatment of HIV-1 Infection or for HIV-1 PrEP

Prior to or when initiating TRUVADA, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] .

Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.3) ].

2.2HIV-1 Screening for Individuals Receiving TRUVADA for HIV-1 PrEP

Screen all patients for HIV-1 infection before initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA [see Indications and Usage (1.2) , Contraindications (4) and Warnings and Precautions (5.2) ].

2.3Recommended Dosage for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing at Least 35 kg

TRUVADA is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of TRUVADA in adults and in pediatric patients weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food [seeClinical Pharmacology (12.3)].

2.4Recommended Dosage for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 17 kg and Able to Swallow a Tablet

The recommended oral dosage of TRUVADA for pediatric patients weighing at least 17 kg and who can swallow a tablet is presented in Table 1. Tablets should be taken once daily with or without food. Weight should be monitored periodically and the TRUVADA dose adjusted accordingly.

Table 1 Dosing for Treatment of HIV-1 Infection in Pediatric Patients Weighing 17 kg to less than 35 kg

Body Weight (kg)	Dosing of TRUVADA (FTC/TDF)
17 to less than 22	one 100 mg /150 mg tablet once daily
22 to less than 28	one 133 mg /200 mg tablet once daily
28 to less than 35	one 167 mg /250 mg tablet once daily

2.5Recommended Dosage for HIV-1 PrEP

The dosage of TRUVADA in HIV-1 uninfected adults and adolescents weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food [see Clinical Pharmacology (12.3) ] .

2.6 Dosage Adjustment in Patients with Renal Impairment

Treatment of HIV-1 Infection

Table 2 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients [seeWarnings and Precautions (5.3)].

No data are available to make dosage recommendations in pediatric patients with renal impairment.

Table 2 Dosage Interval Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance

	Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight
	≥50	30–49	<30 (Including Patients Requiring Hemodialysis)
Recommended Dosing Interval	Every 24 hours	Every 48 hours	TRUVADA is not recommended.

HIV-1 PrEP

TRUVADA for HIV-1 PrEP is not recommended in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min [seeWarnings and Precautions (5.3)].

If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [seeWarnings and Precautions (5.3)].

• •Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. (5.2)
• •Management to reduce the risk of acquiring HIV-1 drug resistance: refer to full prescribing information for additional detail. (5.2)
• •New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering TRUVADA with concurrent or recent use of nephrotoxic drugs. (5.3)
• •Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.4)
• •Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.5)
• •Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.6)

5.1Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection

All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating TRUVADA [see Dosage and Administration (2.1) ] .

Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected patients who have discontinued TRUVADA. Patients infected with HBV who discontinue TRUVADA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination.

5.2Comprehensive Management to Reduce the Risk of Acquiring HIV-1 and Development of HIV-1 Resistance When TRUVADA Is Used for HIV-1 PrEP

Use TRUVADA for HIV-1 PrEP only as part of a comprehensive prevention strategy that includes other prevention measures, such as safer sex practices, because TRUVADA is not always effective in preventing acquisition of HIV-1 [seeClinical Studies (14.3and14.4)].

• • Counsel uninfected individuals about safer sex practices that include consistent and correct use of condoms, knowledge of their HIV-1 status and that of their partner(s), the importance of virologic suppression in their partner(s) with HIV-1, and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis, chlamydia, and gonorrhea).
• •Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use TRUVADA to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only TRUVADA, because TRUVADA alone does not constitute a complete regimen for HIV-1 treatment [seeMicrobiology (12.4)]; therefore, care should be taken to minimize drug exposure in HIV-infected individuals.

• •Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA for HIV-1 PrEP, evaluate seronegative individuals for current or recent signs or symptoms consistent with acute viral infections (e.g., fever, fatigue, myalgia, skin rash) and ask about potential exposure events (e.g., unprotected, or condom broke during, sex with an HIV-1 infected partner) that may have occurred within the last month.
• •If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting HIV-1 PrEP for at least one month and reconfirm HIV-1 status or use a test approved or cleared by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.

While using TRUVADA for HIV-1 PrEP, HIV-1 screening tests should be repeated at least every 3 months, and upon diagnosis of any sexually transmitted infections. Some individuals, such as adolescents, may benefit from more frequent visits and counseling [see Use in Specific Populations (8.4) ] .

• • If a screening test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of HIV-1, including acute or primary HIV-1 infection.

