FDA label 1d5375f3-2529-e027-e063-6394a90af514

BOXED WARNING WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B AND RISK OF DRUG RESISTANCE WITH USE OF TRUVADA FOR PRE-EXPOSURE PROPHYLAXIS (PREP) IN UNDIAGNOSED EARLY HIV-1 INFECTION TRUVADA is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. Therefore, hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are infected with HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS (5.1)]. TRUVADA used for a PrEP indication must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and periodically (at least every 3 months) during use. Drug-resistant HIV-1 variants have been identified with use of TRUVADA for a PrEP indication following undetected acute HIV-1 infection. Do not initiate TRUVADA for a PrEP indication if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed [see WARNINGS AND PRECAUTIONS (5.8)].

5 WARNINGS AND PRECAUTIONS 5.1 HBV Infection It is recommended that all individuals be tested for the presence of chronic hepatitis B virus (HBV) before initiating TRUVADA. TRUVADA is not approved for the treatment of chronic HBV infection, and the safety and efficacy of TRUVADA have not been established in patients infected with HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are infected with HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted. HBV-uninfected individuals should be offered vaccination. 5.2 New 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 VIREAD [see ADVERSE REACTIONS (6.3)]. It is recommended that estimated creatinine clearance be assessed in all individuals prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of TRUVADA, and periodically during TRUVADA therapy. 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]) [see DRUG INTERACTIONS (7.4)]. 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 tenofovir DF. 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 at-risk patients. 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 [see DOSAGE AND ADMINISTRATION (2.4)]. 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 should not be administered to patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis. Pre-exposure Prophylaxis TRUVADA for a PrEP indication should not be used if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see DOSAGE AND ADMINISTRATION (2.4)]. 5.3 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 tenofovir DF and emtricitabine, 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). 5.4 Coadministration with Other Products TRUVADA is a fixed-dose combination of emtricitabine and tenofovir DF. Do not coadminister TRUVADA with other drugs containing emtricitabine, tenofovir DF, or tenofovir alafenamide, including ATRIPLA, COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, VEMLIDY, or VIREAD. Due to similarities between emtricitabine and lamivudine, do not coadminister TRUVADA with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Dutrebis (lamivudine/raltegravir), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), Triumeq (abacavir sulfate/dolutegravir/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). Do not coadminister TRUVADA with HEPSERA (adefovir dipivoxil). 5.5 Bone Effects of Tenofovir DF Bone Mineral Density In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, tenofovir DF 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 [see ADVERSE REACTIONS (6.2) and VIREAD prescribing information]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF. Clinical trials evaluating tenofovir DF 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 tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, consult the VIREAD prescribing information. The effects of tenofovir DF-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 then 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 the use of tenofovir DF [see ADVERSE REACTIONS (6.3)]. Arthralgias 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 products containing tenofovir DF [see WARNINGS AND PRECAUTIONS (5.2)]. 5.6 Immune 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. 5.7 Early Virologic Failure Clinical trials in HIV-1 infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTIs) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a HIV-1 protease inhibitor. In particular, early virologic failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification. 5.8 Comprehensive Management to Reduce the Risk of Acquiring HIV-1 Use TRUVADA for pre-exposure prophylaxis 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 the acquisition of HIV-1 [See CLINICAL STUDIES (14.2 and 14.3)]. 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), and regular testing for other sexually transmitted infections that can facilitate HIV-1 transmission (such as syphilis 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 treatment regimen for HIV-1 treatment [see MICROBIOLOGY (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 a PrEP indication, 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 PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection. While using TRUVADA for a PrEP indication, HIV-1 screening tests should be repeated at least every 3 months. If symptoms consistent with acute HIV-1 infection develop following a potential exposure event, PrEP should be discontinued until negative infection status is confirmed using a test approved 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 [see CLINICAL STUDIES (14.2 and 14.3)].

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.1)]. New Onset or Worsening Renal Impairment [see WARNINGS AND PRECAUTIONS (5.2)]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see WARNINGS AND PRECAUTIONS (5.3)]. Bone Effects of Tenofovir DF [see WARNINGS AND PRECAUTIONS (5.5)]. Immune Reconstitution Syndrome [see WARNINGS AND PRECAUTIONS (5.6)]. 6.1 Adverse Reactions from Clinical Trials Experience in HIV-1 Infected 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Subjects The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir DF, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also TABLE 3 for the frequency of treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group in this trial. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Study 934 –Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviral-naïve subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254) for 144 weeks. Subjects had a mean age of 40 years (range 20 to 73 years) and were predominantly male (88%). Overall, 65% were White, 17% were Black, and 13% were Hispanic. Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naïve subjects receiving VIREAD and/or EMTRIVA (Table 3). Table 3 Selected Treatment-Emergent Adverse Reactions* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFV† AZT/3TC+EFV N=257 N=254 * Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. † From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. ‡ Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. Gastrointestinal Disorder Diarrhea 9% 5% Nausea 9% 7% Vomiting 2% 5% General Disorders and Administration Site Condition Fatigue 9% 8% Infections and Infestations Sinusitis 8% 4% Upper respiratory tract infections 8% 5% Nasopharyngitis 5% 3% Nervous System Disorders Headache 6% 5% Dizziness 8% 7% Psychiatric Disorders Depression 9% 7% Insomnia 5% 7% Skin and Subcutaneous Tissue Disorders Rash event‡ 7% 9% In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, and rhinitis. Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 4). Table 4 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFV* AZT/3TC+EFV N=257 N=254 * From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm3) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% In addition to the laboratory abnormalities described above for Study 934, Grades 3−4 laboratory abnormalities of increased bilirubin (>2.5 × ULN), increased pancreatic amylase (>2.0 × ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 × ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials. Clinical Trials in Pediatric Subjects Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with EMTRIVA in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, consult the EMTRIVA prescribing information. Tenofovir DF: In pediatric clinical trials (Studies 352 and 321) conducted in 184 HIV-1 infected subjects 2 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults. Eighty-nine pediatric subjects (2 to less than 12 years of age) received VIREAD in Study 352 for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score [see WARNINGS AND PRECAUTIONS (5.5)]. For additional information, consult the VIREAD prescribing information. 6.2 Adverse Reactions from Clinical Trial Experience in HIV-1 Uninfected Adult Subjects No new adverse reactions to TRUVADA were identified from two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP), in which 2,830 HIV-1 uninfected adults received TRUVADA once daily for pre-exposure prophylaxis. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only men or transgender women of Hispanic/Latino (72%), White (18%), Black (9%), and Asian (5%) race. The Partners PrEP trial enrolled both men (61−64% across treatment groups) and women in Kenya and Uganda. Table 5 provides a list of all adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx and Partners PrEP trials. Laboratory Abnormalities: Table 6 provides a list of laboratory abnormalities observed in both trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued participation in the study due to an increase in blood creatinine compared with no discontinuations in the placebo group. One subject in the TRUVADA arm of the iPrEx trial discontinued from the study due to an increase in blood creatinine and another due to low phosphorous. In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6% of subjects receiving TRUVADA in the iPrEx trial. Grades 2−3 proteinuria (2–4+) and glycosuria (3+) occurred in less than 1% of subjects treated with TRUVADA in the iPrEx trial and Partners PrEP trial. Table 5 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Partners PrEP Trial iPrEx Trial Partners PrEP Trial FTC/TDF (N=1251) Placebo (N=1248) FTC/TDF (N=1579) Placebo (N=1584) * Not reported or reported below 2%. Gastrointestinal Disorders Diarrhea 7% 8% 2% 3% Abdominal pain 4% 2% -* - Infections and Infestations Pharyngitis 13% 16% - - Urethritis 5% 7% - - Urinary tract infection 2% 2% 5% 7% Syphilis 6% 5% - - Secondary syphilis 6% 4% - - Anogenital warts 2% 3% - - Musculoskeletal and Connective Tissue Disorders Back pain 5% 5% - - Nervous System Disorders Headache 7% 6% - - Psychiatric Disorders Depression 6% 7% - - Anxiety 3% 3% - - Reproductive System and Breast Disorders Genital ulceration 2% 2% 2% 2% Investigations Weight decreased 3% 2% - - Table 6 Laboratory Abnormalities (Highest Toxicity Grade) Reported for Each Subject in the iPrEx Trial and Partners PrEP Trial iPrEx Trial Partners PrEP Trial Grade* FTC/TDF (N=1251) Placebo (N=1248) FTC/TDF (N=1579) Placebo (N=1584) * Grading is per DAIDS criteria. † Grade 1 phosphorus was not reported for the Partners PrEP trial. Creatinine 1 (1.1 – 1.3 × ULN) 27 (2%) 21 (2%) 18 (1%) 12 (<1%) 2–4 (>1.4 × ULN) 5 (<1%) 3 (<1%) 2 (<1%) 1 (<1%) Phosphorus 1 (2.5 – <LLN mg/dL) 81 (7%) 110 (9%) NR † NR † 2–4 (<2.0 mg/dL) 123 (10%) 101 (8%) 140 (9%) 136 (9%) AST 1 (1.25 – <2.5 × ULN) 175 (14%) 175 (14%) 20 (1%) 25 (2%) 2–4 (>2.6 × ULN) 57 (5%) 61 (5%) 10 (<1%) 4 (<1%) ALT 1 (1.25 – <2.5 × ULN) 178 (14%) 194 (16%) 21 (1%) 13 (<1%) 2–4 (>2.6 × ULN) 84 (7%) 82 (7%) 4 (<1%) 6 (<1%) Hemoglobin 1 (8.5–10 mg/dL) 49 (4%) 62 (5%) 56 (4%) 39 (2%) 2–4 (<9.4 mg/dL) 13 (1%) 19 (2%) 28 (2%) 39 (2%) Neutrophils 1 (1000 – 1300/mm3) 23 (2%) 25 (2%) 208 (13%) 163 (10%) 2–4 (<750/mm3) 7 (<1%) 7 (<1%) 73 (5%) 56 (3%) Changes in Bone Mineral Density In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from –0.4% to –1.0% across total hip, spine, femoral neck, and trochanter in the TRUVADA group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving TRUVADA versus 6% of subjects receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in 1.7% of the TRUVADA group compared with 1.4% in the placebo group. No correlation between BMD and fractures was noted [see CLINICAL STUDIES (14.2)]. The Partners PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively); no BMD evaluations were performed during this trial [see CLINICAL STUDIES (14.3)]. 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of VIREAD. No additional adverse reactions have been identified during postapproval use of EMTRIVA. 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, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.