Counsel uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials [seeUse in Specific Populations (8.4),Microbiology (12.4), andClinical Studies (14.3and14.4)].

5.3New Onset or Worsening Renal Impairment

Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of TRUVADA [seeAdverse Reactions (6.2)].

Prior to initiation and during use of TRUVADA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [seeDrug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

Treatment of HIV-1 Infection

Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30–49 mL/min [seeDosage and Administration (2.6)]. No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA is not recommended in patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis.

HIV-1 PrEP

TRUVADA for HIV-1 PrEP is not recommended in uninfected individuals with estimated creatinine clearance less than 60 mL/min. If a decrease in estimated creatinine clearance is observed while using TRUVADA for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [seeDosage and Administration (2.6)].

5.4Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected patients whose immune system responds 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.

5.5Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, TDF (a component of TRUVADA) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [seeAdverse Reactions (6.1)]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF.

Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in adolescent subjects aged 12 years to less than 18 years treated for chronic hepatitis B. In all pediatric trials, skeletal growth (height) appeared to be unaffected.

The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial. If bone abnormalities are suspected, appropriate consultation should be obtained.

Mineralization Defects

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [seeAdverse Reactions (6.1)]. Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [seeWarnings and Precautions (5.3)].

5.6 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC and TDF, components of TRUVADA, alone or in combination with other antiretrovirals. Treatment with TRUVADA should be suspended in any patient or uninfected individual 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).

5.7 Risk of Adverse Reactions Due to Drug Interactions

The concomitant use of TRUVADA and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2) ].

See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRUVADA; review concomitant medications during therapy with TRUVADA; and monitor for adverse reactions associated with the concomitant drugs.

6 Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

• •Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [seeWarnings and Precautions (5.1)].
• •New Onset or Worsening Renal Impairment [seeWarnings and Precautions (5.3)].
• •Immune Reconstitution Syndrome [seeWarnings and Precautions (5.4)].
• •Bone Loss and Mineralization Defects [seeWarnings and Precautions (5.5)].
• •Lactic Acidosis/Severe Hepatomegaly with Steatosis [seeWarnings and Precautions (5.6)].

• •In HIV-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6.1)
• •In HIV-1 uninfected adults in PrEP trials, adverse reactions that were reported by more than 2% of TRUVADA subjects and more frequently than by placebo subjects were headache, abdominal pain, and weight decreased. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-445-3235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects

Clinical Trials in Adult Subjects

In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 3 provides the treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Table 3Selected Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks)

	FTC+TDF+EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of FTC+TDF with efavirenz.	AZT/3TC+EFV
	N=257	N=254
Fatigue	9%	8%
Depression	9%	7%
Nausea	9%	7%
Diarrhea	9%	5%
Dizziness	8%	7%
Upper respiratory tract infections	8%	5%
Sinusitis	8%	4%
Rash eventRash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular.	7%	9%
Headache	6%	5%
Insomnia	5%	7%
Nasopharyngitis	5%	3%
Vomiting	2%	5%

Clinical Trials in Pediatric Subjects

Adverse Reactions from Clinical Trial Experience in Uninfected Subjects Taking TRUVADA for HIV-1 PrEP

Clinical Trials in Adult Subjects

The safety profile of TRUVADA for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received TRUVADA once daily for HIV-1 PrEP. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. Table 5 provides a ul of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx trial, with an incidence greater than placebo.

Table 5 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Greater than Placebo

	FTC/TDF (N=1251)	Placebo (N=1248)
Headache	7%	6%
Abdominal pain	4%	2%
Weight decreased	3%	2%

In the Partners PrEP trial, the frequency of adverse events in the TRUVADA treatment group was generally either less than or the same as in the placebo group.

Clinical Trials in Adolescent Subjects

In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received TRUVADA once daily for HIV-1 PrEP, the safety profile of TRUVADA was similar to that observed in adults. Median duration to exposure of TRUVADA was 47 weeks [seeUse in Specific Populations (8.4)].

In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to TRUVADA by Week 48.

6.2Postmarketing Experience

The following adverse reactions have been identified during postapproval use of TDF. No additional adverse reactions have been identified during postapproval use of FTC. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders allergic reaction, including angioedema

Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders dyspnea

Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)

Skin and Subcutaneous Tissue Disorders rash

Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy

Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions asthenia

The following adverse reactions, uled under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.